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

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An Erratum to this article was published on 19 March 2013

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.

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References

  1. Allen F (2002) Acta Crystallogr Sect B 58(3 Part 1):380

    Google Scholar 

  2. Bernstein J (2002) Polymorphism in molecular crystals, vol 14. Oxford University Press, USA

    Google Scholar 

  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, NJ

  4. Kobayashi Y, Ito S, Itai S, Yamamoto K (2000) Int J Pharm 193(2):137

    Article  CAS  Google Scholar 

  5. Brittain HG (2009) Polymorphism in pharmaceutical solids. Informa Healthcare, New York

  6. Singhal D, Curatolo W (2004) Adv Drug Deliv Rev 56(3):335

    Article  CAS  Google Scholar 

  7. Crowley KJ, Zografi G (2002) J Pharm Sci 91(2):492

    Article  CAS  Google Scholar 

  8. Beyer T, Day GM, Price SL (2001) J Am Chem Soc 123(21):5086

    Article  CAS  Google Scholar 

  9. Bauer J, Spanton S, Henry R, Quick J, Dziki W, Porter W, Morris J (2001) Pharm Res 18(6):859

    Article  CAS  Google Scholar 

  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):2484

    Article  CAS  Google Scholar 

  11. Rascol O, Perez-Lloret S (2009) Expert Opin Pharmacother 10(4):677

    Article  CAS  Google Scholar 

  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, NJ

  13. Ouvrard C, Price SL (2004) Cryst Growth Des 4(6):1119

    Article  CAS  Google Scholar 

  14. Cooper TG, Hejczyk KE, Jones W, Day GM (2008) J Chem Theory Comput 4(10):1795

    Article  CAS  Google Scholar 

  15. Day G, Motherwell W, Jones W (2007) Phys Chem Chem Phys 9(14):1693

    Article  CAS  Google Scholar 

  16. Iwaoka M, Takemoto S, Okada M, Tomoda S (2002) Bull Chem Soc Jpn 75(7):1611

    Article  CAS  Google Scholar 

  17. Burling FT, Goldstein BM (1992) J Am Chem Soc 114(7):2313

    Article  CAS  Google Scholar 

  18. Senger S, Chan C, Convery MA, Hubbard JA, Shah GP, Watson NS, Young RJ (2007) Bioorg Med Chem Lett 17(10):2931

    Article  CAS  Google Scholar 

  19. Senger S, Convery MA, Chan C, Watson NS (2006) Bioorg Med Chem Lett 16(22):5731

    Article  CAS  Google Scholar 

  20. Brameld KA, Kuhn B, Reuter DC, Stahl M (2008) J Chem Inf Model 48(1):1

    Article  CAS  Google Scholar 

  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):3000

    Article  CAS  Google Scholar 

  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, Amsterdam

  23. Nagao Y, Hirata T, Goto S, Sano S, Kakehi A, Iizuka K, Shiro M (1998) J Am Chem Soc 120(13):3104

    Article  CAS  Google Scholar 

  24. Wu S, Greer A (2000) J Org Chem 65(16):4883

    Article  CAS  Google Scholar 

  25. Brooks BR, Bruccoleri RE, Olafson BD, States DJ, Swaminathan S, Karplus M (1983) J Comput Chem 4:187

    Article  CAS  Google Scholar 

  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):1545

    Article  CAS  Google Scholar 

  27. Jorgensen WL, Tirado-Rives J (1988) J Am Chem Soc 110:1657

    Article  CAS  Google Scholar 

  28. Pranata J, Wierschke SG, Jorgensen WL (1991) J Am Chem Soc 113:2810

    Article  CAS  Google Scholar 

  29. Weiner SJ, Kollman PA, Case DA, Singh UC, Ghio C, Alagona G, Profeta J, S., Weiner P (1984) J Am Chem Soc 106:765

  30. Weiner SJ, Kollman PA, Nguyen DT, Case DA (1986) J Comput Chem 7:230

    Article  CAS  Google Scholar 

  31. Halgren TA (1992) J Am Chem Soc 114(20):7827

    Article  CAS  Google Scholar 

  32. Halgren TA (1996) J Comput Chem 17:520

    Article  CAS  Google Scholar 

  33. Halgren TA (1996) J Comput Chem 17:490

    Article  CAS  Google Scholar 

  34. Shivakumar D, Harder E, Damm W, Friesner RA, Sherman W (2012) J Chem Theory Comput 8(8):2553

    Article  CAS  Google Scholar 

  35. Shivakumar D, Williams J, Wu Y, Damm W, Shelley J, Sherman W (2010) J Chem Theory Comput 6(5):1509

    Article  CAS  Google Scholar 

  36. Dauber P, Hagler AT (1980) Acc Chem Res 13(4):105

    Article  CAS  Google Scholar 

  37. Brock CP, Minton RP (1989) J Am Chem Soc 111(13):4586

    Article  CAS  Google Scholar 

  38. Buntine MA, Hall VJ, Kosovel FJ, Tiekink ERT (1998) J Phys Chem A 102(14):2472

    Article  CAS  Google Scholar 

  39. Jorgensen WL, Maxwell DS, Tirado-Rives J (1996) J Am Chem Soc 118(45):11225

    Article  CAS  Google Scholar 

  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):4708

    Article  CAS  Google Scholar 

  41. Campeta AM, Chekal BP, Abramov YA, Meenan PA, Henson MJ, Shi B, Singer RA, Horspool KR (2010) J Pharm Sci 99(9):3874

    CAS  Google Scholar 

  42. Chekal BP, Campeta AM, Abramov YA, Feeder N, Glynn PP, McLaughlin RW, Meenan PA, Singer RA (2009) Org Process Res Dev 13(6):1327

    Article  CAS  Google Scholar 

  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):3586

  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):5179

    Article  CAS  Google Scholar 

  45. Allinger NL, Yuh YH, Lii JH (1989) J Am Chem Soc 111(23):8551

    Article  CAS  Google Scholar 

  46. Schneebeli ST, Bochevarov AD, Friesner RA (2011) J Chem Theory Comput 7(3):658

    Article  CAS  Google Scholar 

  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):440

    Article  CAS  Google Scholar 

  48. Stewart JJP (1989) J Comp Chem 10(2):209

    Article  CAS  Google Scholar 

  49. Stewart JJP (1989) J Comp Chem 10(2):221

    Article  CAS  Google Scholar 

  50. Speakman JC (1997) Molecular structure by diffraction methods. The Chemical Society, London

    Google Scholar 

  51. Kolossváry I, Guida WC (1996) J Am Chem Soc 118(21):5011

    Article  Google Scholar 

  52. Baker CM, Lopes PEM, Zhu X, Roux B, MacKerell AD (2010) J Chem Theory Comput 6(4):1181

    Article  CAS  Google Scholar 

  53. Sun H, Ren P, Fried J (1998) Comp Theor Poly Sci 8(1–2):229

    Article  CAS  Google Scholar 

  54. Neumann MA, Perrin MA (2005) J Phys Chem B 109(32):15531

    Article  CAS  Google Scholar 

  55. Abramov YA (2011) J Phys Chem A 115(45):12809

    Article  CAS  Google Scholar 

  56. Baker RJ, Colavita PE, Murphy DM, Platts JA, Wallis JD (2011) J Phys Chem A 116(5):1435

    Article  Google Scholar 

  57. Jorgensen WL, Schyman P (2012) J Chem Theory Comput. doi:10.1021/ct300180w

    Google Scholar 

  58. Jorgensen WL, Severance DL (1990) J Am Chem Soc 112(12):4768

    Article  CAS  Google Scholar 

Download references

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.

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Authors and Affiliations

  1. Schrodinger Inc., 120 West Forty-Fifth Street, 17th Floor, New York, NY, 10036, USA

    Dmitry Lupyan & Woody Sherman

  2. Pfizer Global Research and Development, Eastern Point Road, Groton, CT, 06340, USA

    Yuriy A. Abramov

Authors
  1. Dmitry Lupyan
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  2. Yuriy A. Abramov
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  3. Woody Sherman
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Correspondence to Yuriy A. Abramov or Woody Sherman.

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Lupyan, D., Abramov, Y.A. & Sherman, W. Close intramolecular sulfur–oxygen contacts: modified force field parameters for improved conformation generation. J Comput Aided Mol Des 26, 1195–1205 (2012). https://doi.org/10.1007/s10822-012-9610-x

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