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Journal of Computer-Aided Molecular Design

, Volume 26, Issue 11, pp 1195–1205 | Cite as

Close intramolecular sulfur–oxygen contacts: modified force field parameters for improved conformation generation

  • Dmitry Lupyan
  • Yuriy A. AbramovEmail author
  • Woody ShermanEmail author
Article

Abstract

The Cambridge Structural Database (CSD) offers an excellent data source to study small molecule conformations and molecular interactions. We have analyzed 130 small molecules from the CSD containing an intramolecular sulfur–oxygen distance less than the sum of their van der Waals (vdW) radii. Close S···O distances are observed in several important medicinal chemistry motifs (e.g. a carbonyl oxygen connected by a carbon or nitrogen linker to a sulfur) and are not treated well with existing parameters in the MMFFs or OPLS_2005 force fields, resulting in suboptimal geometries and energetics. In this work, we develop modified parameters for the OPLS_2005 force field to better treat this specific interaction in order to generate conformations close to those found in the CSD structures. We use a combination of refitting a force field torsional parameter, adding a specific atom pair vdW term, and attenuating the electrostatic interactions to obtain an improvement in the accuracy of geometry minimizations and conformational searches for these molecules. Specifically, in a conformational search 58 % of the cases produced a conformation less than 0.25 Å from the CSD crystal conformation with the modified OPLS force field parameters developed in this work. In contrast, 25 and 37 % produced a conformation less than 0.25 Å with the MMFFs and OPLS_2005 force fields, respectively. As an application of the new parameters, we generated conformations for the tyrosine kinase inhibitor axitinib (trade name Inlyta) that could be correctly repacked into three observed polymorphic structures, which was not possible with conformations generated using MMFFs or OPLS_2005. The improved parameters can be mapped directly onto physical characteristics of the systems that are treated inadequately with the molecular mechanics force fields used in this study and potentially other force fields as well.

Keywords

Force field Conformational analysis OPLS Small molecule crystal structure Computational crystal structure prediction 

Notes

Acknowledgments

We thank Wolfgang Damm and John Shelley for implementing the NBFIX functionality within the Schrodinger Suite. We also thank Ed Harder for helpful discussions regarding force fields and for comments on the manuscript.

References

  1. 1.
    Allen F (2002) Acta Crystallogr Sect B 58(3 Part 1):380Google Scholar
  2. 2.
    Bernstein J (2002) Polymorphism in molecular crystals, vol 14. Oxford University Press, USAGoogle Scholar
  3. 3.
    Abramov YA, Pencheva K (2010) Thermodynamics and relative solubility prediction of polymorphic systems. In: am Ende DJ (ed) Chemical engineering in the pharmaceutical industry: R&D to Manufacturing. Wiley, Hoboken, NJGoogle Scholar
  4. 4.
    Kobayashi Y, Ito S, Itai S, Yamamoto K (2000) Int J Pharm 193(2):137CrossRefGoogle Scholar
  5. 5.
    Brittain HG (2009) Polymorphism in pharmaceutical solids. Informa Healthcare, New YorkGoogle Scholar
  6. 6.
    Singhal D, Curatolo W (2004) Adv Drug Deliv Rev 56(3):335CrossRefGoogle Scholar
  7. 7.
    Crowley KJ, Zografi G (2002) J Pharm Sci 91(2):492CrossRefGoogle Scholar
  8. 8.
    Beyer T, Day GM, Price SL (2001) J Am Chem Soc 123(21):5086CrossRefGoogle Scholar
  9. 9.
    Bauer J, Spanton S, Henry R, Quick J, Dziki W, Porter W, Morris J (2001) Pharm Res 18(6):859CrossRefGoogle Scholar
  10. 10.
    Kempf DJ, Marsh KC, Denissen JF, McDonald E, Vasavanonda S, Flentge CA, Green BE, Fino L, Park CH, Kong XP (1995) Proc Nat Acad Sci 92(7):2484CrossRefGoogle Scholar
  11. 11.
    Rascol O, Perez-Lloret S (2009) Expert Opin Pharmacother 10(4):677CrossRefGoogle Scholar
  12. 12.
    Abramov YA, Zell M, Krzyzaniak JF (2010) Toward a rational solvent selection for conformational polymorph screening. In: am Ende DJ (ed) Chemical engineering in the pharmaceutical industry: R&D to manufacturing. Wiley, Hoboken, NJGoogle Scholar
  13. 13.
    Ouvrard C, Price SL (2004) Cryst Growth Des 4(6):1119CrossRefGoogle Scholar
  14. 14.
    Cooper TG, Hejczyk KE, Jones W, Day GM (2008) J Chem Theory Comput 4(10):1795CrossRefGoogle Scholar
  15. 15.
    Day G, Motherwell W, Jones W (2007) Phys Chem Chem Phys 9(14):1693CrossRefGoogle Scholar
  16. 16.
    Iwaoka M, Takemoto S, Okada M, Tomoda S (2002) Bull Chem Soc Jpn 75(7):1611CrossRefGoogle Scholar
  17. 17.
    Burling FT, Goldstein BM (1992) J Am Chem Soc 114(7):2313CrossRefGoogle Scholar
  18. 18.
    Senger S, Chan C, Convery MA, Hubbard JA, Shah GP, Watson NS, Young RJ (2007) Bioorg Med Chem Lett 17(10):2931CrossRefGoogle Scholar
  19. 19.
    Senger S, Convery MA, Chan C, Watson NS (2006) Bioorg Med Chem Lett 16(22):5731CrossRefGoogle Scholar
  20. 20.
    Brameld KA, Kuhn B, Reuter DC, Stahl M (2008) J Chem Inf Model 48(1):1CrossRefGoogle Scholar
  21. 21.
    Reiter LA, Jones CS, Brissette WH, McCurdy SP, Abramov YA, Bordner J, DiCapua FM, Munchhof MJ, Rescek DM, Samardjiev IJ (2008) Bioorg Med Chem Lett 18(9):3000CrossRefGoogle Scholar
  22. 22.
    Kucsman A, Kapovits I (1985) Non-bonded sulfur–oxygen interaction in organic sulfur compounds. In: Bernardi F, Csizmadia IG, Mangini A (eds) Organic sulfur chemistry: theoretical and experimental advances. Elsevier, AmsterdamGoogle Scholar
  23. 23.
    Nagao Y, Hirata T, Goto S, Sano S, Kakehi A, Iizuka K, Shiro M (1998) J Am Chem Soc 120(13):3104CrossRefGoogle Scholar
  24. 24.
    Wu S, Greer A (2000) J Org Chem 65(16):4883CrossRefGoogle Scholar
  25. 25.
    Brooks BR, Bruccoleri RE, Olafson BD, States DJ, Swaminathan S, Karplus M (1983) J Comput Chem 4:187CrossRefGoogle Scholar
  26. 26.
    Brooks BR, Brooks C III, Mackerell A Jr, Nilsson L, Petrella R, Roux B, Won Y, Archontis G, Bartels C, Boresch S (2009) J Comp Chem 30(10):1545CrossRefGoogle Scholar
  27. 27.
    Jorgensen WL, Tirado-Rives J (1988) J Am Chem Soc 110:1657CrossRefGoogle Scholar
  28. 28.
    Pranata J, Wierschke SG, Jorgensen WL (1991) J Am Chem Soc 113:2810CrossRefGoogle Scholar
  29. 29.
    Weiner SJ, Kollman PA, Case DA, Singh UC, Ghio C, Alagona G, Profeta J, S., Weiner P (1984) J Am Chem Soc 106:765Google Scholar
  30. 30.
    Weiner SJ, Kollman PA, Nguyen DT, Case DA (1986) J Comput Chem 7:230CrossRefGoogle Scholar
  31. 31.
    Halgren TA (1992) J Am Chem Soc 114(20):7827CrossRefGoogle Scholar
  32. 32.
    Halgren TA (1996) J Comput Chem 17:520CrossRefGoogle Scholar
  33. 33.
    Halgren TA (1996) J Comput Chem 17:490CrossRefGoogle Scholar
  34. 34.
    Shivakumar D, Harder E, Damm W, Friesner RA, Sherman W (2012) J Chem Theory Comput 8(8):2553CrossRefGoogle Scholar
  35. 35.
    Shivakumar D, Williams J, Wu Y, Damm W, Shelley J, Sherman W (2010) J Chem Theory Comput 6(5):1509CrossRefGoogle Scholar
  36. 36.
    Dauber P, Hagler AT (1980) Acc Chem Res 13(4):105CrossRefGoogle Scholar
  37. 37.
    Brock CP, Minton RP (1989) J Am Chem Soc 111(13):4586CrossRefGoogle Scholar
  38. 38.
    Buntine MA, Hall VJ, Kosovel FJ, Tiekink ERT (1998) J Phys Chem A 102(14):2472CrossRefGoogle Scholar
  39. 39.
    Jorgensen WL, Maxwell DS, Tirado-Rives J (1996) J Am Chem Soc 118(45):11225CrossRefGoogle Scholar
  40. 40.
    Cohen EEW, Rosen LS, Vokes EE, Kies MS, Forastiere AA, Worden FP, Kane MA, Sherman E, Kim S, Bycott P (2008) J Clin Oncol 26(29):4708CrossRefGoogle Scholar
  41. 41.
    Campeta AM, Chekal BP, Abramov YA, Meenan PA, Henson MJ, Shi B, Singer RA, Horspool KR (2010) J Pharm Sci 99(9):3874Google Scholar
  42. 42.
    Chekal BP, Campeta AM, Abramov YA, Feeder N, Glynn PP, McLaughlin RW, Meenan PA, Singer RA (2009) Org Process Res Dev 13(6):1327CrossRefGoogle Scholar
  43. 43.
    MacKerell AD, Bashford D, Bellott, Dunbrack RL, Evanseck JD, Field MJ, Fischer S, Gao J, Guo H, Ha S, Joseph-McCarthy D, Kuchnir L, Kuczera K, Lau FTK, Mattos C, Michnick S, Ngo T, Nguyen DT, Prodhom B, Reiher WE, Roux B, Schlenkrich M, Smith JC, Stote R, Straub J, Watanabe M, Wiorkiewicz-Kuczera J, Yin D, Karplus M (1998) J Phys Chem B 102(18):3586Google Scholar
  44. 44.
    Cornell WD, Cieplak P, Bayly CI, Gould IR, Merz KM, Ferguson DM, Spellmeyer DC, Fox T, Caldwell JW, Kollman PA (1995) J Am Chem Soc 117(19):5179CrossRefGoogle Scholar
  45. 45.
    Allinger NL, Yuh YH, Lii JH (1989) J Am Chem Soc 111(23):8551CrossRefGoogle Scholar
  46. 46.
    Schneebeli ST, Bochevarov AD, Friesner RA (2011) J Chem Theory Comput 7(3):658CrossRefGoogle Scholar
  47. 47.
    Mohamadi F, Richards NGJ, Guida WC, Liskamp R, Lipton M, Caufield C, Chang G, Hendrickson T, Still WC (1990) J Comp Chem 11(4):440CrossRefGoogle Scholar
  48. 48.
    Stewart JJP (1989) J Comp Chem 10(2):209CrossRefGoogle Scholar
  49. 49.
    Stewart JJP (1989) J Comp Chem 10(2):221CrossRefGoogle Scholar
  50. 50.
    Speakman JC (1997) Molecular structure by diffraction methods. The Chemical Society, LondonGoogle Scholar
  51. 51.
    Kolossváry I, Guida WC (1996) J Am Chem Soc 118(21):5011CrossRefGoogle Scholar
  52. 52.
    Baker CM, Lopes PEM, Zhu X, Roux B, MacKerell AD (2010) J Chem Theory Comput 6(4):1181CrossRefGoogle Scholar
  53. 53.
    Sun H, Ren P, Fried J (1998) Comp Theor Poly Sci 8(1–2):229CrossRefGoogle Scholar
  54. 54.
    Neumann MA, Perrin MA (2005) J Phys Chem B 109(32):15531CrossRefGoogle Scholar
  55. 55.
    Abramov YA (2011) J Phys Chem A 115(45):12809CrossRefGoogle Scholar
  56. 56.
    Baker RJ, Colavita PE, Murphy DM, Platts JA, Wallis JD (2011) J Phys Chem A 116(5):1435CrossRefGoogle Scholar
  57. 57.
    Jorgensen WL, Schyman P (2012) J Chem Theory Comput. doi: 10.1021/ct300180w Google Scholar
  58. 58.
    Jorgensen WL, Severance DL (1990) J Am Chem Soc 112(12):4768CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2012

Authors and Affiliations

  1. 1.Schrodinger Inc.New YorkUSA
  2. 2.Pfizer Global Research and DevelopmentGrotonUSA

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