WO2010119289A2 - A method and system of estimating the cross-sectional area of a molecule for use in the prediction of ion mobility - Google Patents

A method and system of estimating the cross-sectional area of a molecule for use in the prediction of ion mobility Download PDF

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WO2010119289A2
WO2010119289A2 PCT/GB2010/050625 GB2010050625W WO2010119289A2 WO 2010119289 A2 WO2010119289 A2 WO 2010119289A2 GB 2010050625 W GB2010050625 W GB 2010050625W WO 2010119289 A2 WO2010119289 A2 WO 2010119289A2
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molecule
sectional area
cross sectional
differences
estimating
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PCT/GB2010/050625
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French (fr)
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WO2010119289A3 (en
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Keith George Richardson
Iain David Grant Campuzano
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Micromass Uk Limited
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Priority claimed from GB0906467A external-priority patent/GB0906467D0/en
Priority claimed from GB0906466A external-priority patent/GB0906466D0/en
Application filed by Micromass Uk Limited filed Critical Micromass Uk Limited
Priority to EP10722173.1A priority Critical patent/EP2419850B1/en
Priority to US13/264,039 priority patent/US9053290B2/en
Priority to JP2012505240A priority patent/JP5697659B2/en
Publication of WO2010119289A2 publication Critical patent/WO2010119289A2/en
Publication of WO2010119289A3 publication Critical patent/WO2010119289A3/en
Priority to US14/733,191 priority patent/US20150379242A1/en

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    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16C—COMPUTATIONAL CHEMISTRY; CHEMOINFORMATICS; COMPUTATIONAL MATERIALS SCIENCE
    • G16C10/00—Computational theoretical chemistry, i.e. ICT specially adapted for theoretical aspects of quantum chemistry, molecular mechanics, molecular dynamics or the like
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/62—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating the ionisation of gases, e.g. aerosols; by investigating electric discharges, e.g. emission of cathode
    • G01N27/622—Ion mobility spectrometry
    • G01N27/623—Ion mobility spectrometry combined with mass spectrometry
    • G—PHYSICS
    • G06—COMPUTING; CALCULATING OR COUNTING
    • G06F—ELECTRIC DIGITAL DATA PROCESSING
    • G06F17/00—Digital computing or data processing equipment or methods, specially adapted for specific functions
    • G06F17/10—Complex mathematical operations
    • G06F17/18—Complex mathematical operations for evaluating statistical data, e.g. average values, frequency distributions, probability functions, regression analysis
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
    • G16B15/00—ICT specially adapted for analysing two-dimensional or three-dimensional molecular structures, e.g. structural or functional relations or structure alignment
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16C—COMPUTATIONAL CHEMISTRY; CHEMOINFORMATICS; COMPUTATIONAL MATERIALS SCIENCE
    • G16C20/00—Chemoinformatics, i.e. ICT specially adapted for the handling of physicochemical or structural data of chemical particles, elements, compounds or mixtures
    • G16C20/30—Prediction of properties of chemical compounds, compositions or mixtures

Definitions

  • This invention relates to a method of estimating the cross-sectional area of a molecule for use in the prediction of ion mobility for a wide range of molecular species.
  • Ion mobility has the potential to separate isomeric species based on differences in gas phase collision cross-sections ( ⁇ ) and can provide valuable information on ionic conformation through comparisons with theoretical models.
  • ⁇ gas phase collision cross-sections
  • the molecular cross-section is approximated as the rotationally averaged area of the "shadow” cast by the molecule.
  • shadow is used to refer to the projection of a molecule, atom or ellipsoid onto any plane. The plane employed remains fixed throughout the calculation.
  • the projection approximation (PA) has been shown to be a useful method of calculating the cross-section of a molecule to be used in the prediction of ion mobility. It is not possible to calculate the projection approximation cross-section directly, but it is possible to obtain numerical approximations using Monte Carlo techniques. Monte Carlo methods are a class of computational algorithms that rely on repeated random sampling to compute their results and often are used when it is infeasible or impossible to compute an exact result with a deterministic algorithm.
  • n max it is difficult if not impossible to know how many orientations (step 2) are sufficient, and secondly there are situations in which convergence is slow so that naive convergence tests can be misleading.
  • the above algorithm can be improved to allow more than one selection per orientation giving a modified algorithm.
  • One aspect or feature of the invention provides a method of estimating the cross sectional area of a molecule, e.g. for determining the characteristics of predetermined or sample molecules, the method the steps of:
  • the present invention involves a further improvement of the previously known Mobcal algorithm to produce a more efficient implementation of the Mobcal type calculation to provide improved confidence in convergence of the rotationally averaged cross section, obtained to a user-specified accuracy.
  • Another aspect of the present invention provides a method of estimating the cross sectional area of a molecule, e.g. for determining the characteristics of predetermined or sample molecules, the method comprising the steps of:- A) Predicting the geometric structure of the molecule of interest;
  • steps C) to H) for at least N iterations and/or until M independent calculations of the averaged cross sectional area agree within a predetermined range R for X iterations.
  • the above method will be referred to hereinafter as the 'ellipsoidal rejection sampling' method.
  • the value of N may be between 0 and 50, for example between 0 and 30 or between 20 and 50 or between 10 and 40.
  • the value of M may be between 1 and 20, for example between 1 and 10 or 1 and 5 or alternatively between 10 and 20 or 15 and 20 or alternatively between 5 and 15.
  • the value of R may be between 0.1 and 20%, for example 1 and 20% or alternatively between 0.1 and 1 %. [Note that R can be a percentage or an absolute value]
  • the value of X may be between 1 and 20, for example between 1 and 10 or 1 and 5 or alternatively between 10 and 20 or 15 and 20 or alternatively between 5 and 15 .
  • Another aspect of the invention provides a method of determining characteristics of predetermined molecules (e.g. small molecules and proteins, peptides, oligoneucleotides and glycans) comprising the use of a combined ion mobility - mass spectrometry (IM-MS) technique for experimentally determining a range of molecular structures and comparing values that range with those derived by an estimating method according to any of the three immediately preceding paragraphs so as to correlate the differences in the molecule structures with differences in selected predetermined activity of those molecules.
  • IM-MS combined ion mobility - mass spectrometry
  • the method may correlate the differences in the molecular structures with differences in anti-cancer activity of predetermined anti-cancer drugs.
  • the anti cancer drugs are organometallic based drugs.
  • the organometallic drugs are isomeric Ru-based.
  • the IM-MS technique may include the use of travelling wave (T-wave) mobility separation.
  • T-wave travelling wave
  • the method of the present invention gives gas phase interaction radii determination and cross-section algorithm computation to provide separation and characterisation of structurally related isomers by ion mobility.
  • a further aspect of the invention provides a system for determining characteristics of predetermined molecules, the system comprising an ion mobility cell, a mass spectrometer and a processor programmed or configured to determine experimentally a range of molecular structures and compare values of that range with those derived by an estimating a method described above so as to correlate the differences in the molecular structures with differences in selected predetermined activity of those molecules.
  • a yet further aspect of the invention provides a computer program element comprising computer readable program code means for causing a processor to execute a procedure to implement the method described above.
  • the computer program element may be embodied on a computer readable medium.
  • a yet further aspect of the invention provides a computer readable medium having a program stored thereon, where the program is to make a computer execute a procedure to implement the method as described above.
  • Figure 1 is a flow chart illustrating an algorithm according to an embodiment of the present invention.
  • this ellipsoidal rejection sampling algorithm will converge to the desired result faster than that of the prior art algorithms referred to.
  • the IMS device of a mass spectrometer was calibrated using a haemoglobin peptide mixture and other compounds of known collisional cross section, such as polyglycine (http://www.indiana.edu/ ⁇ clemmer/Research/research.htm); a calibration coefficient was then derived.
  • the ion mobility of each small molecule was measured and therefore the experimental collision cross section (CCS) determined.
  • the radius of each of the atoms, specific to an individual small molecule were then "tuned" within the CCS algorithm such that the output of the CCS algorithm closely matched the experimentally derived CCS values for each of the small molecules analysed.
  • An optimal interaction radius value (A 2 ) for C, H, O, S, Cl, F, N & Ru were thus derived.
  • the small molecules used to optimise the CCS algorithm were: C60, C70, pyrene,camphene,phenanthrene, triphenylene, naphthalene, ampicillin, spermine, lorazepam, caffeine, reserpine, raffinose, nifedipine, nimodipine, dexamethazone, diphenylhydramine, metoprolol, glutathione, cysteine, apomorphine, erythromycin, oxytetracyclin, verapamil, salbutamol, acetylsalicylic acid, the 20 naturally occurring common amino acids, angiotensin II, oxytocin, testosterone, ibuprofen, beta-cyclodextrin and the ruthenium containing compounds ru-ortho (and associated HCI neutral loss species), ru-meta (and associated HCI neutral loss species), ru-para (and associated HCI neutral loss species).
  • Certain organometallic drugs are used in the fight against cancer.
  • the platinum-based drug, cisplatin [c/s-diamminedichloridoplatinum(ll)], for example, falls into this category and is one of the leading drugs used in the fight against cancer.
  • DNA is a potential target for many metal-based anticancer drugs and distortions of DNA structure often correlate with anticancer activity.
  • Other metal-based anticancer drugs, such as those based on ruthenium are being developed as alternative treatments to combat cancer. In particular, the aim is to widen the spectrum of anticancer activity, reduce unwanted side effects, and avoid cross-resistance with cisplatin and related drugs.
  • the six isomeric compounds showed well defined arrival time distributions allowing experimental collision cross-sections to be calculated and compared to theoretical values. Excellent agreement was observed between all experimentally- and theoretically-derived results.
  • the difference in shape of the elongated terphenyl arene compared to the more compact shapes is likely to make an important contribution to the significantly higher anti-cancer activity of the elongated structure.
  • the invention reports inferred gas phase interaction radii for H, C, and the previously uninvestigated O, S, Cl, F, N, Fe, Pt and Ru. Furthermore, the method of the present invention demonstrates for the first time that isomeric ruthenium (II) terphenyl anticancer complexes, whose CCSs differ by less than 9. ⁇ A 2 , can be separated and characterised by travelling wave ion mobility.
  • II isomeric ruthenium
  • a suitable ellipsiodal boundary is a sphere of radius R, and the projections of this are always a circle of radius R. In this case acceptance rate is roughly 0.97.

Abstract

A method of estimating the cross-sectional area of a molecule for use in the prediction of ion mobility gives gas phase interaction radii determination and cross-sectional algorithm computation to provide separation and characterisation of structurally related isomers. More specifically, the invention provides a method of correlating the differences in the molecular structures with differences in anti-cancer activity of pre-determined anti-cancer drugs by utilizing a new algorithm for estimating the cross-sectional area of the molecules of such drugs.

Description

A METHOD AND SYSTEM OF ESTIMATING THE CROSS-SECTIONAL AREA OF A MOLECULE FOR USE IN THE PREDICTION OF ION MOBILITY
This invention relates to a method of estimating the cross-sectional area of a molecule for use in the prediction of ion mobility for a wide range of molecular species.
Ion mobility has the potential to separate isomeric species based on differences in gas phase collision cross-sections (Ω) and can provide valuable information on ionic conformation through comparisons with theoretical models. However, to relate the ion mobility derived collision cross-section of a molecule to its structure accurately, it is necessary to obtain prior knowledge of the gas phase radii of the constituent atoms.
The molecular cross-section is approximated as the rotationally averaged area of the "shadow" cast by the molecule. The term "shadow" is used to refer to the projection of a molecule, atom or ellipsoid onto any plane. The plane employed remains fixed throughout the calculation.
The projection approximation (PA) has been shown to be a useful method of calculating the cross-section of a molecule to be used in the prediction of ion mobility. It is not possible to calculate the projection approximation cross-section directly, but it is possible to obtain numerical approximations using Monte Carlo techniques. Monte Carlo methods are a class of computational algorithms that rely on repeated random sampling to compute their results and often are used when it is infeasible or impossible to compute an exact result with a deterministic algorithm.
It is known to obtain prior knowledge of the gas phase radii of the constituent atoms of a molecule by means of an algorithm known as MobCal (httpj/MwwJ^ which includes the following steps:-
(1 ) Set A = O, n = O, and
(2) select a random orientation of the molecule
(3) select a rectangle bounding the molecular shadow and calculate the area of the rectangle = area Abox,
(4) select a point randomly within the rectangle,
(5) if the point lies within the molecular shadow, then A = A + Abox (6) n = n + 1
(7) if n < nmax GOTO 2
(i.e. select another random orientation of the molecule for the next iteration)
(8) End. Result is A/n
However, there are at least two potential (but related) problems with this approach. First, in the selection of nmax, it is difficult if not impossible to know how many orientations (step 2) are sufficient, and secondly there are situations in which convergence is slow so that naive convergence tests can be misleading.
The above algorithm can be improved to allow more than one selection per orientation giving a modified algorithm.
One aspect or feature of the invention provides a method of estimating the cross sectional area of a molecule, e.g. for determining the characteristics of predetermined or sample molecules, the method the steps of:
(1 ) Set A = O, n = O, and
(2) select a random orientation of the molecule (3) select a rectangle bounding the molecular shadow and calculate the area of the rectangle = area Abox
(4) select K points randomly within the rectangle
(5) for each point that lies in the molecular shadow, A = A + Abox/K
(6) n = n + 1 (7) if n < nmax GOTO 2 (next iteration) (8) End. Result is A/n
The above method will be referred to hereinafter as the 'rectangle' method.
However, the present invention involves a further improvement of the previously known Mobcal algorithm to produce a more efficient implementation of the Mobcal type calculation to provide improved confidence in convergence of the rotationally averaged cross section, obtained to a user-specified accuracy.
Another aspect of the present invention provides a method of estimating the cross sectional area of a molecule, e.g. for determining the characteristics of predetermined or sample molecules, the method comprising the steps of:- A) Predicting the geometric structure of the molecule of interest;
B) Assign an ellipsoidal boundary containing the whole of said molecule;
C) Randomly selecting an orientation of the assigned ellipsoidal boundary together with its contained molecule;
D) Calculate a value for the area contained by the elliptical boundary formed by the projection of the ellipsoid at said randomly selected orientation;
E) Randomly selecting a position within the elliptical boundary;
F) Identify whether the position within the elliptical boundary also falls within the cross sectional area of an atom within the molecule of interest;
G) If said F) criterion is met, set said cross sectional area of the molecule at said orientation to the cross sectional area contained by the elliptical boundary calculated in D, if said F criteria is not met, set said cross sectional area of the molecule to 0; H) Calculate an averaged cross sectional area over all said randomly selected orientations;
I) iterate steps C) to H) for at least N iterations and/or until M independent calculations of the averaged cross sectional area agree within a predetermined range R for X iterations.
The above method will be referred to hereinafter as the 'ellipsoidal rejection sampling' method.
According to a feature of the invention the value of N may be between 0 and 50, for example between 0 and 30 or between 20 and 50 or between 10 and 40.
According to another feature of the invention the value of M may be between 1 and 20, for example between 1 and 10 or 1 and 5 or alternatively between 10 and 20 or 15 and 20 or alternatively between 5 and 15.
According to another feature of the invention the value of R may be between 0.1 and 20%, for example 1 and 20% or alternatively between 0.1 and 1 %. [Note that R can be a percentage or an absolute value]
According to another feature of the invention the value of X may be between 1 and 20, for example between 1 and 10 or 1 and 5 or alternatively between 10 and 20 or 15 and 20 or alternatively between 5 and 15 . Another aspect of the invention provides a method of determining characteristics of predetermined molecules (e.g. small molecules and proteins, peptides, oligoneucleotides and glycans) comprising the use of a combined ion mobility - mass spectrometry (IM-MS) technique for experimentally determining a range of molecular structures and comparing values that range with those derived by an estimating method according to any of the three immediately preceding paragraphs so as to correlate the differences in the molecule structures with differences in selected predetermined activity of those molecules.
According to a feature of this aspect of the invention, the method may correlate the differences in the molecular structures with differences in anti-cancer activity of predetermined anti-cancer drugs. Preferably, the anti cancer drugs are organometallic based drugs. Preferably, the organometallic drugs are isomeric Ru-based.
According to another feature of this aspect of the invention, the IM-MS technique may include the use of travelling wave (T-wave) mobility separation.
The method of the present invention gives gas phase interaction radii determination and cross-section algorithm computation to provide separation and characterisation of structurally related isomers by ion mobility.
A further aspect of the invention provides a system for determining characteristics of predetermined molecules, the system comprising an ion mobility cell, a mass spectrometer and a processor programmed or configured to determine experimentally a range of molecular structures and compare values of that range with those derived by an estimating a method described above so as to correlate the differences in the molecular structures with differences in selected predetermined activity of those molecules.
A yet further aspect of the invention provides a computer program element comprising computer readable program code means for causing a processor to execute a procedure to implement the method described above.
The computer program element may be embodied on a computer readable medium.
A yet further aspect of the invention provides a computer readable medium having a program stored thereon, where the program is to make a computer execute a procedure to implement the method as described above. An embodiment of the invention will now be described, by way of example only, with reference to the accompanying drawing, wherein:
Figure 1 is a flow chart illustrating an algorithm according to an embodiment of the present invention.
One algorithm of the present invention is as follows:-
A) Predicting the geometric structure of the molecule of interest;
B) Assign an ellipsoidal boundary containing the whole of said molecule;
C) Randomly selecting an orientation of the assigned ellipsoidal boundary together with its contained molecule;
D) Calculate a value for the area contained by the elliptical boundary formed by the projection of the ellipsoid at said randomly selected orientation;
E) Randomly selecting a position within the elliptical boundary;
F) Identify whether the position within the elliptical boundary also falls within the cross sectional area of an atom within the molecule of interest;
G) If said F) criterion is met, set said cross sectional area of the molecule at said orientation to the cross sectional area contained by the elliptical boundary calculated in D, if said F criteria is not met, set said cross sectional area of the molecule to 0; H) Calculate an averaged cross sectional area over all said randomly selected orientations; I) Iterate steps D) to H) for at least N iterations and/or until M independent calculations of the averaged cross sectional area agree within a predetermined range R for X iterations
For many molecules, this ellipsoidal rejection sampling algorithm will converge to the desired result faster than that of the prior art algorithms referred to.
The following termination procedure has been implemented in conjunction with the above algorithm:-
(1 ) Instantiate N projection approximation calculations (henceforth called objects);
(2) perform iterations for each of these objects in turn, keeping running area estimates for each object; (3) terminate when the area estimates for all objects agree with a user specified tolerance (either percentage or absolute), reporting the overall average of these estimates as the result.
The IMS device of a mass spectrometer was calibrated using a haemoglobin peptide mixture and other compounds of known collisional cross section, such as polyglycine (http://www.indiana.edu/~clemmer/Research/research.htm); a calibration coefficient was then derived. The ion mobility of each small molecule was measured and therefore the experimental collision cross section (CCS) determined. The radius of each of the atoms, specific to an individual small molecule were then "tuned" within the CCS algorithm such that the output of the CCS algorithm closely matched the experimentally derived CCS values for each of the small molecules analysed. An optimal interaction radius value (A2) for C, H, O, S, Cl, F, N & Ru were thus derived.
The small molecules used to optimise the CCS algorithm were: C60, C70, pyrene,camphene,phenanthrene, triphenylene, naphthalene, ampicillin, spermine, lorazepam, caffeine, reserpine, raffinose, nifedipine, nimodipine, dexamethazone, diphenylhydramine, metoprolol, glutathione, cysteine, apomorphine, erythromycin, oxytetracyclin, verapamil, salbutamol, acetylsalicylic acid, the 20 naturally occurring common amino acids, angiotensin II, oxytocin, testosterone, ibuprofen, beta-cyclodextrin and the ruthenium containing compounds ru-ortho (and associated HCI neutral loss species), ru-meta (and associated HCI neutral loss species), ru-para (and associated HCI neutral loss species).
Certain organometallic drugs are used in the fight against cancer. The platinum-based drug, cisplatin [c/s-diamminedichloridoplatinum(ll)], for example, falls into this category and is one of the leading drugs used in the fight against cancer. DNA is a potential target for many metal-based anticancer drugs and distortions of DNA structure often correlate with anticancer activity. Other metal-based anticancer drugs, such as those based on ruthenium, are being developed as alternative treatments to combat cancer. In particular, the aim is to widen the spectrum of anticancer activity, reduce unwanted side effects, and avoid cross-resistance with cisplatin and related drugs. Insights into the physical size and shape of these novel Ru-based drugs are important for elucidation of structure-activity relationships and for optimizing key interactions such as intercalation into DNA. Three novel isomeric Ru-based anticancer drugs have been explained using a combined ion mobility and mass spectrometry (IM-MS) approach together with an estimating method according to the invention. As a stand-alone technique, MS cannot separate isomeric species or provide bulk structural conformational information. However, IM has the ability to rapidly separate isomeric species (on the MS acquisition timescale) based on differences in their collision cross sections (CCS; physical size and shape) in the gas phase, thus providing specific information on ionic configuration. The combination of IM with MS provides an extremely powerful analytical tool.
To investigate the possible benefits of the IM-MS technique, an instrument that is based around "traveling-wave" (T-wave) mobility separation was used to analyze a mixture of three low-molecular-weight isomeric ruthenium terphenyl anticancer complexes {m/z
427 A based on 102Ru). Individual differences in shape have been studied in an attempt to correlate them with differences in anticancer activity. Molecular modelling was also used to generate a range of possible structures and the theoretical CCSs for these structures were calculated for comparison with experimentally derived T-wave values. Excellent agreement was observed between the experimentally and theoretically derived CCS measurements.
The ion mobility derived gas phase interaction radii in combination with the new CCS algorithm, molecular modelling and ion mobility mass spectrometry for the separation and conformational analysis of three low-molecular-weight isomeric organoruthenium anticancer complexes containing ortho-, meta- or para-terphenyl arene ligands (Mw 427.1 ) and the subsequent isomeric HCI neutral loss species (Mw 391.1 ) has been used in accordance with the invention. The six isomeric compounds showed well defined arrival time distributions allowing experimental collision cross-sections to be calculated and compared to theoretical values. Excellent agreement was observed between all experimentally- and theoretically-derived results. The difference in shape of the elongated terphenyl arene compared to the more compact shapes is likely to make an important contribution to the significantly higher anti-cancer activity of the elongated structure.
In summary, the invention reports inferred gas phase interaction radii for H, C, and the previously uninvestigated O, S, Cl, F, N, Fe, Pt and Ru. Furthermore, the method of the present invention demonstrates for the first time that isomeric ruthenium (II) terphenyl anticancer complexes, whose CCSs differ by less than 9.θA2, can be separated and characterised by travelling wave ion mobility. As an extreme example consider the C60 or "Buckminsterfullerene" molecule which consists of 60 carbon atoms arranged on the surface of a hollow sphere of radius R. Projections of this molecule are roughly circular.
Using a rectangular boundary for each trial orientation, and performing the rotations around the centre of the molecule, the acceptance rate is roughly the area of a circle of radius R divided by the area of a square of radius 2R which is (π R2) / (4 R2) = ττ/4 or 0.785.
A suitable ellipsiodal boundary is a sphere of radius R, and the projections of this are always a circle of radius R. In this case acceptance rate is roughly 0.97.
In a series of 10 trials with ten shots per orientation, the ellipsoidal method converged to the required precision with, on average, five times fewer iterations than the rectangular method.
The table below shows results that were obtained using the Mobcal algorithm as compared with the rectangle and ellipsoidal rejection sampling methods.
Figure imgf000009_0001
It will be appreciated by those skilled in the art that any number of combinations of the aforementioned features and/or those shown in the appended drawing provide clear advantages over the prior art and are therefore within the scope of the invention described herein.

Claims

1. A method of estimating the cross sectional area of molecules comprising the steps of:
A) Predicting the geometric structure of the molecule of interest;
B) Assign an ellipsoidal boundary containing the whole of said molecule;
C) Randomly selecting an orientation of the assigned ellipsoidal boundary together with its contained molecule; D) Calculate a value for the area contained by the elliptical boundary formed by the projection of the ellipsoid at said randomly selected orientation;
E) Randomly selecting a position within the elliptical boundary;
F) Identify whether the position within the elliptical boundary also falls within the cross sectional area of an atom within the molecule of interest; G) If said F) criterion is met, set said cross sectional area of the molecule at said orientation to the cross sectional area contained by the elliptical boundary calculated in D, if said F criteria is not met, set said cross sectional area of the molecule to 0;
H) Calculate an averaged cross sectional area over all said randomly selected orientations;
I) Iterate steps D) to H) for at least N iterations and/or until M independent calculations of the averaged cross sectional area agree within a predetermined range R for X iterations
2. A method according to claim 1 , wherein the value of N is between 1-50.
3. A method according to claim 1 , wherein the value of M is between 1-20.
4. A method according to claim 1 or claim 2, wherein the value of R is between 1 and 20%.
5. A method according to claim 1 , wherein the value of X is between 1 and 20.
6. A method of determining characteristics of predetermined molecules comprising the use of a combined ion mobility-mass spectrometry (IM-MS) technique for experimentally determining a range of molecular structures and comparing values of that range with those derived by an estimating a method according to any of the preceding claims so as to correlate the differences in the molecular structures with differences in selected predetermined activity of those molecules.
7. A method according to claim 7 wherein the method correlates the differences in the molecular structures with differences in anti-cancer activity of predetermined anti-cancer drugs.
8. A method according to claim 8 wherein the anti-cancer drugs are organometallic based drugs.
9. A method according to claim 9 wherein the organometallic drugs are isomeric Ru- based.
10. A method according to any of claims 7 to 10 wherein the IM-MS technique includes the use of travelling wave (T-wave) mobility separation.
1 1. A system for determining characteristics of predetermined molecules, the system comprising an ion mobility cell, a mass spectrometer and a processor programmed or configured to determine experimentally a range of molecular structures and compare values of that range with those derived by an estimating a method according to any one of claims 1 to 5 so as to correlate the differences in the molecular structures with differences in selected predetermined activity of those molecules.
12. System according to claim 1 1 further configured to execute the method of any one of claims 6 to 10.
13. A computer program element comprising computer readable program code means for causing a processor to execute a procedure to implement the method of any one of claims 1 to 10.
14. Computer program element according to claim 13 embodied on a computer readable medium.
15. A computer readable medium having a program stored thereon, where the program is to make a computer execute a procedure to implement the method of any one of claims 1 to 10.
PCT/GB2010/050625 2009-04-05 2010-04-15 A method and system of estimating the cross-sectional area of a molecule for use in the prediction of ion mobility WO2010119289A2 (en)

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EP10722173.1A EP2419850B1 (en) 2009-04-15 2010-04-15 A method and system of estimating the cross-sectional area of a molecule for use in the prediction of ion mobility
US13/264,039 US9053290B2 (en) 2009-04-15 2010-04-15 Method and system of estimating the cross-sectional area of a molecule for use in the prediction of ion mobility
JP2012505240A JP5697659B2 (en) 2009-04-15 2010-04-15 Method and system for estimating molecular cross sections for use in predicting ion mobility
US14/733,191 US20150379242A1 (en) 2009-04-05 2015-06-08 Method and System of Estimating the Cross-Sectional Area of a Molecule For Use in the Prediction of Ion Mobility

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GB0906466A GB0906466D0 (en) 2009-04-15 2009-04-15 Method of estimating cross sectional area of a molecule for use in the prediction of ion mobility
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US9053290B2 (en) 2009-04-15 2015-06-09 Micromass Uk Limited Method and system of estimating the cross-sectional area of a molecule for use in the prediction of ion mobility
WO2011128703A1 (en) 2010-04-15 2011-10-20 Micromass Uk Limited Ion mobility method and apparatus for identifying and/or characterising a sample compound
WO2022017548A3 (en) * 2020-07-21 2022-03-03 宁波大学 Reagent and method for chiral structure analysis of ibuprofen molecules
DE102022112760A1 (en) 2021-06-02 2022-12-08 Bruker Scientific Llc EVALUATION USING PHYSICAL-CHEMICAL PROPERTIES FOR STRUCTURE IDENTIFICATION IN ION SPECTROMETRY

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