Advertisement

Journal of Computer-Aided Molecular Design

, Volume 29, Issue 8, pp 725–735 | Cite as

Automated computational screening of the thiol reactivity of substituted alkenes

  • Jennifer M. Smith
  • Christopher N. Rowley
Article

Abstract

Electrophilic olefins can react with the S–H moiety of cysteine side chains. The formation of a covalent adduct through this mechanism can result in the inhibition of an enzyme. The reactivity of an olefin towards cysteine depends on its functional groups. In this study, 325 reactions of thiol-Michael-type additions to olefins were modeled using density functional theory. All combinations of ethenes with hydrogen, methyl ester, amide, and cyano substituents were included. An automated workflow was developed to perform the construction, conformation search, minimization, and calculation of molecular properties for the reactant, carbanion intermediate, and thioether products for a model reaction of the addition of methanethiol to the electrophile. Known cysteine-reactive electrophiles present in the database were predicted to react exergonically with methanethiol through a carbanion with a stability in the 30–40 kcal mol−1 range. 13 other compounds in our database that are also present in the PubChem database have similar properties. Natural bond orbital parameters were computed and regression analysis was used to determine the relationship between properties of the olefin electronic structure and the product and intermediate stability. The stability of the intermediates is very sensitive to electronic effects on the carbon where the anionic charge is centered. The stability of the products is more sensitive to steric factors.

Keywords

Electrophiles Thiol Michael addition DFT Carbanion intermediate Computational high-throughput screening Irreversible inhibition Covalent modifier 

Notes

Acknowledgments

We thank NSERC of Canada for funding through a Discovery Grant (Application No. 418505-2012) and an Undergraduate Student Research Award for JMS. JMS thanks the Dean of Science of Memorial University for a travel grant. Computational resources were provided by the Compute Canada Consortium (CCI: djk-615-ac). We thank Archita Adluri for proofreading the manuscript. We thank the reviewers for meticulous examination of the manuscript.

Supplementary material

10822_2015_9857_MOESM1_ESM.txt (43 kb)
Supplementary material 1 (TXT 42 kb)
10822_2015_9857_MOESM2_ESM.pdf (2.1 mb)
Supplementary material 2 (PDF 2188 kb)

References

  1. 1.
    Enoch SJ, Ellison CM, Schultz TW, Cronin MTD (2011) Crit Rev Toxicol 41(9):783CrossRefGoogle Scholar
  2. 2.
    Potashman MH, Duggan ME (2009) J Med Chem 52(5):1231CrossRefGoogle Scholar
  3. 3.
    Gersch M, Kreuzer J, Sieber SA (2012) Nat Prod Rep 29(6):659CrossRefGoogle Scholar
  4. 4.
    Miller RM, Taunton J (2014) Chapter four—targeting protein kinases with selective and semi-promiscuous covalent inhibitors. In: Kevan MS (ed) Methods in enzymology, vol 548. Academic Press, New York, p 93Google Scholar
  5. 5.
    Rabindran SK, Discafani CM, Rosfjord EC, Baxter M, Floyd MB, Golas J, Hallett WA, Johnson BD, Nilakantan R, Overbeek E, Reich MF, Shen R, Shi X, Tsou H-R, Wang Y-F, Wissner A (2004) Cancer Res 64(11):3958CrossRefGoogle Scholar
  6. 6.
    Zhou W, Hur W, McDermott U, Dutt A, Xian W, Ficarro SB, Zhang J, Sharma SV, Brugge J, Meyerson M, Settleman J, Gray NS (2010) Chem Biol 17(3):285–295. doi: 10.1016/j.chembiol.2010.02.007 CrossRefGoogle Scholar
  7. 7.
    Pan Z, Scheerens H, Li S-J, Schultz BE, Sprengeler PA, Burrill LC, Mendonca RV, Sweeney MD, Scott KCK, Grothaus PG, Jeffery DA, Spoerke JM, Honigberg LA, Young PR, Dalrymple SA, Palmer JT (2007) Chem Med Chem 2(1):58CrossRefGoogle Scholar
  8. 8.
    Ettari R, Micale N, Schirmeister T, Gelhaus C, Leippe M, Nizi E, Di Francesco ME, Grasso S, Zappalà M (2009) J Med Chem 52(7):2157CrossRefGoogle Scholar
  9. 9.
    Serafimova IM, Pufall MA, Krishnan S, Duda K, Cohen MS, Maglathlin RL, McFarland JM, Miller RM, Frödin M, Taunton J (2012) Nat Chem Biol 8(5):471CrossRefGoogle Scholar
  10. 10.
    Mulliner D, Wondrousch D, Schuurmann G (2011) Org Biomol Chem 9(24):8400CrossRefGoogle Scholar
  11. 11.
    Hoyle CE, Bowman CN (2010) Angew Chem Int Ed 49(9):1540CrossRefGoogle Scholar
  12. 12.
    Lutolf MP, Tirelli N, Cerritelli S, Cavalli L, Hubbell JA (2001) Bioconj Chem 12(6):1051CrossRefGoogle Scholar
  13. 13.
    Nair DP, Podgórski M, Chatani S, Gong T, Xi W, Fenoli CR, Bowman CN (2014) Chem Mater 26(1):724CrossRefGoogle Scholar
  14. 14.
    Krishnan S, Miller RM, Tian B, Mullins RD, Jacobson MP, Taunton J (2014) J Am Chem Soc 136(36):12624CrossRefGoogle Scholar
  15. 15.
    London N, Miller RM, Krishnan S, Uchida K, Irwin JJ, Eidam O, Gibold L, Cimermančič P, Bonnet R, Shoichet BK, Taunton J (2014) Nat Chem Biol 10(12):1066CrossRefGoogle Scholar
  16. 16.
    Schwöbel JAH, Wondrousch D, Koleva YK, Madden JC, Cronin MTD, Schüürmann G (2010) Chem Res Toxicol 23(10):1576CrossRefGoogle Scholar
  17. 17.
    Krenske EH, Petter RC, Zhu Z, Houk KN (2011) J Org Chem 76(12):5074CrossRefGoogle Scholar
  18. 18.
    Capoferri L, Lodola A, Rivara S, Mor M (2015) J Chem Inf Model 55(3):589CrossRefGoogle Scholar
  19. 19.
    Irwin JJ, Shoichet BK, Mysinger MM, Huang N, Colizzi F, Wassam P, Cao Y (2009) J Med Chem 52(18):5712CrossRefGoogle Scholar
  20. 20.
    Del Rio A, Sgobba M, Parenti M, Degliesposti G, Forestiero R, Percivalle C, Conte P, Freccero M, Rastelli G (2010) J Comput Aided Mol Des 24(3):183CrossRefGoogle Scholar
  21. 21.
    Ouyang X, Zhou S, Su CTT, Ge Z, Li R, Kwoh CK (2013) J Comput Chem 34(4):326CrossRefGoogle Scholar
  22. 22.
    Smith JM, Jami Alahmadi Y, Rowley CN (2013) J Chem Theory Comput 9(11):4860CrossRefGoogle Scholar
  23. 23.
    Hori K, Higuchi S, Kamimura A (1990) J Org Chem 55(23):5900CrossRefGoogle Scholar
  24. 24.
    Bolton EE, Wang Y, Thiessen PA, Bryant SH (2008) Chapter 12—PubChem: integrated platform of small molecules and biological activities. In: Ralph AW, David CS (eds) Annual reports in computational chemistry, vol 4. Elsevier, p 217Google Scholar
  25. 25.
    Schmidt TJ, Ak M, Mrowietz U (2007) Bioorg Med Chem 15(1):333CrossRefGoogle Scholar
  26. 26.
    Edwards PM (1975) Br J Ind Med 32(1):31Google Scholar
  27. 27.
    Guengerich FP, Geiger LE, Hogy LL, Wright PL (1981) Cancer Res 41(12 Part 1):4925Google Scholar
  28. 28.
    Schwartz PA, Kuzmic P, Solowiej J, Bergqvist S, Bolanos B, Almaden C, Nagata A, Ryan K, Feng J, Dalvie D, Kath JC, Xu M, Wani R, Murray BW (2014) Proc Natl Acad Sci 111(1):173CrossRefGoogle Scholar
  29. 29.
    Parr RG, Szentpály L, Liu S (1999) J Am Chem Soc 121(9):1922CrossRefGoogle Scholar
  30. 30.
    Taylor JB, Kennewell PD (1981) Introductory medicinal chemistry. Ellis Horwood Limited, ChichesterGoogle Scholar
  31. 31.
    Weininger D (1988) J Chem Inf Comput Sci 28(1):31CrossRefGoogle Scholar
  32. 32.
    O’Boyle N, Banck M, James C, Morley C, Vandermeersch T, Hutchison G (2011) J Cheminform 3(1):33CrossRefGoogle Scholar
  33. 33.
    Wang J, Wang W, Kollman PA, Case DA (2006) J Mol Graph Model 25(2):247CrossRefGoogle Scholar
  34. 34.
    Wang J, Wolf RM, Caldwell JW, Kollman PA, Case DA (2004) J Comput Chem 25(9):1157CrossRefGoogle Scholar
  35. 35.
    Earl DJ, Deem MW (2005) Phys Chem Chem Phys 7(23):3910CrossRefGoogle Scholar
  36. 36.
    Brooks BR, Brooks CL, Mackerell AD, Nilsson L, Petrella RJ, Roux B, Won Y, Archontis G, Bartels C, Boresch S, Caflisch A, Caves L, Cui Q, Dinner AR, Feig M, Fischer S, Gao J, Hodoscek M, Im W, Kuczera K, Lazaridis T, Ma J, Ovchinnikov V, Paci E, Pastor RW, Post CB, Pu JZ, Schaefer M, Tidor B, Venable RM, Woodcock HL, Wu X, Yang W, York DM, Karplus M (2009) J Comput Chem 30(10):1545CrossRefGoogle Scholar
  37. 37.
    Rowley CN CHARMM Conformation Search. https://github.com/RowleyGroup/charmm-conformation. Accessed 15 May 2015
  38. 38.
    Dewar MJS, Thiel W (1977) J Am Chem Soc 99(15):4899CrossRefGoogle Scholar
  39. 39.
    TURBOMOLE V6.6 2014, a development of University of Karlsruhe and Forschungszentrum Karlsruhe GmbH, 1989–2007, TURBOMOLE GmbH, since 2007. http://www.turbomole.com
  40. 40.
    Adamo C, Barone V (1999) J Chem Phys 110(13):6158CrossRefGoogle Scholar
  41. 41.
    Schäfer A, Huber C, Ahlrichs R (1994) J Chem Phys 100(8):5829CrossRefGoogle Scholar
  42. 42.
    Chai J-D, Head-Gordon M (2008) J Chem Phys 128(8):084106CrossRefGoogle Scholar
  43. 43.
    Spartan ‘10 (2010) Wavefunction Inc., Irvine, CAGoogle Scholar
  44. 44.
    Lamoureux G, Roux B (2006) J Phys Chem B 110(7):3308CrossRefGoogle Scholar
  45. 45.
    Kreevoy MM, Eichinger BE, Stary FE, Katz EA, Sellstedt JH (1964) J Org Chem 29(6):1641CrossRefGoogle Scholar
  46. 46.
    Dunning TH (1989) J Chem Phys 90(2):1007CrossRefGoogle Scholar
  47. 47.
    Woon DE, Dunning TH (1993) J Chem Phys 98(2):1358CrossRefGoogle Scholar
  48. 48.
    Tomasi J, Mennucci B, Cammi R (2005) Chem Rev 105(8):2999CrossRefGoogle Scholar
  49. 49.
    Reed AE, Weinstock RB, Weinhold F (1985) J Chem Phys 83(2):735CrossRefGoogle Scholar
  50. 50.
    Glendening ED, Reed AE, Carpenter JE, Weinhold F (2003) NBO Version 3.1. Gaussian Inc., Pittsburg, PA. http://www.gaussian.com/g_tech/g_ur/m_citation.htm
  51. 51.
    Mennucci B (2012) Wiley Interdiscip Rev Comput Mol Sci 2(3):386CrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Department of ChemistryMemorial University of NewfoundlandSt. John’sCanada

Personalised recommendations