JP2002514811A - Generation of virtual combinatorial libraries of compounds - Google Patents

Abstract

Abstract: A method is disclosed for computer-generated a virtual library of compounds, including methods for adding fragments, using reagents, and tracking the transformations performed. The tracking table generated for sample compound C1 contains the following entries: (a) listing the order of the fragments used, and (b) listing the transformations performed for each synthetic pathway.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[Cross-reference to related applications]

This application is related to U.S. Patent Application No. 60/085, filed May 12, 1998.
No. 09 / 076,405, filed May 12, 1998, all of which are incorporated herein by reference in their entirety, claiming priority to US092. Have been.

[0002]

FIELD OF THE INVENTION

The present invention is directed to a method for producing a virtual combinatorial library of small molecules and other ligands. Members or molecules of this combinatorial library are produced in silico and identified in silico
Designed to combine. The present invention also provides for the incorporation of library members into desired target molecules, thereby allowing library members to be in silicic with such targets.
o Includes methods of bonding.

[0003]

BACKGROUND OF THE INVENTION

Combinatorial chemistry is a recent addition to the chemist's toolbox and refers to the chemistry area that deals with the synthesis of many chemical components. This generally means
This is achieved by compressing a small number of reagents into any combination defined by a given reaction sequence. Advances in this area of chemistry include the use of chemical software tools and advances in computer hardware that have enabled us to consider much more than the practical synthesis of library compounds. The concept of "virtual library" is used to indicate a collection of candidate structures that could theoretically arise from combinatorial synthesis involving the reaction of interest and the reagents that effect the reaction. Compounds to be synthesized in the field are selected from this virtual library.

[0004] Project Library (MDL Information Sys
tems, San Leandro, CA) is said to be a desktop software system that supports the operation of combinatorial research (Practical Guid
e to Combinatorial Chemistry, AW Czarnik and SH DeWitt, eds., 1997
, ACS, Washington, D.C. C. ). The software is said to include an information management module to represent and retrieve building blocks, individual molecules, complete combinatorial libraries and mixtures of molecules, and a computational support module to track mixtures and separate compound libraries. ing.

[0005] Molecular Diversity Manager (Tripos,
Inc. (St. Louis, MO) is said to be a set of software modules for creating, selecting, and managing compound libraries (Practica
l Guide to Combinatorial Chemistry, AW Czarnik and SH DeWitt, eds.
, 1997, ACS, Washington, D.C. C. ). The LEGION and SELECTOR modules are said to be useful for creating libraries and for characterizing molecules in terms of two- and three-dimensional structural fingerprints, substitution variables, topology indices and physicochemical variables. .

[0006] Afferent Systems (San Francisco, CA) is said to provide combinatorial library software to create virtual molecules for databases. It is said to do this by reacting precursor molecules virtually and selecting molecules that can be synthesized in the field (Wilson, C & EN,
April 27, 1998, p. 32).

[0007] Although only Project Library and Molecular Diversity Manager are commercially available, these products efficiently track the reagents and synthesis conditions utilized to introduce fragments into the desired compound being produced. Do not provide the benefits to In addition, these products do not track the mixed compounds produced by introducing multiple fragments using multiple reagents. Therefore, it is desirable to have methods available for treating mixed compounds, as well as methods for tracking the chemical reactions or transformations used in the synthesis of individual compounds and mixtures thereof.

[0008]

SUMMARY OF THE INVENTION

According to the present invention, there is provided a method for producing a virtual combinatorial library of small molecules. These library molecules or members are produced in silico. Larger molecular weight library members, such as those that are inherently polymers, can also be produced using the methods of the invention.

[0009] The present invention further provides a method for constructing a library member comprising the steps of:
Methods are provided to track and maintain the fragments, reagents and unique combinations thereof used in production. Also provided in the invention is a method of adjusting the information required for in silico production of a library, as a teaching designed to direct the on-site synthesis of library members on a device such as a parallel array synthesizer. The invention also provides a method of in silico incorporation of a library member into an identified target molecule. According to these methods, individual library members can be bound to a desired target molecule, and a library molecule exhibiting high affinity binding to a target can be identified.

[0010] Identify molecular interaction sites, identify compounds that may interact with the molecular interaction sites of RNA and other biological molecules, synthesize such compounds, and analyze their binding There are a number of ways to do this, but the preferred methodology is described in U.S. Pat.
No./076,405, 09 / 076,447, 09 / 076,206, 09
Nos. / 076/214 and 09 / 076,404, both of which were filed on May 12, 1998, both of which are assigned to the assignee of the present invention. All of the above applications are incorporated herein by reference in their entirety.

The present invention is directed to computer techniques used for in silico design and synthesis of low molecular combinatorial libraries. This library member
Produced in silico. The invention also encompasses a method of tracking and storing information obtained during in silico creation of library members in a relational database for later access and use. In this patent specification, in silico refers to creating in computer memory, ie silicon or a similar chip.
In other words, in silico means "virtual."

According to the method of the present invention, each compound or library member is decomposed into its components or components, referred to as fragments. Thus, each compound produced will contain its constituent fragments, and the overall molecular formula of each of these fragments will be considered to be the molecular formula of the compound produced. This decomposition can be done in a wide variety of ways using chemical intuition. As such, a wide variety of fragment components may be identified, each of which lends itself to readily available reagents and reactions to produce various compounds. In addition, each fragment is associated with at least one reagent corresponding to the required chemical used to introduce the desired fragment into the compound produced in silico. Compound degradation is based on the ease of synthesis of the reagent, the commercial availability of the reagent, or both. The fragments and reagents are each stored in a relational database and are described with respect to the signature of the database. Certain fragments may be available from a variety of starting materials or reaction schemes. Thus, when a library is produced, it necessarily builds a database, and the fragments used in the construction of the library can be stored in a database that uses a corresponding set of reagents and reaction conditions. If another library is produced, the fragment information stored in the previous database can be used to produce this new compound library. Similarly, if a third library is produced, much more fragments, reagents and reaction information is available in the database. Thus, the method of the present invention represents a dynamic method of constructing a database related to the construction of a compound library. Initial library production requires database entries for the fragments, reagents and conversions required for the desired library. However, as the database expands, more and more fragments and reagents become available in the database, which simplifies the production of subsequent compound libraries, makes the operation of combinatorial synthesis more routine, more easily and It can be achieved effectively.

[0013] Fragments recorded in the database can be defined using identifying characteristics.
The identifying characteristics that define the fragment include (such as 2D or 3D files)
Structural expressions, names, molecular weights, molecular formulas, and attachment or nodal points (indicating the site at which a fragment attaches or joins to other fragments of the compound produced in silico) are included. Although a two-dimensional representation is used to describe the present invention, this is further simplified by the use of symbolic representations that do not refer to a particular chemical entity. The symbolic representation used herein only indicates how fragments can be tracked in the method of the present invention. Other signatures may be added to the database. Properties that are desired to be tracked may be included in this database, including biological data, chemical kinetics, or other physicochemical properties. In addition, fragments can also be created by modifying reagents, but such modifications can be added to the database regarding changes made to the reagent structure. Some of the identifying properties associated with any fragment may be common to the properties of the corresponding reagent. Related fragments created in this way can be stored in a relational database.

The identifying characteristics that define the reagent include structural representation, name, molecular weight, molecular formula, and source such as commercial or specific user-defined compounds.
For commercially available reagents, a catalog number or link to a web page may be provided. There may be some commonality between the signature associated with the reagent and that associated with the relevant fragment.

Further, according to the present invention, a compound is the sum of various transformations. Transformations are those named for chemical synthesis according to the present invention. The conversion is a 1: 1 linkage of the fragment and the reagent. Thus, each transformation describes a unique transformation of the reagent into the corresponding fragment, as introduced into the compound. If the compound produced in silico is broken down into its constituent fragments and the corresponding reagent is identified,
Each fragment is linked in a 1: 1 relationship with the corresponding reagent and describes a transformation. Thus, according to the present invention, it is possible to regard the transformation as a source of the fragment, thereby linking the fragment to a particular synthetic method or reaction. The description of the conversion in the method of the present invention also includes auxiliary reagents used to effect the reaction indicated by the conversion, such as temperature and pressure conditions, catalysts, activators, solvents or other additives. Conditions are also included.

Combinations of 1: 1 linkages of fragments and reagents involve different transformations. Thus, each transformation is unique. The present invention allows one to track fragments for reactions or conversions in which the fragments are introduced into compounds of a library. Thus, the database describes not only the compounds produced for the constituent fragments, but also the synthetic pathways that produce those compounds, ie, the relevant transformations that produce the library compounds. In this way, a user of the present invention can produce a virtual library of compounds simply by selecting the desired fragments. In another approach, a user can also produce a compound by selecting the chemical reaction pathways required for the practical synthesis of the compound. In another approach, a user may produce a compound by selecting the chemical route required for the practical synthesis of the compound. This is achieved by selecting the appropriate transformation associated with the production of the desired compound. Here, the user uses intuition, or uses an in silico expert system to assist in the selection of the transformations that are expected to enable the production or synthesis of the desired compound. Each transformation created in silico is stored in a relational database and described by its signature. The identifying characteristics that define the conversion include the fragments, reagents, and auxiliary reagents or conditions necessary to effect the conversion of the reagents into fragments as incorporated into the compound.

For example, consider in FIG. 1 the in silico production of compound CI by the method of the present invention.
As shown in FIG. 1, when CI (molecular formula: C ₁₂ H ₁₈ N ₂ O ₅ S ₁ ) is decomposed, its constituent fragments are _Fi (molecular formula: H ₂ NO) and F _ii (molecular formula: C ₅ H _9). NO
) And F _iii (molecular formula: C ₇ H ₇ O ₃ S). _Fi can also be a hydroxylamine component attached to a solid support, i.e., PO-NH, where P is a solid support. When the molecular formulas of the fragments are combined, the molecular formula of the compound CI is obtained.

As shown in FIG. 2, each of the fragments F _i , F _ii and F _iii is stored in a relational database and has a structural representation (which may be two-dimensional or three-dimensional), an identifier or name, a molecular formula and Described in terms of signatures, including junctions or nodes that identify locations on the fragment that link to other fragments of compound CI. Other information, such as molecular weight, can also be associated with fragments in this database.

As shown in FIG. 3, each of the corresponding reagents (R _i , R _ii and R _iii ) is also stored in a relational database and is described by its signature. The identifying characteristics used to define the reagent include structural expressions, identifiers or names, and molecular formulas.
As with the fragments, other relevant information such as molecular weight and source (commercially available or user supplied, quantity on hand, special handling, etc.) are stored in the database in association with the individual reagents Can be done.

Next, the respective transformations associated with the in silico production of compound CI are also relevant data.
Stored on base. As shown in FIG. 4, the conversion T_iIs the reagent R_i To fragment F_iAnd T_iiIs R_iiTo F_iiAnd T_iiiIs R_iiiTo F _iii Connect with Also, conversion T_iIs the reaction condition α and T_iiIs the reaction condition β, and
T_iiiIs the reaction condition required for each conversion, such as reaction condition γ.
ing. Conversion T_iii, The reagent R_iiiIs hydroxylamid attached to the solid support
Fragment F_iiiIs hydroxylamid attached to the solid support
Component.

Although each fragment may be reached or produced by a particular corresponding reagent, the present invention also provides two or more reagents so that two or more transformations result in the same fragment. Also included are common fragments that can be produced by As shown in FIG. 5, the common fragment CH ₃ —CH ₂ —C (＝ O) —
Can be reached via conversion A utilizing the reagent X (acid chloride) CH ₃ —CH ₂ —C (＝ O) Cl. This common fragment also, CH ₃ -CH ₂ -C a reagent Y (acid chloride) (= O) -O-C (= O) in silico via the conversion B utilizing -CH ₂ -CH ₃ It can be introduced into the compound produced. Thus, according to the method of the present invention, a common fragment can be introduced into a compound via two or more different reagents, and thus via two or more separate transformations.

In another approach, a common reagent may be utilized to effect two or more transformations that form two or more different fragments. Thus, this represents two or more different transformations associated with different conditions.
For example, as shown in FIG. 6a, the common reagent Z, CH ₃ —CH ₂ —NH ₂ , can be utilized to introduce an alkene fragment into a compound under conditions that favor a Schiff base formation reaction. This represents the transformation X. However, the same common reagent Z can also be used to introduce amide fragments into a compound by using different sets of conditions making up transformation Y. Thus, a common reagent can introduce two or more fragments into the final compound produced in silico and is associated with two or more conversions depending on the conditions associated with each conversion.

Furthermore, when a fragment is introduced into a compound, it is further modified,
It can be modified and converted to another fragment without affecting other chemical changes inside the formed compound. As an example, consider CH ₃ —CH ₂ —C (＝ O) CH ₂ —Cl, a common reagent Z ′ shown in FIG. 6b. The common reagent Z ′ corresponds to a fragment having the structure CH ₃ —CH ₂ —C (＝ O) CH ₂ —. The common reagent Z 'can be used to introduce an alkene fragment into the final compound (representing transformation X') under conditions that favor reduction and dehydration. However, the common reagent Z 'can also be used to introduce a hydroxyalkyl fragment into the final compound under conditions which favor reduction. This represents the transformation Y '.

The present invention can be more generally described by a symbolic representation. The use of symbolic representations to describe the method of the invention is because such representations are not limited to a particular chemistry. The symbolic representation only illustrates how to use the invention for a number of chemical components. Each symbol used in the expressions describing the invention is one
One compound or multiple compounds may be represented because the invention is not limited to tracking a single compound, but may be used to track the vast number of compounds that can be produced.

FIG. 7 shows the symbol addition of the fragment producing compound CI ′. This file
Fragment is a structure that is added sequentially to produce compound CI ', F_{i '}, F _{ii '} And F_{iii '}Having. Structure, F_{i '}, F_{ii '}And F_{iii '}Represents the compound CI '
This is a symbolic representation of the fragment to be formed. These fragments are structurally
Expressions, names, molecular formulas, and each of them, including binding sites or nodes
Can be stored in a relational database along with the corresponding signatures for. Compound
Looking at CI and CI ', the commonality between compound CI and the symbolic representation of compound CI'
And the similarity between the chemical structure of the fragment and the symbol structure of the fragment
Become clear.

FIG. 8 shows a table of the symbol reagents. Reagents R1-R10 can be described for their structure, name, molecular formula, molecular weight, source, and other information desired to be associated with these reagents. R3 and R4 are two different reagents, but can be used to introduce the same fragment into a compound. It depends on the reaction conditions used that reagent R3 is used in a transformation associated with one set of conditions, while reagent R4 is used in another transformation associated with a different set of conditions. Because. The reagent R5 is composed of a mixture of two kinds of reagents or components. These can be (R)-and (S) -stereoisomers, D- and L-isomers, or two completely different reagents. Although R5 is represented herein as a mixture of only two reagents or components, those skilled in the art will recognize that the method of the present invention can be performed using a mixture of two or more reagents. Would. A typical reagent mixture used for library construction may have four, five, or more individual reagents making up the mixture.

FIG. 9 shows a table of symbol fragments. Fragments F1 to F8 are stored in a relational database along with structural representations, names, molecular weights, molecular formulas, and identifying characteristics including binding sites or nodes. This table shows the symbolic representation of the various fragments introduced into the library compounds by use of the symbolized reagents in FIG. Thus, it is found that the fragment F1 can be introduced into the compound by using the reagent R1. In the fragment F1, X is the identifier of the binding site. This indicates that the site where F1 is attached to another fragment of the compound is X. Similarly, fragment F2 can be obtained by utilizing reagent R2 (
At the X site).

However, fragment F3 can be introduced into a compound by use of either reagent R3 or R4. This allows for selection in the selection of reagents to be used and allows for consideration of the compatibility of the chemistry involved in introducing other fragments into the compound. Next, fragment F4 (which is a mixture of fragments) can be introduced through the use of reagent R5, which is a mixture of reagents, as shown in FIG.

Fragment F5 has two attachment sites, indicating that other fragments can be attached at sites X and Y when F5 is introduced into the compound. The presence of two binding sites is a factor in the assembly of the compound when processing F5.
Indicates that two connections can be made. Again, depending on the reaction conditions used and the chemistry involved when introducing other fragments to assemble the compound, F5 can be converted to the compound using either reagent R6 or R7, as before. Can be introduced.

Fragments F7 and F8 can be introduced into compounds created in silico by utilizing reagents R9 and R10, respectively. Each of these fragments has three binding sites, and the compounds are used in silicic
o Indicates that three ties to other fragments can occur during construction. Fragments F7 and F8 have three attachment sites;
It is understood that there may be more than two attachment sites on a fragment, allowing more attachment to the fragment when introduced into the compound using appropriate reagents.

If the above fragment table and reagent table are in place in the relational database, the method of the present invention creates a table of conversions by linking fragments to reagents to form a unique conversion. FIG. 10 shows a symbol conversion table in which fragments are linked to reagents in a 1: 1 relationship. The signature describing each transformation includes a 1: 1 linkage between the fragment and the reagent (one-to-one linkage) and the introduction of the fragment into the compound using solvent, concentration, temperature and pressure conditions or appropriate reagents. Reaction conditions that include the auxiliary reagents necessary to effect Auxiliary reagents include:
Includes catalysts, activators, acids, bases or other chemicals or additives necessary to effect the above fragment introduction. For example, a base can be added at any time with an alkyl halide to capture the acid produced by the use of the alkyl halide.

As can be seen in FIG. 10, transformation T1 ligates fragment F1 to reagent R1. T1 also specifies the reaction conditions (α) associated with this 1: 1 ligation. Similarly, T
2 links F2 to R2 under condition β. Transformations T3 and T4 are related to the common fragment F3, but are each unique. Conversion T3 links common fragment F3 to reagent R3 under condition α, while conversion T4 links common fragment F3 to another reagent R4 under different conditions, condition δ. For example, reagent R3 can be an alkyl chloride and R4 can be an alkyl iodide. Although these reagents are similar (both are alkyl halides), they may be used under different reaction conditions. Using different reagents to effect the introduction of the same fragment into the compound produced in silico represents two unique transformations. This indicates that there are two separate or unique synthetic methods to introduce the same fragment into the compound. Depending on the integrity of the chemical steps involved in the synthesis of the compound, certain transformations may be preferred over other transformations that introduce the same fragment into the compound.

Conversion T5 ligates fragment F4 to reagent R5. R5 is (R)-and (
S) -stereoisomers, D- and L-isomers, or a mixture of reagents, such as two or more different reagents. As a result, the use of R5 introduces a mixture of fragments F4 into the compound. One skilled in the art will recognize that the multiple reagents of R5 can be mixed together and will not react with each other, but will be selected to react under similar reaction conditions. For example, R5 can be composed of a mixture of acid chlorides. They do not react with each other, but react under similar conditions with nucleophiles. Also, those skilled in the art will recognize that reagents are not limited to one or two components or constituent reagents, but are actually two or three.
It will also be appreciated that species, four, five or more reagents or components may be included.

When using a mixture of reagents, the individual component reagents may each have a different chemical reaction rate. If this is not done, the product will appear disproportionately in the resulting compound. To solve this, the concentration of each reagent in the reaction mixture is adjusted relative to the other reagents in the mixture so that the relative velocities are the same. This results from a comparison of the reactivity of the selected standard reagent with the respective reagents. The standardized reaction rates can be used to adjust the concentration of each constituent reagent of the reagent mixture to compensate for various reaction rates. In this way, a mixture of reagents having different reaction rates can be used in one reagent mixture to produce an equal amount of the desired compound in the library.

Transforms T6 and T7 are similar to transforms T3 and T4, but differ in the conditions that identify each of these transforms. Conversion T6 links fragment F5 to reagent R6 under condition ε, while conversion T7 converts the same fragment F5 to a different reagent R6.
7 under a different condition (condition α). Since the conditions associated with transformations T6 and T7 are different, this allows one to select chemistry that is compatible with other fragments while a particular synthesis is used. This is a very useful and crucial consideration when synthesizing a true library. When it is desired to introduce the fragment F5 into a compound, it is the actual chemistry used to assemble this compound that can be considered first in selecting the conversion T6 or T7 and thus the reagent R6 or R7. . This is in direct contrast to other chemistry database products that only consider the structure of the compound and not the actual chemistry needed to assemble the compound.

Transformations T9 and T10 link fragment F7 to reagent R9 and fragment F8 to reagent R10, respectively. Both transformations are identified as being related to the reaction γ. Fragments F7 and F8 have three attachment sites, but these fragments may have more than two attachment sites, thereby increasing the complexity of the compound produced and being used to attach other fragments It is understood that the number of possible reaction rounds is increased. If three different reagent mixtures of five reagents each are used for the three sites shown, 125 compounds are produced for fragment F7 and an additional 125 compounds for fragment F8. Would.

The method of the present invention can be used to produce a single compound or a mixture of compounds. The mixture contains two or more compounds, and at the beginning of library production,
The next step in library production is a mixture of reagents (ie, a mixture of fragments)
Or combining such techniques may involve the use of two or more reagents (ie, the introduction of two or more fragments). Figures 11 and 1
2 illustrates this aspect of the invention.

As shown in FIG. 11, the method of the present invention can be used to produce a single compound such as C1 and C4, or produces a mixture M1 comprising compounds C2 and C3. Can also be used for The production of the library is the first round (
That is, it starts by selecting the fragment F7 (having three binding sites) in the nth round). In the second synthesis round (ie, n + 1 round), F7 combines with fragment F2 to form synthesis pathway P1a, resulting in formation of composite fragment CF1. F7 has three binding sites (ie, X, Y and Z). Thus, the n + 1 round is completed when X, Y, and Z are each used to attach to other fragments, if desired. X, Y and Z
To go around each other and to attach fragments to these sites occurs in this order. Once the sites X, Y and Z of the selected fragment in the first synthesis round (ie n rounds) have been completely consumed, proceeding around the binding site present in the next additional fragment Construct a compositing round (ie, a third compositing round, or n + 2 rounds). Again, when all desired attachment sites on this fragment have been used, the special synthesis round is complete. This repetition of the ligation over the desired and available ligation sites of the fragment to be added continues until the desired compound is produced.

As shown in FIG. 11, CF1 is then subjected to a synthetic pathway P1b, where fragment F1 is introduced into CF1, thereby forming a composite fragment CF2. CF2 is then subjected to a synthetic pathway P1c, where fragment F5 is added to CF2, leading to the formation of composite fragment CF3. This concludes the n + 1 round of synthesis (ie, introducing fragments to assemble the compound or the second round of synthesis). Since fragment F5 has two attachment sites, CF3 has an available attachment site (ie, site Y). This part (part Y
) Constitutes the n + 2 round of synthesis (ie, the third round) because all the desired attachment sites on the previously added fragment have been consumed. Next, CF3 is subjected to a synthetic pathway P2, where fragment F4 is introduced into CF3 at attachment site Y. Since F4 is a mixture of two components, a mixture of two compounds, C2 and C3 (M1) is produced.

However, single compounds can also be produced using this fragment introduction scheme. That is, compound C1 can be produced by subjecting CF3 to synthetic pathway P1d, where CF3 binds to fragment F3, which attaches to site Y of CF3. Introduction of fragment F3 into CF3 is the third synthesis round (ie, n
+2 rounds), leading to the production of C1.

In another approach, CF3 is subjected to synthetic pathway P3a, where fragment F6 is introduced into CF3 to form CF4. This is the third synthesis round (
That is, (n + 2 rounds). CF4 has another available site (ie,
There is a site Y) to which the fragment F2 can be attached via the synthetic pathway P3b. This produces compound C4, which is a more complex compound due to the number of sites of attachment of the selected fragment and the number of synthetic pathways utilized. The addition of fragment F6 to C4 constitutes the third synthesis round (ie, n + 2 rounds). The addition of fragment F2 to CF4 results in the fourth synthesis round,
Or n + 3 rounds, because fragment F6 is added to CF3 and CF4
Because P3b is involved in the addition of the fragment (fragment F2) onto the site generated by completely consuming the available binding sites on the previously added fragment within (ie, site Y of CF4). It is. That is, the addition of the fragment F6 completes the n + 2 round (or the third synthesis round) because F6 is attached to the last available binding site of CF3 (that is, the site Y of CF3).

For the reaction resulting in pathway P1c of FIG. 11, a single fragment (F
5) can be added to CF2 via the use of either reagent R6 or R7 (and thus via the transformations associated with R6 and R7). Although these additions are represented as two unique transformations to track in the database of the present invention, they actually perform the same chemical transformation. Thus, simultaneous tracking of compounds produced by the methods of the present invention is not only useful in dealing with a virtual library of compounds, but also allows the user to choose the synthetic pathway by which the compounds are synthesized in situ. It is also to provide. Thus, this tracing aspect of the invention is a novel and unique approach that describes the fragments introduced, the transformations (or reactions) associated with the fragments, and the alternative transformations that lead to the introduction of a common fragment into the desired compound. Method. The present invention allows not only to track individual compounds produced by the use of multiple reagents, but also to track multiple compounds produced through multiple conversions simultaneously. Although the methods described herein represent the tracking aspects of the invention in terms of symbolic representations or diagrams, various computer algorithm codes and techniques may be utilized for the discrete or simultaneous tracking aspects described above. It will be clear to those skilled in the art.

The invention further provides a method of producing a mixture of compounds in a one-pot fashion by initiating library production using various starting fragments in a one-pot fashion. One-pot production or synthesis of compounds requires a single reaction vessel (ie, one-pot)
To form a number of compounds. This is possible if compatible chemistries are selected. Examples of such a single vessel include, but are not limited to, a multi-well plate (eg, a 96-well plate), a reaction flask (eg, a 25 mL flask), or even an industrial reactor. The reaction or conversion is independent of the size of the reactor,
It is performed in one tank. This concept of one-pot synthesis is independent of the production of a virtual library of compounds, since the virtual library is only produced in silico. However, the concept of one-pot synthesis becomes relevant when field synthesis of compound libraries is performed. The compounds can be tracked separately for assembly of the compounds to produce distinct chemical structures, but can be grouped together in a synthesis that can be done in the same “pot”.

An example of a one-pot synthesis in which the complex reagent R5 is added to form a mixture M1 is shown in FIG.
It was shown to. Another one-pot synthesis is shown in FIG. 12, where an additional mixture of compounds is produced. By starting with fragments F7 and F8 in the first round of synthesis (ie n rounds), a mixture M2 comprising compounds C1 and C2 can be produced. Each of the above fragments has three attachment sites on which other fragments can be introduced. As a result, when these two fragments were subjected to the synthetic pathway P1a, F7 and F8 were linked to the fragment F5
And the composite fragments CF1 and CF5 are formed in one pot. CF1 and CF2 are then subjected to synthetic pathway P1b, where fragment F1
Is introduced at site Y into CF1 and CF5, thereby forming the composite fragments CF2 and CF6. CF2 and CF6 are then subjected to synthetic pathway P1c, where fragment F5 is introduced at site Z into these composite fragments,
CF3 and CF7 are formed. This results in a second synthesis round (ie, n + 1
Round) is completed. Since fragment F5 contains two binding sites,
After introduction into CF3 and CF7, there remains an available attachment site (ie, site Y) for further introduction of another fragment. Therefore, CF3 and CF7
Is converted via the synthetic pathway P1d to a mixture of compounds C1 and C5 (M2), wherein CF3 and CF7 bind to fragment F3 attached to site Y on fragment F5 of CF3 and CF7. The introduction of fragment F3 at site Y in CF3 and CF7 represents a third round of synthesis (ie, n + 2 rounds).

Another symbolic example for one-spot production of a mixture of compounds according to the present invention is shown in FIG. In silico production of the compound begins with the selection of fragment F7, which has three attachment sites (X, Y and Z). This represents the first synthesis round (ie, n rounds). F7 is then subjected to a synthetic pathway P1a, where F7 binds to fragment F2. F2 attaches to site X on fragment F7 to form composite fragment CF1. At this stage, CF1 is subjected to two synthetic routes, P1b and P1b ′. In P1b, fragment F1 is used to be introduced into site Y on CF1 to form composite fragment CF2, whereas in P1b ′, fragment F3 is used to be introduced into site Y on CF1 to form composite fragment CF8. In this way, a mixture of complex fragments (CF2 and CF8) is formed. The two fragments, F1 and F3, are one pot of the compound if the chemistry associated with the introduction of these fragments into the compound is compatible (as from a single reagent bottle when the field synthesis is performed). It can be introduced together for production. If not compatible, these fragments can be introduced separately. CF2 and CF8 are then subjected to the synthetic pathway P1c, where both composite fragments are at site Z on CF2 and CF8.
And thus combined with the composite fragments CF3 and CF
9 is formed. The second round of synthesis (ie, n
+1 round) is completed. Since fragment F5 has two attachment sites, there is still a site Y available to attach to another fragment. Thus, CF3 is subjected to synthetic pathway P3, where CF3 binds to fragment F4. The introduction of F4 represents a third synthesis round (ie, n + 2 rounds).
As shown in FIG. 9, F4 is a mixture of fragments (and is introduced with the addition of a mixture of reagents). As a result, compounds C2 and C3 are produced by synthetic route P2. At the same time, CF9 binds to fragment F4 via synthetic pathway P2 ', producing compounds C7 and C8. Thus, C2, C3, C7 and C
A mixture comprising M3 is formed.

The present invention also provides a method of producing a more complex mixture of compounds. One example is shown in FIGS. 14a and 14b, where a mixture M4 is produced and contains 16 compounds. The compound of mixture M4 has a first synthesis round (ie, n rounds)
By starting together with fragments F7 and F8. These fragments combine with fragment F2 introduced at site X in each of fragments F7 and F8 to form composite fragments CF1 and CF5. After this, at site Y of these composite fragments CF1 and CF5, a mixture of fragments F1 and F3 is introduced and the four composite fragments, C
F2, CF6, CF8 and CF11 are formed. These composite fragments then combine with a mixture of fragments F5 and F6. Since both F5 and F6 have two binding sites, sites X of F5 and F6 are CF2, CF6, CF8 and CF11.
At the site Z, 8 complex fragments, CF3, CF7, CF9, CF1
2. Form a mixture of CF13, CF14, CF15 and CF16. This completes the second synthesis round (ie, n + 1 round). Fragment F5
And F6 have two attachment sites, X and Y, so that the eight composite fragments have available attachment sites (site Y) into which another fragment can be introduced.
Has one more. The binding of the fragment to site Y of the eight composite fragments represents a third round of synthesis (ie, n + 2 rounds). Next, CF3
, CF7, CF9, CF12, CF13, CF14, CF15 and CF16, the fragment F4 is introduced. Since fragment F4 is a mixture of two constituent fragments, 16 compounds, C2, C3, C7, C8, C9, C10, C
11, C12, C13, C14, C15, C16, C17, C18, C19 and C20 are produced. Thus, it can be seen that using a large number of fragments in a one-spot fashion and combining with a mixture of fragments can produce a more complex mixture of compounds. The examples in FIGS. 14a and 14b show that 16 unique compounds are produced as mixture M4 when the library is produced starting with two fragments. One of skill in the art will appreciate that if this library production is initiated with more than two fragments, or if multiple fragments are added to the same precursor fragment, a more complex mixture of compounds may be produced. You.

The present invention also provides methods for tracking fragment addition at various rounds of synthesis. This explanation system is achieved by representing a synthesis round correlated to the addition of fragments. For purposes of describing the present invention, a tabulation method for tracking fragments is described herein, but other algorithms, algorithmic codes, computer readable media, and various software coding techniques known to those skilled in the art. Those skilled in the art will appreciate that such tracking can be utilized. The fragment addition tracking table can be used to produce a structural representation of the compound and create a virtual library where in-situ synthesis of the compound is not desired. On the other hand, a conversion tracking table is used to select the appropriate conversion and, in the case of multiple conversions, to synthesize the compound by selecting the preferred conversion to introduce the required fragment into the compound being synthesized. Can be used for

FIG. 15 describes compound C1 with a fragment added for each synthesis round. The first synthesis round (ie, n rounds) uses fragment F7
Start with the selection. This is followed by a second synthesis round (ie, n + 1 rounds)
In, fragments F2, F1 and F5 are sequentially added. Finally, compound C1 is produced by the addition of fragment F3 in the third synthesis round (ie, round n + 2). The compounds produced in this way are stored as a two-dimensional virtual library or
It can be converted to a three-dimensional virtual library that can be used for silico merging.

To generate a virtual library of compounds and incorporate library members into target molecules, it is sufficient to add the compounds to a relational database of fragments to track fragment addition in various rounds of synthesis. is there. However, when a hands-on synthesis of the desired compounds of the library is made, the steps of the hands-on synthesis, reagents, solvents, concentrations, auxiliary compounds required, and various other syntheses to provide a hands-on synthesis of the actual compounds Factors need to be identified. Such synthetic steps, reagents, solvents, concentrations and auxiliary compounds are indeed incorporated in the above transformations. Thus, by utilizing the concept of conversion, the present invention provides a way to track the compounds produced, not only in terms of the fragments added, but also in the synthesis parameters required per synthesis round.

FIG. 15 also shows the production of compound C1 for the various transformations utilized in the synthesis round. Compound C1 is synthesized by the four synthetic routes because a number of transformations are available that can introduce the same fragment into the compound being synthesized.
Thus, as seen in FIG. 15, the selection of fragment F7 constitutes a transform T9 in the first synthesis round (ie, n rounds). Fragment F2
, Which is achieved by utilizing the transformation T2. Next, the fragment F1 is added via the transformation T1. Fragment F5, on the other hand, can be added using reagent R6 via conversion T6 along synthetic pathways 1 and 3, or added using reagent R7 via conversion T7 along synthetic pathways 2 and 4. Similarly, the final fragment, F3, is added using reagent R3 via conversion T3 along synthetic pathways 1 and 2, or using reagent R4 via conversion T4 along synthetic pathways 3 and 4. I can do it. Thus, FIG. 15 shows that compound C1 can be synthesized in practice by one of four different synthetic schemes, which scheme can be followed or tabulated and illustrating the use of the method of the present invention. These four tables are C1
Each of the four synthetic routes for production is fully described. Thus, the user of the present invention has all of the available alternative routes to carry out the same reaction (ie, introduces the same fragment), so that the preferred or most appropriate synthesis to produce the desired compound You can select a route.

FIG. 16 shows a similar conversion tracking table for compounds C2 and C3 of mixture M1. Synthesis of compounds C2 and C3 begins with the selection of fragment F7, which represents transformation T9 (step 1 of FIG. 16) in the first round of synthesis (ie, n rounds). Then, conversion 2 of the second synthesis round (ie, n + 1 round) (step 2)
) Binds F7 to fragment F2. In the same round, fragment F1 is added sequentially by transformation T1 and fragment F5 by transformation T7 (steps 3 and 4). Finally, the third synthesis round (ie, n + 2 rounds)
In the above, the fragment F4 is added. F4 is 2 (for the two constituent reagents)
Since a mixture consisting species composition fragments, various synthetic methods have converted T5 can be achieved (i.e., T5 ¹ and T5 ²⁾ To illustrate, this step (step 5)
Is duplicated in the table. Step 5 represents compounds C2 and C3. Thus, according to the present invention, when there is more than one reagent associated with a particular conversion, the table is duplicated for each such reagent.

FIG. 17 shows a conversion tracking table for compounds C1 and C5 in mixture M3. As the synthesis starts with two fragments, F7 and F8, the trace starts with two parallel tables (step 1 in FIG. 17). In the first synthesis round (ie, n rounds), F7 is selected by transform T9, while F8 is selected by transform T10. The second synthesis round (ie, n + 1 round) begins with the introduction of fragment F2 by transformation T2 in step 2. In step 3, fragment F1 is introduced into the compound by conversion T1. In step 4, fragment F5 is introduced by transformation T7. This completes the second synthesis round (ie, n + 1 round). Finally, in the third synthesis round (ie, round n + 2), the transformation T4 is used to introduce (in step 5) a fragment F3 that produces a mixture M2 comprising compounds C1 and C5. In this example, the table is duplicated from the beginning of the synthesis scheme since a mixture of fragments F7 and F8 was used initially.

The conversion tracking table for compounds C2, C3, C7 and C8 in mixture M3 is shown in FIG.
Synthesis of these compounds begins with the first round of synthesis (ie, n rounds) in which fragment F7 is selected. This represents the transformation T9 (shown in step 1 of FIG. 18). Step 2 of FIG. 18 illustrates a second synthesis round (ie, n + 1 round),
It involves the addition of fragment F2 by transformation T2. Steps 1 and 2 each involve a single transformation, while step 3 involves two different transformations, where two different fragments are introduced into the compound through the use of two different reagents. That's why. Therefore, the double replication of the table in step 3 is due to the fact that two different reagents
Different transformations introduce two different fragments. In step 3, transformation T3 is used to introduce fragment F3, while transformation T1 is used to introduce fragment F1. The second synthesis round (ie, n + 1 round) is completed with the transformation T7 of step 4 introducing fragment F5. In the final synthesis round (ie, the third or n + 2 round), the transform T5 is used to introduce the fragment F4. Since F4 is a mixture of two structural fragment table of step 5 is being dual replicates for converting T5 ¹ and T5 ^2, respectively represent the structure fragment F4.

The above diagram represents only one way in which various fragments, reagents and conversions can be tracked during the production or synthesis of a single compound or a mixture of compounds. However, one of ordinary skill in the art will appreciate that various other algorithmic schemes may be utilized to track and account for the fragments introduced by the transformation when the compound is produced in silico.

[0055] Library members or compounds produced by the methods of the invention can be converted to a three-dimensional representation using commercially available software. This three-dimensionally structured compound can then be coalesced onto the identified target, also represented in a three-dimensionally structured form.

Docking of these library members (or ligands) entails in silico binding of this member to the desired target molecule. Various theories and computational methods for studying and optimizing the interaction of small molecules with biological target molecules such as proteins and nucleic acids are known in the literature. Drug design tools based on these structures are very useful in modeling the interaction between small molecule ligands and proteins and optimizing these interactions. Generally, this type of study was performed when the structure of a protein receptor was known by examining the individual small molecules one by one for that receptor. Usually, these small molecules were molecules that had already crystallized with the receptor and were associated with other molecules that had previously crystallized together, or where there was some cohesive knowledge of the interaction with the receptor. . A notable advance in this area has been the development of a software program called DOCK that enables a structure-based database search to discover and confirm the interaction of known molecules with the receptor of interest (Kuntz et al.,
Acc. Chem. Res., 1994, 27, 117; Gschwend and Kuntz, J. Comput.-Aided Mol
Des., 1996, 10, 123). DOCK has a 3D structure generated in silico,
It allows the screening of molecules for which no prior knowledge of the interaction with the receptor is available. Accordingly, DOCK provides tools to help discover new ligands for the receptor of interest. Thus, DOCK can be used to incorporate a compound produced by the method of the invention into a desired target molecule.

The DOCK program has been applied to identify protein targets and ligands that bind to them. The DOCK software program is SPHGEN (Kuntz, e
et al., J. Mol. Biol., 1982, 161, 269) and CHEMGRID (Meng et al.,
J. Comput. Chem., 1992, 13, 505). SPHGEN generates overlapping region clusters that describe the solvent accessible surface of the binding pocket within the target receptor. CHEMGRID pre-calculates and stores the information needed to calculate (score) the force of the field where the binding molecule interacts with the target in a grid file. This calculation function approximates the interaction energy of molecular mechanics, and includes van der Waals force and electrostatic elements. DOCK uses the selected region cluster to localize the ligand molecule to a target site on the receptor. Each molecule of the already generated 3D database is tested in thousands of orientations within its target site, and each orientation is evaluated by computational functions. Only the orientation with the best score for each compound screened is stored in the output file. Finally, every compound in the database is ranked in order of its score, and the best candidate group is then screened experimentally.

Using DOCK, ligands have been identified for several protein targets. Recent work in this area has produced a paper on the use of DOCK to identify and design small molecule ligands that exhibit binding specificity for nucleic acids, such as RNA duplexes. RNA plays an important role in many diseases, such as AIDS, viral and bacterial infections, but little research has been done on small molecules that can specifically bind to RNA. Compounds with specificity for RNA duplexes have been identified using the methodology of DOCK, based on the geometry unique to the deep major groove (Chen et al., Biochemistry, 1997, 36, 11402; Kuntz et al., Acc. C
hem. Res., 1994, 27, 117). r (UAAGGAGGUGAU) r (AUCAC
Using the latest X-ray structure of CUCCUUA) as a model structure for type A RNA duplexes, DOCK has identified several aminoglycosides as candidate ligands characterized by shape complementarity to the RNA groove. Binding experiments then revealed that one of these aminoglycosides not only preferentially binds to RNA over B-type DNA, but also that the ligand binds in the targeted RNA major groove. Recently, the problem of ligand recognition in DNA quadruplex has been
Has been reported (Chen et al., Proc. Natl. Acad. Sci., 199).
6, 93, 2635).

There are currently no reports on the evaluation of virtual libraries against RNA targets. Reports on the production of virtual libraries are from the perspective of library design, production, and screening against protein targets. Similarly, work in the field of producing RNA models has been reported in the literature. However, based on a three-dimensional model of the RNA structure, a structure for examining a virtual library to identify ligands that bind to such targets, such as small molecules, oligonucleotides or other nucleic acids There are no reports on the use of the design approach. The present invention provides for the construction of three-dimensional models of RNA structures, the construction of virtual ligand libraries, including small molecules, macromolecules, oligonucleotides and other nucleic acid molecules, the creation of such virtual libraries for RNA targets. in silico screening, calculating and identifying the best potential binders from such libraries, and finally synthesizing such molecules in a combinatorial format and testing them experimentally to Identifying new ligands to such targets provides a solution to this problem. The methods of the present invention allow for the identification of library members that bind with high affinity to a target molecule, thus enabling the identification of library members that will be molecules that are potentially synthesized and developed as lead drug candidates. Support search methods.

[Brief description of the drawings]

FIG. 1 shows the compound, Compound CI, degraded into constituent fragments.

FIG. 2 shows various discriminating characteristics of the fragments constituting compound CI.

FIG. 3 shows various distinguishing characteristics of the reagents used to introduce the corresponding fragments that make up Compound CI.

FIG. 4 shows a list of transformations linking fragments and reagents involved in the production of compound CI.

FIG. 5 is a schematic diagram of introducing a common fragment using two different reagents.

FIG. 6a is a schematic for using a single reagent to introduce two different fragments into a compound. FIG. 6b is a schematic showing the use of a common reagent to introduce a common fragment into a compound that can be further converted to two different fragments within the compound being produced.

FIG. 7 shows symbol addition of a fragment that produces the compound CI ′, which is a symbol compound.

FIG. 8 is a table of symbolic reagents.

FIG. 9 is a table of symbol fragments.

FIG. 10 is a table of symbol conversion.

FIG. 11 shows the production of the individual compounds, compounds C1 and C4, and the mixture, mixture M1.

FIG. 12 shows the production of the following mixture, Mixture M2.

FIG. 13 shows the production of an additional mixture, Mixture M3.

FIGS. 14a and b show the production of an additional mixture, Mixture M4.

FIG. 15 shows that the added compound and / or the compound C
1 shows a table tracking 1.

FIG. 16 shows a table tracking mixture M1 with the transformations performed.

FIG. 17 shows a table tracking mixture M2 with the transformations performed.

FIG. 18 shows a table tracking mixture M3 with the transformations performed.

──────────────────────────────────────────────────続 き Continuation of front page (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR , BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS , JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Sways, Eric 92009 California, USA , Carlsbad, Palenque Street 7789 F-term (reference) 4H006 AA02 5B046 AA00 BA02 DA02 EA03 FA06 KA03 KA06 5B075 ND20 NK10 NK43 PQ02 QM08 UU18

Claims (26)

[Claims] 1. A method of producing a virtual library of compounds in silico, comprising: a group of related fragments, each of said related fragments forming part of said compound; Selecting in silico a group in which each of the fragments has at least one attachment site; in at least one additional fragment having at least one attachment site
silico selecting; and connecting the additional fragment to the relevant fragments in silic by linking the additional fragment to the relevant fragment
o ligating to produce a virtual library of said compounds. 2. A method of producing a virtual library of compounds in silico, comprising: a first fragment comprising a portion of said compounds and having at least one binding site. In silico selecting fragments; in silico selecting a group of related fragments, each of said related fragments having at least one binding site; and Connecting each of the groups of related fragments to the first fragment in silico by linking the respective binding sites of the group of related fragments to the first site to produce a virtual library of the compounds. A method comprising: 3. A method of producing a virtual library of compounds in silico, comprising: a first group of related fragments, each of said related fragments constituting part of said compounds; Selecting in silico a first group having one binding site in silico; an additional group of fragments, wherein each of the fragments has at least one binding site. And linking each binding site of the first group of related fragments to a respective binding site of an additional group of fragments, thereby connecting the first of the related fragments to each additional group of fragments. Linking each of the groups in silico to produce a virtual library of said compounds. 4. The method of claim 1, wherein each of said fragments is introduced in silico into said compounds by use of a corresponding reagent. 5. The method of claim 2, wherein each of said fragments is introduced in silico into said compounds by use of a corresponding reagent. 6. The method of claim 3, wherein each of said fragments is introduced in silico into said compounds by use of a corresponding reagent. 7. Each compound of a virtual library of various compounds is in silico
A method of identifying, comprising: decomposing the compounds into fragments; and identifying each of the fragments for transformation, wherein the transformation comprises combining the fragment and the fragment with a compound. A one-to-one linkage with the reagents used to introduce the DNA into the reagent. 8. The method according to claim 1, wherein the conversion is further associated with auxiliary reagents or reaction conditions.
The method according to claim 7. 9. A method for producing a virtual library of compounds in silico, comprising: decomposing the compounds into fragments; converting each of the fragments into a fragment and one of the compounds. Express in silico as a conversion that is a one-to-one linkage with the reagent used to introduce the fragments; a first group of the fragments, each of which forms part of the compound And selecting in silico a first group in which each of the fragments has at least one attachment site; in at least one additional fragment having at least one attachment site
silico selecting; and linking the additional fragment to the first group of fragments in silico by linking the linking site of the additional fragment to the linking site of the members of the first group of fragments. Producing a virtual library of said compounds. 10. A method for producing a virtual library of compounds in silico, comprising: decomposing the compounds into fragments; converting each of the fragments into a fragment and one of the compounds. Represented in silico as a transformation that is a one-to-one linkage with the reagent used to introduce the fragment; a fragment that forms part of the compounds and has at least one binding site Selecting in silico the first fragment; in a group of additional fragments each having at least one attachment site
selecting the silico group; and linking the group of additional fragments to the first fragment in silico by linking the linking site of the additional fragment group to the linking site of the first fragment; A method comprising producing a virtual library of compounds. 11. A method for producing a virtual library of compounds in silico, comprising: decomposing the compounds into fragments; converting each of the fragments into a fragment and one of the compounds. Express in silico as a conversion that is a one-to-one linkage with the reagent used to introduce the fragments; a first group of the fragments, each of which forms part of the compound And selecting, in silico, a first group in which each of the fragments has at least one attachment site; in a group of additional fragments each having at least one attachment site.
selecting at least some of the fragments of the first group by linking the attachment sites of the members of the additional fragments to the attachment sites of the members of the first group of fragments. In silico linking at least some members of said group of additional fragments to members to produce a virtual library of said compounds. 12. Each compound of a virtual library of various compounds is in silic
o A method of identifying, comprising: decomposing the compounds into fragments; adding the fragments together in successive synthesis rounds; and tracking the addition of the fragments of the compounds. How to be. 13. Each compound of a virtual library of various compounds is in silic
o A method of identifying: decomposing the compounds into fragments; replacing each of the fragments with a fragment and a reagent used to introduce the fragment into one of the compounds. Representing in silico as transformations that are one-to-one connected; adding said transformations together in successive rounds of synthesis; and tracking the transformations in silico. 14. A method for storing information about members of a member of a virtual library of compounds, comprising: decomposing each of the compounds into fragments; concatenating respective fragments of each of the compounds together. And tracking the order of linkage for each compound. 15. The method of claim 2, further comprising: combining two or more compounds of the library together to form a mixture; and bringing together tracking information for each of the members of the mixture. 15. The method according to 14. 16. Combining two or more compounds of the library together to form a mixture; Combining two or more compounds of the library together to form an additional mixture. 15. The method of claim 14, further comprising: combining tracking information for each of the mixture members; and combining tracking information for each of the additional mixture members. 17. A method for storing information about member compounds in a virtual library of compounds, comprising: decomposing the compounds into fragments; replacing each of the fragments with a fragment; Representing each transformation of the compounds together as a transformation which is a one-to-one linkage with the reagent used to introduce the fragment into one of the compounds; and Tracking the concatenation order. 18. The method of claim 18, further comprising: combining two or more compounds of the library together to form a mixture; and linking together tracking information for each of the members of the mixture. Item 18. The method according to Item 17. 19. Combining two or more compounds of the library together to form a mixture; Combining two or more compounds of the library together to form an additional mixture. 18. The method of claim 17, further comprising: concatenating tracking information for each of the members of the mixture together; and concatenating tracking information for each of the members of the additional mixture. 20. The method of claim 17, further comprising defining each of said transformations to further include information related to the synthesis of a fragment from a reagent.
The method described in. 21. A method of storing information about member compounds of a virtual library of compounds, comprising: decomposing each of the compounds into fragments; two or more members of the library. Combining the compounds together to form a mixture; linking the respective fragments of the compounds together; and tracking the linking order of the members of the mixture. 22. A method of storing information about member compounds of a virtual library of compounds, comprising: decomposing each of the compounds into fragments; combining the compounds of the library with mixtures. Combining each mixture into mixtures comprising two or more member compounds of the library; linking together fragments of each of the compounds; and each of the mixtures Tracking the concatenation order of the members of the method. 23. A method for storing information about member compounds of a virtual library of compounds, comprising: decomposing each of the compounds into fragments; replacing each of the fragments with a fragment; Expressing as a transformation that is a one-to-one connection with a reagent used to introduce the fragment into one of the compounds; two or more compounds of the library are ganged together to form a mixture Linking the transformations for each of the compounds together; and tracking the linking order of the members of the mixture. 24. The method of claim 23, further comprising defining each said transformation to further include information related to the synthesis of a fragment from a reagent. 25. A method for storing information about member compounds of a virtual library of compounds, comprising: decomposing each of the compounds into fragments; replacing each of the fragments with a fragment; Expressing as a transformation that is a one-to-one linkage with a reagent used to introduce the fragment into one of the compounds; the compounds of the library as mixtures, wherein each mixture is Grouping together a mixture comprising two or more member compounds of the library; linking together the transformations for each of said compounds; and tracking the order of connection of the members of each said mixture. A method comprising: 26. The method of claim 25, further comprising defining each of said transformations to further include information related to the synthesis of a fragment from a reagent.