CN109559786A - Lead compound discovery and synthetic method based on quantum group intelligent optimization - Google Patents
Lead compound discovery and synthetic method based on quantum group intelligent optimization Download PDFInfo
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Abstract
Lead compound discovery and synthetic method based on quantum group intelligent optimization, including step 1, the new lead compound of combined prediction is initial to model, target validation, quantum screening；Step 2, activity rating and quantum group intelligent optimization, establish training set and test set, and quantum group training calculates test set accuracy；Step 3, drug effect optimization and toxicological activity are eliminated, and drug effect optimization, toxicological activity is eliminated；Step 4, zoopery and clinical trial.The present invention constructs lead compound using quantum group intelligent optimization, can accurately describe the effective ingredient based on the active ingredient and pharmacological activity based on chemical analysis；It is had higher success rate using quantum screening and quantum group Intelligent Optimal Design new drug, and helps to substantially reduce new drug design cost；Quantum group intelligent optimization model can more realistically carry out lead compound simulated experiment on computers, in conjunction with zoopery and clinical trial, be capable of providing more true drug and design a model and method.
Description
Technical field
The present invention relates to lead compound fields and Computer-Aided Drug Design field, especially a kind of to be based on quantum group
The lead compound of intelligent optimization is found and synthetic method.
Background technique
Since the mankind are born, the research and development and test of new drug are all extremely time-consuming, laborious, expensive and full of risk
Process.The statistics of official shows that the listing process average of usual new drug needs the research and development time and more than ten00000000 of more than ten years
The R & D Cost of dollar.With the fast development of computer and information technology, it is attempted to using computer technology auxiliary development
New drug improves the success rate of new drug development and reduces its cost.On October 5th, 1981, the U.S. " Fortune " magazine have delivered opinion
Literary ＂ Next Industrial Revolution:Designing Drugs by Computer at Merck ＂, it is open to propose
Novel drugs research and development and simulation, i.e. Computer-Aided Drug Design (Computer-Aided Drag are carried out using computer technology
Design, CADD).So-called area of computer aided pharmaceutical synthesis is exactly this phase interaction by simulating and calculating receptor with ligand
With carrying out the optimization and design of lead compound.High-speed computation and large buffer memory using computer, can fast and accurately know
Other bioactive molecule, finds the structure-activity relationship of bioactive molecule, substantially reduces the discovery time of lead compound, saves a large amount of people
Power, financial resources, material resources.In general, Computer-Aided Drug Design can be divided into the drug design (Ligand-based based on ligand
Drug design, LBDD) and drug based on target structures design (Structure-based drug design, SBDD).
In the past few decades, Computer-Aided Drug Design is becoming better and approaching perfection day by day, and occurs a variety of methods, including biological information successively
, homologous modeling, pharmacophore, molecular docking, Quantitative Structure effect, High Throughput Screening Assay (High-throuput screening,
HTS), virtual screening technology (Virtual screening), molecular dynamics simulation etc..
Currently, Computer-Aided Drug Design oneself through being widely used in the different phase of medicament research and development, significantly reduce new drug
The problems such as cost in research and development, risk.But current area of computer aided new drug development still has certain defect, hinders people
Class further obtains the process of new drug.
Firstly, the accuracy of reactive compound discovery is to be improved.The accuracy of reactive compound discovery generally includes two
A main aspect, i.e., the active ingredient based on chemical analysis, and with pharmacological activity be guiding effective ingredient.If improved
The accuracy of reactive compound discovery, it is necessary to cannot blindly be separated in the separation and Extraction purification process of chemical analysis therein
Composition, but always using active ingredient as purpose object.New drug development is instructed to can be improved newly by pharmacological activity or bioactivity
The accuracy of medicine discovery, but assessment object during new drug development is the various mixing containing different compounds actually
Object, Activity Assessment result can not provide more reference informations for new drug development, and the discovery of reactive compound is caused to be still
Blindness, and it is also difficult to avoid that the reactive compound composition lost needed for us during new drug development.
Secondly, current Computer-Aided Drug Design success rate is lower.The development of computer technology be discovery activity at
Part and design new drug provide a large amount of advanced technology, but so far, the discovery for the reactive compound that is not significantly increased is imitated
Rate.Such as Computer-Aided Drug Design is used for the Large-scale Screening of active symptom of a trend compound (Hit), wherein random screening
Technology is recognized is subversive for (random screening) or high flux screening (highthroughput screening)
New drug development technology.However, the success rate that these methods screen Hit is still lower.The development of Computer-Aided Drug Design
Process is it can be found that the asynchronous and concurrency difference that various new technologies combine is the important of restricted activity compound design success rate
One of factor.
Again, current Computer-Aided Drug Design higher cost.Current Computer-Aided Drug Design often needs
Construct and maintain compound library, design automation detection method, to verifying of screening technique etc., these complicated new drug developments
Process generally requires higher setting up cost, limits further genralrlization and the application of Computer-Aided Drug Design.Although
A large amount of new technologies and optimisation technique, including molecular chemistry technology and biology pharmacological activity are additionally used during new drug development
Assessment technique, but traditional model and mathematical method are often used when using these technologies, it is difficult to improve Efficiency or drop
Low design cost.
Finally, current Computer-Aided Drug Design authenticity is insufficient.Virtual screening be it is a kind of with computer to rely on
New drug design aids, only truly simulate reaction and the drug effect of drug molecule and organism protein molecule
Reliable data supporting can be provided for new drug development.But current all kinds of Computer-Aided Drug Design means or virtual
The authenticity of screening technique is still insufficient, for example carries out random screening using computer mould quasi-random numbers.Further, how right
The drug effect and molecular docking programs of new drug score according to true scene, how to consider human body constitution and biological property,
Reducing false positive etc. is still Medical circle and pharmacy circle outstanding question.So exploring novel new drug research side
Method and means, especially non-classical research and development technology are the important channels for improving reactive compound discovery efficiency.
With the fast development of computer technology, especially quantum-mechanical rapid development, for discovery lead compound and
Research newtype drug provides technical possibility, still, up to the present, does not still have in the market a kind of based on quantum gunz
The lead compound discovery that can optimize and synthetic method.
Summary of the invention
In order to solve the problems such as current lead compound finds low efficiency, accuracy is not high, effect is limited, the present invention is provided
A kind of lead compound discovery and synthetic method based on quantum group intelligent optimization, this method is by using quantum group intelligent optimization
Combination lead compound model, passes through training and drug effect and toxicology are constantly updated in study, it is easier to it is more preferable, malicious to obtain drug effect
The lower drug of reason activity.
The technical scheme adopted by the invention is as follows:
Lead compound discovery and synthetic method based on quantum group intelligent optimization, comprising the following steps:
Step 1, the new lead compound of combined prediction:
Sub-step 1-1, it is initial to model: to use the physiology of main compound in data-base recording and analysis various kinds of drug ingredient
The structure of active structure and its corresponding pharmacological activity and target is established its structure effect and is closed after the description of quantum state wave function
It is model；
Target validation: sub-step 1-2 is confirmed by structure of the computer system to target, is calculated using quantum searching
Method is attempted to search target similar with its in the database, determines that lead compound is prepared to orient；
Quantum screening: sub-step 1-3 is oriented according to quantum search algorithm and is determined lead compound；If can not determine, root
Random combine is carried out according to quantum random number, obtains one group of compound；
Step 2, activity rating and quantum group intelligent optimization:
Sub-step 2-1, establishes training set and test set: carrying out to size, the consistent compound structure three-dimensional figure of brightness
Black and whiteization and inverse are handled；By compound activity by picture classification, the corresponding digital label of every one kind picture affix, and dosage
Sub- state wave function description；Wherein, a part of picture is as training set, and another part picture is as test set；
Sub-step 2-2, quantum group training: establishing quantum group intelligent optimization model and training, learning algorithm, and training,
Training is completed after the value of error function is less than specified error with the error step-up error function of desired value in learning process
And save data after training；
Sub-step 2-3 calculates test set accuracy: if meeting the requirements, can be judged by this activity rating model unknown
Compound activity carries out biological experiment afterwards；It is such as undesirable, then expand search range, returns to previous step.
Step 3, drug effect optimization and toxicological activity are eliminated:
Drug effect optimization: sub-step 3-1 establishes quantum pharmacodynamic assessment function and assesses drug effect；Pharmacological activity is evaluated
Underproof lead compound after being analyzed its data obtained, is corrected and reconfigures rear return step 2；Pass through
The parallel optimization of multiple groups quantum group, if bioactivity or pharmacological activity evaluation meet scheduled value, i.e. completion drug effect optimization；Pass through
The parallel optimization of multiple groups quantum group can find out the satisfactory multiple groups lead compound of drug effect at the appointed time, and certainly
Row selects optimal lead compound combination.
Sub-step 3-2, toxicological activity are eliminated: being collected the compound with toxicological activity, are analyzed its structure, establish related poison
Manage the database of active compound structure；Quantum toxicological activity valuation functions are established to assess toxicological activity；To toxicity
The underproof lead compound of activity rating after being analyzed its data obtained, is corrected after reconfiguring and returns to step
Rapid 2；The lead compound combination that drug effect is best, toxicological activity is minimum can be searched at the appointed time.
Step 4, zoopery and clinical trial:
Sub-step 4-1 carries out zoopery: if obvious adverse reaction occurs in animal after reagent, updating number described in step 1
According to library, and adjusting training collection and test set, quantum intelligent optimization is re-started, i.e., each constituent contains in change compound
Amount, re-starts step 2；If animal does not occur obvious adverse reaction after reagent, one group of animal is changed, zoopery is continued,
Without obvious adverse reaction after meeting the zoopery of specified quantity, then next stage is transferred to；
Sub-step 4-2, carry out clinical trial: select aspiration crowd test, if the lead compound toxicological activity compared with
Greatly or toxicological activity is smaller but larger to Health Impact, then updates database described in step 1, and adjusting training collection and survey
Examination collection re-starts quantum intelligent optimization, i.e., the content of each constituent, re-starts step 2 in change compound；If reagent
Human body does not occur obvious adverse reaction afterwards, changes one group of volunteer, continues clinical trial, until meeting the human body of specified quantity
Without obvious adverse reaction after experiment.
Structure-activity relationship described in step 1 is to obtain the chemical structure database of main compound in drug ingedient, and make to count
According to the compound structure and its pharmacological activity and target construction one-to-one correspondence in library；The orientation determines that lead compound refers to
After determining target construction, by analyzing clinical symptoms, fitting is oriented to compound corresponding to corresponding pharmacological activity.
It is to convert tri-dimensional picture for the structural formula of compound described in step 2；The test set accuracy refers to, with
The test set activity that activity criteria's function evaluation test collection obtains calculates accuracy compared with real property.
Pharmacological activity described in step 3 refers to the effect that drug is directly played in molecular level or respective horizontal.
Before animal reagent described in step 4, the animal that one group of life habit, health status, age need to be selected to be not much different,
It puts signs on respectively, carries out adaptation training to allow it to be familiar with environment.
Compared with traditional lead compound finds method, the present invention is based on the lead compound of quantum group intelligent optimization hairs
Now significantly it is had an advantage that with synthetic method:
Firstly, present invention discover that the accuracy of reactive compound is higher.Due to using quantum group intelligent optimization to construct guide
Compound can accurately describe the effective ingredient based on the active ingredient and pharmacological activity based on chemical analysis.Guide's chemical combination
The quantum group intelligent optimization of object, additionally it is possible to carry out accurate performance evaluation and data analysis, more accurately calculate active ingredient or
The physicochemical property of effective ingredient, including from the intermolecular relevant effect of quantum mechanics angle analysis, superposition, tangle effect,
Uncertainty etc. avoids to provide more reference informations and non-classical physicochemical property for us in new drug development
The reactive compound composition needed for us is lost in the process.
Secondly, the present invention designs having higher success rate for new drug.It is 0 different from classical data non-1, or vice versa, quantum information
Have massive parallelism, can be easily accomplished | 0 > with | the superposition of 1 > state and quantum operator calculate, and can complete bulk information
Database search find the compound for meeting pharmacophore model.And quantum calculation can generate real random number, without
The pseudo random number being same as in traditional counting, so that the probability that different lead compounds combine is greatly improved, it can be found that classical meter
Calculate indiscoverable combination.In addition, passing through the parallel optimization of multiple groups quantum group, the time complexity of calculating can reduce,
So that corresponding calculating process and detection are more simplified, but more useful information can be included.
Again, technology used in the present invention helps to substantially reduce new drug design cost.Compared to traditional analysis and calculating
Technology, quantum group intelligent optimization can carry out a large amount of lead compound simplation examination experiment parallel on computers, drop significantly
High setting up cost needed for high cost needed for low traditional detection method and new drug development process.Different from classic optimisation,
Quantum group intelligent optimization model can exclude theoretical generated model error of classic optimisation itself or experimental error.This method energy
Classical new drug development theory, calculation method, the deficiency of experimental system are enough made up, for example in testing stage, is capable of providing non-classical
Quantum group intelligent optimization model and mathematical method, to drug molecule different isomer carry out physiological activity detection, and for whether
It needs to separate or further operating provides guidance.
It designs a model and method finally, the present invention is capable of providing more true drug.Relative to existing Classic couture
Method or technique, quantum group intelligent optimization model can more realistically carry out quantum mechanics simulated experiment on computers, avoid
Generated error when traditional counting modeling molecular dynamics behavior.Quantum group intelligent optimization model can also generate very
Positive random number can analyze a large amount of compounds, calculate and select the different parameters of lead compound, and be lead compound
Quantum state wave function relationship, i.e., real quantitative structure activity relationship are established between property and parameter.Further, pass through zoopery
Truthful data is obtained with human experimentation, and proofreads and update quantum group intelligent optimization model；It further, can be to existing new
Medicine design provides more authentic and valid virtual screening, pharmacodynamic assessment, biological property simulation, false positive simulation etc., is new drug
Research and development provide a kind of new thinking and approach.
Detailed description of the invention
Fig. 1 is flow chart of the method for the present invention.
Specific embodiment
Lead compound discovery and synthetic method, specific embodiment based on quantum group intelligent optimization include:
Step 1, the new lead compound of combined prediction:
Sub-step 1-1, it is initial to model: database used, it is preferable that use disk array, maximum storage capacity 24TB, outside
4 6Gb/ seconds SAS ports of each controller of host channel are connect, stand-alone disk quantity 12, double SAS controllers are hard equipped with 12
The cabinet of disc holder, product weight are less than 20kg；Preferably, database server, cpu frequency are not less than 2.1GHz, and intelligence adds
Fast dominant frequency 2.6GHz, maximum CPU quantity 4, making technology 14nm, three-level caches 30MB, bus specification QPI 8GT/s, CPU core
12 core of the heart (Magny-Cours), 24 thread of CPU line number of passes, mainboard expansion slot most 6 PCIe, type of memory DDR4, memory
Capacity 32GB, memory standard configuration 2 × 16G 2400T-R DDR4, memory bank quantity 48, maximum memory capacity 3072GB, hard disk connect
Mouthful type SATA/SAS, standard configuration hard-disk capacity 120GB or more, hard disk support 8 pieces of 2.5 inches of SFF (extendible), Magnetic Disk Controler
Smart Array P440AR/2GB array cache controller, 1 1Gb 331FLR Ethernet Adaptation Unit of network controller, four ends
Mouth controller, 2 1200W hot plug power supplys of power supply；Preferably, two and the above homotype database server can be selected；It is excellent
Selection of land, database software are Oracle Database 12c second edition Oracle Solaris (x86 system, 64).Preferably,
The server and Database Systems formed using quantum computer and quantum memory.
The database includes following data: the data of lead compound, the pathological characteristics data of illness, drug number
According to.
Use the physiological activity structure of main compound in data-base recording and analysis various kinds of drug ingredient and its corresponding
Pharmacological activity and target structure, by quantum state wave function description after, establish its structure-activity relationship model；
Quantum state wave function can be at | 0 > or | one of 1 > state can also be in | 0 > or | in any superposition state of 1 > state.
Therefore, one n quantum memories have up to 2n coherent superposition state | and φ >, up to 2n number can be indicated simultaneously.
Further, multiple groups quantum group can parallel computation, quantum state wave function is available as under type describes ground state | φ > and superposition state |
φi>:
Structure-activity relationship model is used to for the three-dimensional structure parameter and physical and chemical parameter of a series of lead compounds and drug effect being fitted
Quantitative relationship out further according to this Composition noval chemical compound and predicts its activity, or its structure is optimized and improved.
Specific embodiment include: analyze normal cell in existing therapeutic agent work active ingredient group, conformation,
The physics such as three-dimensional structure, energy, chemistry, optical property information data corresponding with pathological state, and analysis signaling molecule
The mechanism of action or sick cell normal condition under working mechanism data；The cell that lesion occurs for analysis is in certain pathology
The information data of symptom, simple molecule is detected by molecular probe or how fragment carries out with large biological molecule active site
In conjunction with the record obtained data information of molecular probe mechanism；By to molecule or fragment and large biological molecule active sites
The analysis of the interaction situation of point, finds the possible binding site and combination of these molecules or fragment in active site
When Gibbs free；Analysis obtains the information data in gained receptor protein activity site and analysis sick cell in the above process
Cell membrane on receptor protein three-dimensional structure information data.
Genetic recombination data form genetic recombination library, can utilize the compound of gene recombination technology synthesizing new structure,
Or utilize the new structural active matter of micro-organisms.Further, it can be improved microbial secondary metabolite to synthesize
Two kinds there is the antibiotic biosynthesis gene of similar route of synthesis to recombinate by the substrate specificity of certain enzymes in journey, from
And synthesize the novel hybrid antibiotics different from the product of two parental plants.
Sub-step 1-2, target validation: attempting to search target similar with its using quantum search algorithm in the database,
Determine that lead compound is prepared to orient.
Preferably, quantum search algorithm uses quantum Grover searching algorithm, realizes in unprocessed information library to satisfaction
The target of condition successfully searches element, and is reduced to computation complexity by the O (N) of classical searching algorithmRealize data
The secondary acceleration of search.Wherein, input side includes a n quantum bit register and one containing several two words bits
Oracle working space, the core of the algorithm are that a solution of search problem is found out using least Oracle call number.Into
One step, multiple groups quantum group is capable of the search of parallel computation, phase-shifting method can also be used to improve Grover searching algorithm, raising is searched
Without hesitation can.
The sharpest edges of this new drug development method are using based on target spot " with a definite target in view " type, it is possible to according to target
Design and optimization high potency drugs quickly；Further, the controlled syntheses and screening by Bioexperiment in subsequent step 4 and
The inspection of human experimentation, and corresponding adjustment can be made and updated, therefore even if target compound has the affine work of very strong receptor
Property, once find that bioavilability, in vivo metabolism or toxicity are unqualified in testing, and also result in this in subsequent step detection
Compound synthesis cancels and restarts.Because of target compound tool obtained in traditional target molecules design and optimization process
There are more polar group or hydrophobic grouping, target validation of the invention is it can be found that caused external high living in later period inspection
Property, cell and internal test are invalid, improve the accuracy and validity of the lead compound MOLECULE DESIGN based on receptor structure,
And consider in the design compound absorb, distribution, metabolism, excretion and toxicity in terms of property, have more preferably authenticity and
Practicability.
Quantum screening: sub-step 1-3 is oriented according to quantum search algorithm and is determined lead compound；If can not determine, root
Random combine is carried out according to quantum random number, obtains one group of compound.
Preferably, quantum random number uses the quantum random number generator unrelated with device, wherein uses enough times weight
Multiple experiment obtains a kind of probability behavior, and analyzes the property of probability behavior, provides corresponding generating random number efficiency accordingly, is formed
Complete free stochastic source.
Present method be advantageous in that be possible to construct the lead compound for the completely new type structure for being different from tradition screening,
It is limited in that the designed molecule of quantum screening may be difficult to realize using traditional chemical synthesis, it may be considered that optimization meter
Calculation machine algorithm carries out perfect.Preferably, quantum screening range can be limited in specified binding site or lead compound data
Library carries out, i.e., is screened using traditional molecular docking technology incorporating quantum, matches the small of receptor combination pocket and lead compound
Molecule three-dimensional structure, then using quantum-mechanical energy function or based on training, learning function to this molecular docking
Performance is evaluated, to select to evaluate highest one in conjunction with receptor in conjunction with pocket group compound.
It, can be in microorganism in the activity of some target enzymes of great expression using gene recombination technology and quantum screening technique
The heart, receptor or subunit of receptor etc., meet the Large-scale Screening in new drug development to sample；Further, it can determine
Not very clear drug effect target position in the past is not the target position that classical screening technique can not obtain.
Step 2, activity rating and quantum group intelligent optimization:
Sub-step 2-1, establishes training set and test set: carrying out to size, the consistent compound structure three-dimensional figure of brightness
Black and whiteization and inverse are handled, and are described with quantum state wave function, wherein a part of picture is as training set, another part picture
As test set.
Quantum state wave function can be at | 0 > or | one of 1 > state can also be in | 0 > or | in any superposition state of 1 > state.
Therefore, one n quantum memories have up to 2nA coherent superposition state | φ >, up to 2n number can be indicated simultaneously.
Quantum state wave function is available as under type describes ground state | φ > and superposition state | φi>:
During quantum group intelligent optimization, Screening Samples are generally divided into independent three parts, it may be assumed that training set (train
Set), verifying collection (validation set) and test set (test set).Training set is tested for estimating lead compound model
Card collection is for verification algorithm structure or the parameter of lead compound model complexity, and test set is then used to detect final choosing
The function and performance for the optimal model compounds selected.Preferably, three parts are all randomly selected from Screening Samples, typical to divide
Using the 50% of the total sample of training set Zhan, and verifies collection and test set and respectively account for 25%.Further, multiple groups quantum group can be parallel
It calculates, generates different training sets (train set), verifying collection (validation set) and test set (test set).
Further, training set and test set can observe two or two by 3-D view in molecular simulation environment
The docking situation of a above molecular model, including its be how by the matching of geometry, chemical environment and energy to
Form best combination.Further, training set and test set need to obtain and observe target organisms macromolecular and small molecule
The three-dimensional structure information of object is closed, this depends on the three-dimensional structure database for the lead compound established in step 1；Then, it measures
Subgroup can intelligently dock the molecule in library with target molecules one by one, this process is passed through by a large amount of quantum group
Constantly training and study are completed, small molecule compound continued to optimize in trained and learning process where position orientation and
The dihedral angle conformation of intramolecule flexible bond, and the best conformation of constantly search small molecule compound and target macromolecule effect,
It calculates the interaction between different molecular and combines energy；Theoretically, as long as it is more with sufficiently large molecule in compound database
Sample by constantly training and learns that ideal molecule integrated structure may be hunted out from library.
Sub-step 2-2, quantum group training: establishing quantum group intelligent optimization model and training, learning algorithm, and training,
It is completed after training and saving training after being less than specified error in learning process with the error step-up error function of desired value
Data.
Preferably, quantum group intelligent optimization model is used based on the quanta particle group model for tangling operation, so that population
Movement closer to principle of quantum mechanics, further, multiple groups quantum group being capable of parallel computation.Enable ai≤xi≤bi, i=1,2,
L, n；N is variables number；[ai,bi] it is variable xiRange.In quantum group intelligent optimization model, the general of quantum bit can be used
Rate amplitude is encoded:
Wherein, θijFor the random number between (0,2 π).Each quanta particle is accounted in entire search space there are two position, not right
Answer quantum state | 0 > and | 1 > two probability amplitudes:
Pic=(cos (θi1), cos (θi2), L cos (θin))
Pis=(sin (θi1),sin(θi2), L sin (θin))
In quantum group intelligent optimization model, it is empty to pass through solution in every one-dimensional equal [- 1,1] for quantum particle swarm search space
Between convert after, the quality of quanta particle current location can be calculated.Particle pjI-th of quantum bit can mark as αi j, βi j]T,
Then solution space variable are as follows: [αi j, βi j]T.Respectively correspond quantum state | 0 > and | 1 > two probability amplitudes can rewrite are as follows:
Corresponding quanta particle position are as follows:
Remember quanta particle piThe optimal location that current search arrives are as follows:
XiI=(cos (θiI1),cos(θiI2),L cos(θiIn))
The optimal location that entire quantum population searches at present:
Xg=(cos (θg1),cos(θg2),L cos(θgn))
Quantum particle swarm state updates rule description are as follows:
(1) particle piThe update of quantum bit argument increment
△θij(t+1)=w △ θij(t)+c1r1(△θl)+c2r2(△θg)
(2) particle piThe update of quantum bit probability amplitude
Wherein, i=1,2, L m；J=1,2, L, n.The update operation of particle position can be using quantum U realization.
If meeting iteration termination condition, algorithm is terminated, and otherwise returns to update population state again.Further, multiple groups
Quantum group can parallel computation, to obtain multiple groups optimum results.
Quantum group training technique is the core link for realizing intelligent optimization, covers the core of Computer-Aided Drug Design
Functional Design, the design including combinatorial chemical library, the design of three-dimensional structure chemistry relational database, molecular structure cluster point in library
Analysis, the quick predict of compound pharmacological properties, series compound three-dimensional quantitative structure activity relationship, the building of pharmacophore and drug
The simulation of the precision computer of molecule and acceptor interaction.These training purposes be then to complete from one comprising hundreds of thousands,
Height is picked out in even millions of compound libraries represents molecular diversity and all possible bioactive molecule of drug similitude,
And biology test is carried out as candidate lead compound, to reduce new drug development time and cost.
Sub-step 2-3 calculates test set accuracy: if meeting the requirements, can be judged by this activity rating model unknown
Compound activity carries out biological experiment afterwards；It is such as undesirable, then expand search range, returns to previous step.
Preferably, activity rating model is assessed using multiple target, including bioactivity, pharmacological activity, biochemical reaction
Required temperature, reaction conversion percentage, product stablize time, half-life period etc. when time, reaction conversion.Equipped with n activity
Evaluation goal, they are general independent mutually, and activity rating model is represented by multiple target valuation functions:
F (x)=[f1(x),f2(x),...,fn(x)]T
It meets following constraints:
gi..., (x) >=0, i=1,2 n
Further, multiple groups quantum group can parallel computation activity rating model, thus obtain multiple groups candidate as a result, simultaneously from
The optimal lead compound combination of row selection activity.
Step 3, drug effect optimization and toxicological activity are eliminated:
Sub-step 3-1, drug effect optimization: establishing quantum pharmacodynamic assessment function and assess drug effect, and can be in regulation
It is interior to search the optimal lead compound combination of drug effect.
Preferably, quantum pharmacodynamic assessment function is assessed using multiple target, including drug indication, drug usage and dosage,
Required temperature, drug absorption percentage, drug product stablize time, drug when drug response time, drug response conversion
Half-life period, excretion of drug approach and speed, adverse drug reaction and taboo, pharmacokinetic parameter etc..Equipped with n pharmacodynamic assessment
Target, they are general independent mutually, and activity rating model is represented by multiple target valuation functions:
F'(x)=[f1'(x),f2'(x),...,fn'(x)]T
It meets following constraints:
gi' (x) >=0, i=1,2 ..., n
Further, quantum pharmacodynamic assessment function is described using quantum state wave function:
| f'(x) >=[| f1'(x)>,|f2'(x)>,...,|fn'(x)>]T
It meets following constraints:
|gi' (x) > >=| 0 >, i=1,2 ..., n
By the way that the synthesis compound that combinatorial chemistry and compound combination library combinatorial chemistry obtain needs to carry out drug effect, toxicity is commented
Estimate and optimize, both the drug effect including some basic small molecules (such as amino acid, nucleotide, monosaccharide) and toxicity assessment, were also wrapped
It includes and constructs different compound combination progress drug effect and toxicity assessment to the chemistry or biosynthesis program of step 2, it is therefore an objective to
It obtains drug effect scoring highest, the diversity compound that toxicity scores minimum, establishes candidate medical compounds library.In conjunction with the later period
Zoopery and human experimentation further screened, so as to drug effect optimization and toxicity optimization meet actual animal or human body
Situation, at the same in more new database data so as to guide new drug development and lead compound from now on discovery.Preferably, it designs
Biochip or synthesis pearl etc. solid phase carrier materials surface carry out fabricated in situ, In situ Screening using linkage function, and it is excellent in
Excellent realization drug effect is selected to optimize.
Further, multiple groups quantum group can parallel computation quantum pharmacodynamic assessment function, thus obtain multiple groups candidate as a result,
And the voluntarily optimal lead compound combination of selection drug effect.
Sub-step 3-2, toxicological activity are eliminated: being collected the compound with toxicological activity, established the assessment of quantum toxicological activity
Function assesses toxicological activity；Further, the elder generation that drug effect is best, toxicological activity is minimum can be searched at the appointed time
Lead compound combination.
Preferably, quantum toxicological activity valuation functions are assessed using multiple target, including drug usage and dosage, drug response
Time, drug drug interaction, adverse drug reaction and taboo, overdose risk, pregnant drug toxicity, children poison
Property, the excretion of old man's medicine toxicity, toxicity and neutralization, pharmacokinetic parameter etc..Target is assessed equipped with n toxicological activity, they
General independent mutually, activity rating model is represented by multiple target valuation functions:
F " (x)=[f1"(x),f2"(x),...,fn"(x)]T
It meets following constraints:
gi" (x) >=0, i=1,2 ..., n
Further, quantum pharmacodynamic assessment function is described using quantum state wave function:
| f " (x) >=[| f1"(x)>,|f2"(x)>,...,|fn"(x)>]T
It meets following constraints:
|gi" (x) > >=| 0 >, i=1,2 ..., n
Further, multiple groups quantum group can parallel computation quantum toxicological activity valuation functions, to obtain multiple groups candidate
As a result, the simultaneously voluntarily minimum lead compound combination of selection toxicological activity.
Step 4, zoopery and clinical trial:
Sub-step 4-1 carries out zoopery: drug effect and toxicological activity in order to verify lead compound, it is desirable to provide dynamic
Fundamental required for object experimental study, including experimental animal, experimental facilities, information and reagent.They can be regarded as
Fundamental in Life Science Experiment research, may be simply referred to as AEIR element.Preferably, the higher instrument and equipment of service precision,
Chemical reagent and information system, to provide accurately data supporting for quantum group intelligent optimization, and the number used that timely updates
According to library；Further, the higher zoopery of precision, and it is more identical with quantum screening and evaluation data in abovementioned steps, more can
The use of experiment number and experimental animal is reduced, to reduce new drug development cost and research and development time.
Sub-step 4-2 carries out clinical trial: need to select volunteer to carry out the system experimentation research of new drug, with verifying or
Drug effect, toxic side effect, adverse reaction, the absorption of drug, distribution, metabolism and the discharge process of experimental drug are disclosed, it is final to determine
The efficacy and safety of researched and developed drug.Further, clinical trial is generally divided into the clinical trial of I, II, III, IV phase and EAP
The data of clinical trial, each issue of experiment upload to database, and with the computation model in correction or more new database, mould is continuously improved
The accuracy and safety of type.The clinical trial of I phase provides foundation to formulate dosage regimen, including preliminary clinical pharmacology, people
The experiment of body safety evaluatio and pharmacokinetic studies；Further, tolerance test understands experimental drug with preliminary for testing
Object is to the safety conditions of human body and human tolerance and adverse reaction；Further, pharmacokinetic studies are for understanding people
Body is to the disposal process of experimental drug, absorption, distribution, metabolism including experimental drug, situations such as eliminating.The clinical trial of II phase is used
In therapeutic effect preliminary assessment, therapeutic effect and safety including the drug researched and developed to target patient, are to determine to medicament
Amount provides data supporting；Preferably, clinical trial is compareed using random blind, it is parallel needs to be arranged control group progress double blind random
Control experiment.The clinical trial of III phase is for confirming therapeutic effect, further treatment of the researched and developed drug of verifying to target patient
Effect, safety, interests and risk provide experimental basis for formal drug legislation application and examination；Preferably, using random
Blind control experiment carries out application study after new drug listing for applicant, investigates researched and developed drug and environment is being widely used
Under drug effect, toxicological activity, general population or the special population interests and risk that use, and dosage is improved.IV
Clinical trial phase is for application study after new drug listing, the main curative effect of medication investigated under the conditions of being widely used and bad anti-
It answers, assesses general population or use interests and risk in special population, and improve dosage.EAP clinical trial is not for
It is suitble to participate in the patient or volunteer of control experiment, is capable of providing the new drug in clinical trial under given conditions and controls
It treats, also provides data supporting and optimization for the research and development of new drug.
The data of clinical trial can collect in database, and update lead compound data, illness data, human body or
Organism response data, adjusting training collection (train set), verifying collection (validation set) and test set (test set)
Parameter, and pharmacodynamic assessment function and toxicological activity valuation functions are improved, to provide more accurate data branch for drug effect optimization
It holds, and improves pharmaceutical synthesis efficiency.
The above embodiments are only the preferred technical solution of the present invention, and are not construed as limitation of the invention, this hair
Bright protection scope should be with the technical solution of claim record, technical characteristic in the technical solution recorded including claim
Equivalents are protection scope.Equivalent replacement i.e. within this range is improved, also within protection scope of the present invention.
Claims (8)
1. lead compound discovery and synthetic method based on quantum group intelligent optimization, it is characterised in that the following steps are included:
Step 1, the new lead compound of combined prediction:
Sub-step 1-1, it is initial to model: to use the physiological activity of main compound in data-base recording and analysis various kinds of drug ingredient
The structure of structure and its corresponding pharmacological activity and target establishes its structure-activity relationship mould after the description of quantum state wave function
Type；
Target validation: sub-step 1-2 is confirmed by structure of the computer system to target, is existed using quantum search algorithm
It attempts to search target similar with its in database, determines that lead compound is prepared to orient；
Quantum screening: sub-step 1-3 is oriented according to quantum search algorithm and is determined lead compound；If can not determine, according to amount
Sub- random number carries out random combine, obtains one group of compound；
Step 2, activity rating and quantum group intelligent optimization:
Sub-step 2-1, establishes training set and test set: carrying out black and white to size, the consistent compound structure three-dimensional figure of brightness
Change and is handled with inverse；By compound activity by picture classification, the corresponding digital label of every one kind picture affix, and use quantum state
Wave function description；Wherein, a part of picture is as training set, and another part picture is as test set；
Quantum group training: sub-step 2-2 establishes quantum group intelligent optimization model and training, learning algorithm, and in training, study
It completes training after the value of error function is less than specified error with the error step-up error function of desired value in the process and protects
Deposit data after training；
Sub-step 2-3 calculates test set accuracy: if meeting the requirements, can judge unknown chemical combination by this activity rating model
Object activity, carries out biological experiment afterwards；It is such as undesirable, then expand search range, returns to previous step；
Step 3, drug effect optimization and toxicological activity are eliminated:
Sub-step 3-1, drug effect optimization: the quantum pharmacodynamic assessment function for establishing multidimensional assesses drug effect, including bioactivity
And pharmacological activity；Underproof lead compound is evaluated to bioactivity or pharmacological activity, after its data obtained is analyzed,
It is corrected and reconfigures rear return step 2；By the parallel optimization of multiple groups quantum group, the biology for improving lead compound is living
Property and pharmacological activity take highest one group of drug effect optimal value if there is multiple groups evaluating drug effect to meet scheduled value；
Sub-step 3-2, toxicological activity are eliminated: being collected the compound with toxicological activity, analyzed its structure, it is living to establish related toxicity
The database of the compound structure of property；Quantum toxicological activity valuation functions are established to assess toxicological activity；To toxicological activity
Underproof lead compound is evaluated, after its data obtained is analyzed, is corrected and reconfigures rear return step 2；
By the parallel computation of multiple groups quantum group, it can be found that the association between a variety of possible false positives, and different false positives, from
And effectively reduce false positive；
Step 4, zoopery and clinical trial:
Sub-step 4-1 carries out zoopery: if obvious adverse reaction occurs in animal after reagent, updating data described in step 1
Library, and adjusting training collection and test set re-start quantum intelligent optimization, i.e., the content of each constituent in change compound,
Re-start step 2；If animal does not occur obvious adverse reaction after reagent, one group of animal is changed, zoopery is continued, until
Meet after the zoopery of specified quantity without obvious adverse reaction, is then transferred to next stage；
Sub-step 4-2 carries out clinical trial: select aspiration crowd to test, if the lead compound toxicological activity is larger, or
Toxicological activity is smaller but larger to Health Impact, then updates database described in step 1, and adjusting training collection and test set,
Quantum intelligent optimization is re-started, i.e., the content of each constituent, re-starts step 2 in change compound；If reagent descendant
Body does not occur obvious adverse reaction, changes one group of volunteer, continues clinical trial, until meeting the human experimentation of specified quantity
Afterwards without obvious adverse reaction.
2. the lead compound discovery based on quantum group intelligent optimization and synthetic method, feature exist according to claim 1
In:
Structure-activity relationship described in step 1 is to obtain the chemical structure database of main compound in drug ingedient, and make database
In compound structure and its pharmacological activity and target construction correspond；The orientation determines that lead compound refers to true
After determining target construction, by analyzing clinical symptoms, fitting is oriented to compound corresponding to corresponding pharmacological activity.
3. the lead compound discovery based on quantum group intelligent optimization and synthetic method, feature exist according to claim 1
In:
Database in step 1 includes the data of lead compound, pathological characteristics data, the drug data of illness.
4. the lead compound discovery based on quantum group intelligent optimization and synthetic method, feature exist according to claim 1
In:
It is to convert tri-dimensional picture for the structural formula of compound described in step 2；The test set accuracy refers to, with activity
The test set activity that canonical function evaluation test collection obtains calculates accuracy compared with real property.
5. the lead compound discovery based on quantum group intelligent optimization and synthetic method, feature exist according to claim 1
In:
In sub-step 2-1, training set and test set can observe two or two by 3-D view in molecular simulation environment
The docking situation of above molecular model is how to pass through the matching of geometry, chemical environment and energy to shape including it
At best combination；
Training set and test set need to obtain and observe the three-dimensional structure information of target organisms macromolecular and small molecule compound, this
Three-dimensional structure database dependent on the lead compound established in step 1；Then, quantum colony intelligence can be by point in library
Son is docked with target molecules one by one, this process is to pass through constantly training and in three-dimensional space by a large amount of quantum group
Completion is practised, by the intelligence learning and training of multiple quantum groups, small molecule compound is continuous in trained and learning process
The dihedral angle conformation of position orientation and intramolecule flexible bond where optimization, and constantly search for small molecule compound and target
The best three-dimensional conformation of macromolecular effect calculates the interaction between different molecular and combines energy.
6. the lead compound discovery based on quantum group intelligent optimization and synthetic method, feature exist according to claim 1
In:
Pharmacological activity described in step 3 refers to the effect that drug is directly played in molecular level or respective horizontal.
7. the lead compound discovery based on quantum group intelligent optimization and synthetic method, feature exist according to claim 1
In:
Before animal reagent described in step 4, the animal that one group of life habit, health status, age need to be selected to be not much different, respectively
It puts signs on, carries out adaptation training to allow it to be familiar with environment.
8. the lead compound discovery based on quantum group intelligent optimization and synthetic method, feature exist according to claim 1
In:
Clinical trial is generally divided into the clinical trial of I, II, III, IV phase and EAP clinical trial, and the data of each issue of experiment upload to number
The accuracy and safety of model are continuously improved with the computation model in correction or more new database according to library；
The clinical trial of I phase provides foundation to formulate dosage regimen, including preliminary clinical pharmacology, human safety evaluation experimental
And pharmacokinetic studies；Tolerance test is used to test and tentatively understands experimental drug to the safety conditions and human body of human body
Tolerance and adverse reaction；Pharmacokinetic studies are for understanding human body to the disposal process of experimental drug, including experimental drug
Absorption, distribution, metabolism, eliminate situations such as；
The clinical trial of II phase is used for therapeutic effect preliminary assessment, the therapeutic effect and peace including the drug researched and developed to target patient
Quan Xing, to determine that dosage provides data supporting；
The clinical trial of III phase for confirming therapeutic effect, further the researched and developed drug of verifying to the therapeutic effect of target patient,
Safety, interests and risk provide experimental basis for formal drug legislation application and examination；
IV clinical trial phase is for application study after new drug listing, the main curative effect of medication investigated under the conditions of being widely used and not
Good reaction assesses general population or use interests and risk in special population, and improves dosage；
EAP clinical trial is capable of providing place for being not suitable for participating in the patient or volunteer of control experiment under given conditions
In the Drugs in Therapy of clinical trial, data supporting and optimization also are provided for the research and development of new drug.
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