Analyzing Molecular Conformations Using the Cambridge Structural Database. Jason Cole Cambridge Crystallographic Data Centre

Transcription

1 Analyzing Molecular Conformations Using the Cambridge Structural Database Jason Cole Cambridge Crystallographic Data Centre 1

2 The Cambridge Structural Database (CSD) 905,284* USOPEZ a natural product intermediate, crystallised as a cyclohexane solvate CSD Growth Adding ~60,000 entries per year; *As of 17-Aug

3 The Cambridge Crystallographic Data Centre About us A not-for-profit, charitable institution, est Self-financing and self-administering since 1989 No investors, no shareholders No national, EU or international grant support Funded entirely by contributions A University of Cambridge Partner Institute, recognized for postgraduate degrees of the University of Cambridge 3

4 Cambridge Structural Database System Molecular geometry The world s repository of small molecule crystal structures Molecular interactions 4

5 Mogul A Knowledge Base of Molecular Geometries keys describe the chemical environment Bruno, I. J.; Cole, J. C.; Kessler, M.; Luo, J.; Motherwell, W. D. S.; Purkis, L. H.; Smith, B. R.; Taylor, R.; Cooper, R. I.; Harris, S. E.; Orpen, A. G. J. Chem. Inf. Com. Sci. 2004, 44, rotamer distributions torsion angles bond lengths bond angles ring geometries 5

6 Classical Use Cases Distribution of the observed relative fractions of the CCC O torsion angle for various R1-substituted benzamides in the CSD. Regression analysis against affinity was used to predict the optimal torsion angle Published in: Pei-Pei Kung et al J. Med. Chem. 2016, 59, DOI: /acs.jmedchem.6b00515 Copyright 2016 American Chemical Society 6

7 Classical Use Cases Selectivity & Potency Published in: Brian S. Safina et al;; ACS Med. Chem. Lett. 2017, 8, DOI: /acsmedchemlett.7b00170 Copyright 2017 American Chemical Society 7

8 Energy and frequency No. of crystal structures DE 6-31G* Crystallographic Torsional Distributions and Calculated Energy Profiles Allen, et al., J. Comp.-Aided Mol. Design, 10, ,1996 8

9 Symmetric molecules Z = 1 Z = 1/2 BARNUE CAGYOY 9

10 Thermal motion & Unresolved Disorder ITUZEE R-factor:

11 Thermal motion: opportunity 11

12 Thermal motion: opportunity Sampling across the full torsional range 12

13 Thermal motion: opportunity 13

14 Thermal motion: opportunity Possible to interpret motion of CF3 groups potential for correlated distributions 14

15 Application Example: The CSD Conformer Generator Mogul molecule (minimise) get rotamer and ring distributions sample and score conformers select diverse subset An input molecule optionally minimized to adjust bond lengths and angles CSD rotamer and ring distributions are incrementally applied Generated conformers are assigned scores based r.freq. (a.prob.) Conformers are monitored to avoid clashes Diverse subset of conformations clustering *Taylor, R.; Cole, J.; Korb, O.; McCabe, P. J. Chem. Inf. Model. 2014, 54 (9),

16 Rotamers R A R D R B X Y R E R C R F Geometry around central bond X-Y could be defined by any of up to 9 torsions Simplify by defining 1 reference torsion Each central bond contributes to 1 rotamer distribution 180 < τ 180 capture asymmetric distributions 16

17 Structural Data Assigned 2nd 1st 3rd Torsion angles selected in probability order Unusual to reduce conformational space 17

18 Score conformers p 2 p 1 Torsional frequencies probability Ring frequencies probability Overall conformer probability (score) p = p 1 p 2 p n In reality work with ln p = ln p ln(p n ) 18

19 First Version Critique Very effective on published test sets But some issues due to Data coverage Ring coverage 19

20 More Relevant Selecting Distributions Geometric CSD Distributions Fine Enough Data? Use distribution No More Data Medium Enough Data? Use distribution No Coarse Enough Data? Use distribution 20

21 Rotamers Existing Version Enough Data means at least 50 observations Robust, but at the expense of coverage For 11,700 structures randomly selected from the ZINC clean drug like set Molecules affected 738(6.3%) Rotamers affected 790(1.2%) 21

22 Improvements: For sparse distributions, use Kernel Density Estimation to fit distribution KDE smoothing accounts for more uncertainty in sparse distributions 15 observations becomes sufficient 22

23 Rotamers New Version Enough Data means at least 15 observations Still Robust, better coverage For 11,700 structures randomly selected from the ZINC clean drug like set Before After Molecules affected 738(6.3%) 0 Rotamers affected 790(1.2%) 30 X C C X Average RMSD of best generated conformer reduces from 0.45 to 0.34Å 23

24 Handling Rings Existing Version For isolated rings Template conformations from CSD-derived template library* Exclude aromatic/delocalized rings which are likely to be planar Includes ring size, ring atom types, ring atom coordination, ring bond types, substituent size and substituent orientation For fused rings (exactly 1 bond in common) Use templates for component rings Superimpose common atoms Set position of common atoms to average If RMSD of common atoms > 0.3 Å, reject template *Taylor, R.; Cole, J.; Korb, O.; McCabe, P. J. Chem. Inf. Model. 2014, 54 (9),

25 Handling Rings New Version Now handle bridged rings (more than 1 bond in common) Add keys for shortest bridge formed by each atom Bridged rings groups based on bridge lengths (number of bonds) 7/8/9, 10+, (1-6 not grouped) Start with templates for each component Assemble fused/bridged rings by combining components (up to 6) All combinations of templates created Common atom positions set to midpoints of template rings Reject if common atom RMSD > 0.3 Å Assembly optimized to account for unusual bond lengths/angles 25

26 Rings What if we don t have a template? We can build one using CSD derived rotamer data/libraries What if we can t construct a reasonable template? We can use the input structure as is. However In subset of 11,700 ZINC clean, drug-like molecules 278 had rings without templates Template generation successful for all

27 Validation Done against the Platinum set* - Diverse Subset Filtered to remove geometrical errors due to: Low resolution data Misinterpretation in electron density Protein-bound ligands, similar properties to DrugBank Approved Drugs 2859 structures Input structures obtained from Platinum set authors CSD Conformer generator considers flexible torsions and rings only Any errors in bond angles/lengths would propagate to poor RMSDs Run via the CSD Python API *Friedrich, N.-O.; et al. J. Chem. Inf. Model. 2017, 57 (3),

28 Ensemble Sizes CSD Conformer Generator can set maximum ensemble size 50: Compare with Platinum set results 200: Default value 10,000: Exhaustive search Max ensemble of 50 conformations Max ensemble of 200 conformations 28

29 Ensembles of 10,000 Conformations Number of Rotatable Bonds Percent at Maximum Ensemble Size n = 50 n = 200 n = % 0% 0% 2 9% 2% 0% 3 46% 11% 0% 4 80% 43% 0% 5 97% 84% 2% 6 99% 96% 6% 7 100% 98% 25% 8 100% 97% 29% 9 100% 100% 32% % 97% 30% % 100% 29% % 97% 23% % 100% 12% % 100% 11% % 100% 22% % 100% 20% 29

30 Successes Successfully generated reference conformation at x Å RMSD Ensemble size = 50 Success with ensemble size of % 99.9% 94.1% 99.1% 83.9% 96.6% 57.2% 75.0% 30

31 Compared to other methods Diverse Set Results Ensemble = 50 Taken from Platinum Set Paper* *Friedrich, N.-O.; et al. J. Chem. Inf. Model. 2017, 57 (3),

32 Compared to other methods Diverse Set Results Ensemble = 250 Ensemble = 200 Taken from Platinum Set Paper* *Friedrich, N.-O.; et al. J. Chem. Inf. Model. 2017, 57 (3),

33 Some interesting failures PDB 3f7z, Ligand 34O Best RMSD at ensemble = 50: 2.37 Å Observed Best RMSD But, at ensemble = 200: 0.43 Å (rank = 171) 33

34 PDB 3ahg, ligand HTD Best RMSD: 1.45 Å (rank 22) Observed Best RMSD Overlay (on SN ring) Twisted ring Planar ring This is an unusual geometry CSD search for ring 402 hits All planar (max RMSD between atoms and plane = 0.12 A) Observed structure RMSD = 0.28 (18 std deviations from mean) Transition state structure - strained 34

35 PDB 4ax9, ligand N5N Best RMSD: 2.65 Å (rank 27) (ensemble = 200 best 1.65 Å, rank 65) Observed Best RMSD Intramolecular Hbond No generated conformer has this Hbond (even at 10000) There is no intramolecular hydrogen bonding term 35

36 Future Work Addition of intramolecular hydrogen bonding term Addition of nitrogen templates (switching between pyramidal and planar Ns) Improvement of intramolecular clash term Implementation of best-first tree search Paper: In preparation Better data libraries 36

37 Acknowledgements Jason Cole Murry Read Oliver Korb Patrick McCabe Robin Taylor John Liebeschuetz Paul Sanschagrin CCDC Colleagues Thank you! We are hiring! CSD Authors/Depositors (440,000+) 37

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39 Run times Previous Version Ensemble = 50 Ensemble = Single process, single thread on Xeon E5-2643v2 (3.5 GHz) Time is for reading input, generating conformers (not saving output) 39

40 Timing differences Ens Size Mean(orig) Mean(new) Orig - New Ens = 50 Ens = 200 Ens =

41 Mean RMSD (of best conformer) Ensemble size = 50 Outliers 1.5 x Upper Quartile Range 75 th percentile Mean Median 25 th percentile 1.5 x Lower Quartile Range (Numbers indicate number of structures with n rotatable bonds) 42

42 Mean RMSD (of best conformer) Ensemble size = 50 Ensemble size =

43 Mean RMSD (of best conformer) Difference in mean RMSD if only 50 or 200 conformations generated instead of 10,000 44

44 Cumulative Successes Ensemble size = 50 45

45 Run times New Version Ensemble = 50 Ensemble = Single process, single thread on Xeon E5-2643v2 (3.5 GHz) Time is for reading input, generating conformers (not saving output) 46