Location via proxy:   [ UP ]  
[Report a bug]   [Manage cookies]                
Skip to main content
Springer Nature Link
Log in

Prediction of protein–ligand binding affinity by free energy simulations: assumptions, pitfalls and expectations

  • Perspective
  • Published:
Journal of Computer-Aided Molecular Design Aims and scope Submit manuscript

Abstract

Many limitations of current computer-aided drug design arise from the difficulty of reliably predicting the binding affinity of a small molecule to a biological target. There is thus a strong interest in novel computational methodologies that claim predictions of greater accuracy than current scoring functions, and at a throughput compatible with the rapid pace of drug discovery in the pharmaceutical industry. Notably, computational methodologies firmly rooted in statistical thermodynamics have received particular attention in recent years. Yet free energy calculations can be daunting to learn for a novice user because of numerous technical issues and various approaches advocated by experts in the field. The purpose of this article is to provide an overview of the current capabilities of free energy calculations and to discuss the applicability of this technology to drug discovery.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Jhoti H (2007) Structure-based drug discovery. Springer, Dordrecht

    Google Scholar 

  2. Jorgensen WL (2004) Science 303:1813–1818

    Article  CAS  Google Scholar 

  3. Klebe G (2006) Drug Discov Today 11:580–594

    Article  CAS  Google Scholar 

  4. McInnes C (2007) Curr Opin Chem Biol 11:494–502

    Article  CAS  Google Scholar 

  5. Taylor RD, Jewsbury PJ, Essex JW (2002) J Comput Aided Mol Des 16:151–166

    Article  CAS  Google Scholar 

  6. Warren GL, Andrews CW, Capelli AM, Clarke B, LaLonde J, Lambert MH, Lindvall M, Nevins N, Semus SF, Senger S, Tedesco G, Wall ID, Woolven JM, Peishoff CE, Head MS (2006) J Med Chem 49:5912–5931

    Article  CAS  Google Scholar 

  7. Cozzini P, Kellogg GE, Spyrakis F, Abraham DJ, Costantino G, Emerson A, Fanelli F, Gohlke H, Kuhn LA, Morris GM, Orozco M, Pertinhez TA, Rizzi M, Sotriffer CA (2008) J Med Chem 51:6237–6255

    Article  CAS  Google Scholar 

  8. Kokh DB, Wenzel WG (2008) J Med Chem 51:5919–5931

    Article  CAS  Google Scholar 

  9. Sherman W, Day T, Jacobson MP, Friesner RA, Farid R (2006) J Med Chem 49:534–553

    Article  CAS  Google Scholar 

  10. Verdonk ML, Mortenson PN, Hall RJ, Hartshorn MJ, Murray CW (2008) J Chem Inf Model 48:2214–2225

    Article  CAS  Google Scholar 

  11. Gilson MK, Zhou HX (2007) Annu Rev Biophys Biomol Struct 36:21–42

    Article  CAS  Google Scholar 

  12. Mobley DL, Dill KA (2009) Structure 17:489–498

    Article  CAS  Google Scholar 

  13. Guimaraes CRW, Boger DL, Jorgensen WL (2005) J Am Chem Soc 127:17377–17384

    Article  CAS  Google Scholar 

  14. Mobley DL, Graves AP, Chodera JD, McReynolds AC, Shoichet BK, Dill KA (2007) J Mol Biol 371:1118–1134

    Article  CAS  Google Scholar 

  15. Fujitani H, Tanida Y, Ito M, Jayachandran G, Snow CD, Shirts MR, Sorin EJ, Pande VS (2005) J Chem Phys 123:084108

    Article  CAS  Google Scholar 

  16. Michel J, Verdonk ML, Essex JW (2006) J Med Chem 49:7427–7439

    Article  CAS  Google Scholar 

  17. Michel J, Verdonk ML, Essex JW (2007) J Chem. Theory Comput 3:1645–1655

    Article  CAS  Google Scholar 

  18. Deng YQ, Roux B (2006) J Chem. Theory Comput. 2:1255–1273

    Article  CAS  Google Scholar 

  19. Michel J, Essex JW (2008) J Med Chem 51:6654–6664

    Article  CAS  Google Scholar 

  20. Wang JY, Deng YQ, Roux B (2006) Biophys J 91:2798–2814

    Article  CAS  Google Scholar 

  21. Aqvist J, Luzhkov VB, Brandsdal BO (2002) Acc Chem Res 35:358–365

    Article  CAS  Google Scholar 

  22. Massova I, Kollman PA (2000) Perspectives in Drug Discovery and Design 18:113–135

    Article  CAS  Google Scholar 

  23. Mobley DL, Chodera JD, Dill KA (2007) J Chem. Theory Comput. 3:1231–1235

    Article  CAS  Google Scholar 

  24. Boyce SE, Mobley DL, Rocklin GJ, Graves AP, Dill KA, Shoichet BK (2009) J Mol Biol 394:747–763

    Article  CAS  Google Scholar 

  25. Tanida Y, Ito MS, Fujitani H (2007) Chem Phys 337:135–143

    Article  CAS  Google Scholar 

  26. Oostenbrink C, van Gunsteren WF (2004) Proteins Struct Funct Genet 54:237–246

    Article  CAS  Google Scholar 

  27. Steinbrecher T, Hrenn A, Dormann KL, Merfort I, Labahn A (2008) Bioorg Med. Chem. 16:2385–2390

    Article  CAS  Google Scholar 

  28. Pan CF, Mezei M, Mujtaba S, Muller M, Zeng L, Li JM, Wang ZY, Zhou MM (2007) J Med Chem 50:2285–2288

    Article  CAS  Google Scholar 

  29. Jorgensen WL, Ruiz-Caro J, Tirado-Rives J, Basavapathruni A, Anderson KS, Hamilton AD (2006) Bioorg Med. Chem. Lett. 16:663–667

    Article  CAS  Google Scholar 

  30. Ruiz-Caro J, Basavapathruni A, Kim JT, Bailey CM, Wang LG, Anderson KS, Hamilton AD, Jorgensen WL (2006) Bioorg Med. Chem. Lett. 16:668–671

    Article  CAS  Google Scholar 

  31. Thakur VV, Kim JT, Hamilton AD, Bailey CM, Domaoal RA, Wang LG, Anderson KS, Jorgensen WL (2006) Bioorg Med. Chem. Lett. 16:5664–5667

    Article  CAS  Google Scholar 

  32. Kim JT, Hamilton AD, Bailey CM, Domoal RA, Wang LG, Anderson KS, Jorgensen WL (2006) J Am Chem Soc 128:15372–15373

    Article  CAS  Google Scholar 

  33. Zeevaart JG, Wang LG, Thakur VV, Leung CS, Tirado-Rives J, Bailey CM, Domaoal RA, Anderson KS, Jorgensen WL (2008) J Am Chem Soc 130:9492–9499

    Article  CAS  Google Scholar 

  34. Jorgensen WL (2009) Acc Chem Res 42:724–733

    Article  CAS  Google Scholar 

  35. Michel J, Harker EA, Tirado-Rives J, Jorgensen WL, Schepartz A (2009) J Am Chem Soc 131:6356–6357

    Article  CAS  Google Scholar 

  36. Gilson MK, Given JA, Bush BL, McCammon JA (1997) Biophys J 72:1047–1069

    Article  CAS  Google Scholar 

  37. Boresch S, Tettinger F, Leitgeb M, Karplus M (2003) J Phys. Chem. B 107:9535–9551

    Article  CAS  Google Scholar 

  38. Ben Naim A (2006) Molecular Theory of Solutions. Oxford University press, Oxford

    Google Scholar 

  39. Leach A (1996) Molecular Modelling: Principles and Applications. Longman, Harlow, UK

    Google Scholar 

  40. Zwanzig RW (1954) J Chem Phys 22:1420–1426

    Article  CAS  Google Scholar 

  41. Kollman P (1993) Chem Rev 93:2395–2417

    Article  CAS  Google Scholar 

  42. Wu D, Kofke DA (2005) J Chem Phys 123:084109

    Article  CAS  Google Scholar 

  43. Wu D, Kofke DA (2005) J Chem Phys 123:054103

    Article  CAS  Google Scholar 

  44. Jorgensen WL, Ravimohan C (1985) J Chem Phys 83:3050–3054

    Article  CAS  Google Scholar 

  45. Lu ND, Kofke DA, Woolf TB (2004) J Comput Chem 25:28–39

    Article  CAS  Google Scholar 

  46. Bennett CH (1976) J Comput Phys 22:245–268

    Article  Google Scholar 

  47. Shirts MR, Bair E, Hooker G, Pande VS (2003) Phys Rev Lett 91:140601

    Article  CAS  Google Scholar 

  48. Shirts MR, Chodera JD (2008) J Chem Phys 129:124105

    Article  CAS  Google Scholar 

  49. Liu HY, Mark AE, vanGunsteren WF (1996) J Phys Chem 100:9485–9494

    Article  CAS  Google Scholar 

  50. Oostenbrink BC, Pitera JW, van Lipzig MMH, Meerman JHN, van Gunsteren WF (2000) J Med Chem 43:4594–4605

    Article  CAS  Google Scholar 

  51. Oostenbrink C, van Gunsteren WF (2003) J Comput Chem 24:1730–1739

    Article  CAS  Google Scholar 

  52. Oostenbrink C, van Gunsteren WF (2005) Proc Natl. Acad. Sci. U. S. A. 102:6750–6754

    Article  CAS  Google Scholar 

  53. Mezei M (1987) J Chem Phys 86:7084–7088

    Article  CAS  Google Scholar 

  54. Jarzynski C (1997) Physical Review E 56:5018–5035

    Article  CAS  Google Scholar 

  55. Jarzynski C (1997) Phys Rev Lett 78:2690–2693

    Article  CAS  Google Scholar 

  56. Cossins BP, Foucher S, Edge CM, Essex JW (2008) J Phys. Chem. B 112:14985–14992

    Article  CAS  Google Scholar 

  57. Cossins BP, Foucher S, Edge CM, Essex JW (2009) J Phys. Chem. B 113:5508–5519

    Article  CAS  Google Scholar 

  58. Oostenbrink C, van Gunsteren WF (2006) Chem Phys 323:102–108

    Article  CAS  Google Scholar 

  59. Ytreberg FM, Swendsen RH, Zuckerman DM (2006) J Chem Phys 125:184114

    Article  CAS  Google Scholar 

  60. Owicki JC, Scheraga HA (1977) Chem Phys Lett 47:600–602

    Article  CAS  Google Scholar 

  61. Kumar S, Bouzida D, Swendsen RH, Kollman PA, Rosenberg JM (1992) J Comput Chem 13:1011–1021

    Article  CAS  Google Scholar 

  62. Bartels C, Karplus M (1998) J Phys Chem B 102:865–880

    Article  CAS  Google Scholar 

  63. Woods CJ, Camiolo S, Light ME, Coles SJ, Hursthouse MB, King MA, Gale PA, Essex JW (2002) J Am Chem Soc 124:8644–8652

    Article  CAS  Google Scholar 

  64. Wang J, Gu Y, Liu HY (2006) J Chem Phys 125:094907

    Article  CAS  Google Scholar 

  65. Kong XJ, Brooks CL (1996) J Chem Phys 105:2414–2423

    Article  Google Scholar 

  66. Guo ZY, Durkin J, Fischmann T, Ingram R, Prongay A, Zhang RM, Madison V (2003) J Med Chem 46:5360–5364

    Article  CAS  Google Scholar 

  67. Knight JL, Brooks CL (2009) J Comput Chem 30:1692–1700

    Article  CAS  Google Scholar 

  68. Laio A, Parrinello M (2002) Proc Natl Acad Sci USA 99:12562–12566

    Article  CAS  Google Scholar 

  69. Gervasio FL, Laio A, Parrinello M (2005) J Am Chem Soc 127:2600–2607

    Article  CAS  Google Scholar 

  70. Mezei M (1987) Mol Phys 61:565–582

    Article  CAS  Google Scholar 

  71. Guarnieri F, Mezei M (1996) J Am Chem Soc 118:8493–8494

    Article  CAS  Google Scholar 

  72. Resat H, Mezei M (1994) J Am Chem Soc 116:7451–7452

    Article  CAS  Google Scholar 

  73. Resat H, Mezei M (1996) Biophys J 71:1179–1190

    Article  CAS  Google Scholar 

  74. Clark M, Guarnieri F, Shkurko I, Wiseman J (2006) J Chem Inf Model 46:231–242

    Article  CAS  Google Scholar 

  75. Clark M, Meshkat S, Wiseman JS (2009) J Chem Inf Model 49:934–943

    Article  CAS  Google Scholar 

  76. Mezei M (1980) Mol Phys 40:901–906

    Article  CAS  Google Scholar 

  77. Clark M, Meshkat S, Talbot GT, Carnevali P, Wiseman JS (2009) J Chem Inf Model 49:1901–1913

    Article  CAS  Google Scholar 

  78. Chang CE, Gilson MK (2004) J Am Chem Soc 126:13156–13164

    Article  CAS  Google Scholar 

  79. Chang CEA, Chen W, Gilson MK (2007) Proc Natl Acad Sci USA 104:1534–1539

    Article  CAS  Google Scholar 

  80. Rekharsky MV, Mori T, Yang C, Ko YH, Selvapalam N, Kim H, Sobransingh D, Kaifer AE, Liu SM, Isaacs L, Chen W, Moghaddam S, Gilson MK, Kim KM, Inoue Y (2007) Proc Natl Acad Sci USA 104:20737–20742

    Article  CAS  Google Scholar 

  81. Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML (1983) J Chem Phys 79:926–935

    Article  CAS  Google Scholar 

  82. Michel J (2006) The Use of Free Energy Simulations as Scoring Functions, PhD Thesis, University of Southampton. Available at http://www.julienmichel.net/docs/jmichel-thesiscomp.pdf

  83. Pitera JW, Van Gunsteren WF (2002) Mol Simul 28:45–65

    Article  CAS  Google Scholar 

  84. Steinbrecher T, Mobley DL, Case DA (2007) J Chem Phys 127:214108

    Article  CAS  Google Scholar 

  85. Beutler TC, Mark AE, Vanschaik RC, Gerber PR, van Gunsteren WF (1994) Chem Phys Lett 222:529–539

    Article  CAS  Google Scholar 

  86. Zacharias M, Straatsma TP, McCammon JA (1994) J Chem Phys 100:9025

    Article  CAS  Google Scholar 

  87. Shirts MR, Pitera JW, Swope WC, Pande VS (2003) J Chem Phys 119:5740

    Article  CAS  Google Scholar 

  88. Michel J, Orsi M, Essex JW (2008) J Phys Chem B 112:657–660

    Article  CAS  Google Scholar 

  89. Metropolis N, Rosenbluth AW, Rosenbluth MN, Teller AH, Teller E (1953) J Chem Phys 21:1087–1092

    Article  CAS  Google Scholar 

  90. Martin MG, Siepmann JI (1999) J Phys Chem B 103:4508–4517

    Article  CAS  Google Scholar 

  91. Siepmann JI, Frenkel D (1992) Mol Phys 75:59–70

    Article  CAS  Google Scholar 

  92. Dodd LR, Boone TD, Theodorou DN (1993) Mol Phys 78:961–996

    Article  CAS  Google Scholar 

  93. Ulmschneider JP, Jorgensen WL (2003) J Chem Phys 118:4261–4271

    Article  CAS  Google Scholar 

  94. Hetenyi B, Bernacki K, Berne BJ (2002) J Chem Phys 117:8203–8207

    Article  CAS  Google Scholar 

  95. Chen JH, Im W, Brooks CL (2005) J Comput Chem 26:1565–1578

    Article  CAS  Google Scholar 

  96. Cooke B, Schmidler SC (2008) J Chem Phys 129:164112

    Article  CAS  Google Scholar 

  97. Izaguirre JA, Hampton SS (2004) J Comput Phys 200:581–604

    Article  CAS  Google Scholar 

  98. Mehlig B, Heermann DW, Forrest BM (1992) Phys Rev B 45:679–685

    Article  Google Scholar 

  99. Mitsutake A, Sugita Y, Okamoto Y (2001) Biopolymers 60:96–123

    Article  CAS  Google Scholar 

  100. Garcia AE, Onuchic JN (2003) Proc Natl Acad Sci USA 100:13898–13903

    Article  CAS  Google Scholar 

  101. Woods CJ, Essex JW, King MA (2003) J Phys Chem B 107:13703–13710

    Article  CAS  Google Scholar 

  102. Woods CJ, Essex JW, King MA (2003) J Phys Chem B 107:13711–13718

    Article  CAS  Google Scholar 

  103. Gelb LD (2003) J Chem Phys 118:7747–7750

    Article  CAS  Google Scholar 

  104. Michel J, Taylor RD, Essex JW (2006) J Chem Theory Comput 2:732–739

    Article  CAS  Google Scholar 

  105. Woods CJ, Manby FR, Mulholland AJ (2008) J Chem Phys 128:014109

    Article  CAS  Google Scholar 

  106. Humphreys DD, Friesner RA, Berne BJ (1994) J Phys Chem 98:6885–6892

    Article  CAS  Google Scholar 

  107. Jayachandran G, Shirts MR, Park S, Pande VS (2006) J Chem Phys 125:084901

    Article  CAS  Google Scholar 

  108. Ponder JW, Case DA (2003) Adv Prot Chem 66:27–85

    Article  CAS  Google Scholar 

  109. 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 117:5179–5197

    Article  CAS  Google Scholar 

  110. MacKerell AD, Bashford D, Bellott M, 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 102:3586–3616

    Article  CAS  Google Scholar 

  111. Jorgensen WL, Maxwell DS, TiradoRives J (1996) J Am Chem Soc 118:11225–11236

    Article  CAS  Google Scholar 

  112. Schuler LD, Daura X, van Gunsteren WF (2001) J Comput Chem 22:1205–1218

    Article  CAS  Google Scholar 

  113. Duan Y, Wu C, Chowdhury S, Lee MC, Xiong GM, Zhang W, Yang R, Cieplak P, Luo R, Lee T, Caldwell J, Wang JM, Kollman P (2003) J Comput Chem 24:1999–2012

    Article  CAS  Google Scholar 

  114. Wang JM, Wolf RM, Caldwell JW, Kollman PA, Case DA (2004) J Comput Chem 25:1157–1174

    Article  CAS  Google Scholar 

  115. Udier-Blagovic M, De Tirado PM, Pearlman SA, Jorgensen WL (2004) J Comput Chem 25:1322–1332

    Article  CAS  Google Scholar 

  116. Jorgensen WL, Jensen KP, Alexandrova AN (2007) J Chem Theory Comput 3:1987–1992

    Article  CAS  Google Scholar 

  117. Michel J, Tirado-Rives J, Jorgensen WL (2009) J Am Chem Soc 131:15403–15411

    Article  CAS  Google Scholar 

  118. Deng YQ, Roux B (2008) J Chem Phys 128:115103

    Article  CAS  Google Scholar 

  119. Michel J, Tirado-Rives J, Jorgensen WL (2009) J Phys Chem B 113:13337–13346

    Article  CAS  Google Scholar 

  120. Dong F, Olsen B, Baker NA (2008) Biophysical tools for biologists: vol. 1 in vitro techniques, pp. 843–870

  121. Mobley DL, Bayly CI, Cooper MD, Shirts MR, Dill KA (2009) J Chem Theory Comput 5:350–358

    Article  CAS  Google Scholar 

  122. Mobley DL, Dill KA, Chodera JD (2008) J Phys Chem B 112:938–946

    Article  CAS  Google Scholar 

  123. Michel J, Taylor RD, Essex JW (2004) J Comput Chem 25:1760–1770

    Article  CAS  Google Scholar 

  124. Barillari C, Taylor J, Viner R, Essex JW (2007) J Am Chem Soc 129:2577–2587

    Article  CAS  Google Scholar 

  125. Lee MS, Salsbury FR, Olson MA (2004) J Comput Chem 25:1967–1978

    Article  CAS  Google Scholar 

  126. Allen MP, Tildesley DJ (1990) Computer Simulations of Liquids. Oxford University Press, Oxford, UK

    Google Scholar 

  127. Aqvist J (1990) J Phys Chem 94:8021–8024

    Article  Google Scholar 

  128. Sagui C, Darden TA (1999) Annu Rev Biophys Biomol Struct 28:155–179

    Article  CAS  Google Scholar 

  129. Heinz TN, Hunenberger PH (2005) J Chem Phys 123:034107

    Article  CAS  Google Scholar 

  130. Kastenholz MA, Hunenberger PH (2006) J Chem Phys 124:224501

    Article  CAS  Google Scholar 

  131. Kastenholz MA, Hunenberger PH (2006) J Chem Phys 124:124106

    Article  CAS  Google Scholar 

  132. Donnini S, Mark AE, Juffer AH, Villa A (2005) J Comput Chem 26:115–122

    Article  CAS  Google Scholar 

  133. Aqvist J (1996) J Comput Chem 17:1587–1597

    Article  Google Scholar 

  134. Jensen KP, Jorgensen WL (2006) J Chem Theory Comput 2:1499–1509

    Article  CAS  Google Scholar 

  135. Shirts MR, Mobley DL, Chodera JD, Pande VS (2007) J Phys Chem B 111:13052–13063

    Article  CAS  Google Scholar 

  136. Shivakumar D, Deng Y, Roux B (2009) J Chem Theory Comput 5:919–930

    Article  CAS  Google Scholar 

  137. Gresh N, Cisneros GA, Darden TA, Piquemal JP (2007) J Chem Theory Comput 3:1960–1986

    Article  CAS  Google Scholar 

  138. Lamoureux G, Roux B (2003) J Chem Phys 119:3025–3039

    Article  CAS  Google Scholar 

  139. Patel S, Brooks CL (2004) J Comput Chem 25:1–15

    Article  CAS  Google Scholar 

  140. Ren PY, Ponder JW (2003) J Phys Chem B 107:5933–5947

    Article  CAS  Google Scholar 

  141. Gallivan JP, Dougherty DA (1999) Proc Natl Acad Sci USA 96:9459–9464

    Article  CAS  Google Scholar 

  142. Jiao D, Golubkov PA, Darden TA, Ren P (2008) Proc Natl Acad Sci USA 105:6290–6295

    Article  CAS  Google Scholar 

  143. Khoruzhii O, Donchev AG, Galkin N, Illarionov A, Olevanov M, Ozrin V, Queen C, Tarasov V (2008) Proc Natl Acad Sci USA 105:10378–10383

    Article  CAS  Google Scholar 

  144. Khandelwal A, Lukacova V, Comez D, Kroll DM, Raha S, Balaz S (2005) J Med Chem 48:5437–5547

    Article  CAS  Google Scholar 

  145. Brown P, Woods C, McIntosh-Smith S, Manby FR (2008) J Chem Theory Comput 4:1620–1626

    Article  CAS  Google Scholar 

  146. Chipot C (2008) J Chem Theory Comput 4:2150–2159

    Article  CAS  Google Scholar 

  147. Jorgensen WL, Thomas LL (2008) J Chem Theory Comput 4:869–876

    Article  CAS  Google Scholar 

  148. Villa A, Zangi R, Pieffet G, Mark AE (2003) J Comput Aided Mol Des 17:673–686

    Article  CAS  Google Scholar 

  149. Cheng Y, Prusoff WH (1973) Biochem Pharmacol 22:3099–3108

    Article  CAS  Google Scholar 

  150. Krohn KA, Link JM (2003) Nucl Med Biol 30:819–826

    Article  CAS  Google Scholar 

  151. Wissner A, Berger DM, Boschelli DH, Floyd MB, Greenberger LM, Gruber BC, Johnson BD, Mamuya N, Nilakantan R, Reich MF, Shen R, Tsou HR, Upeslacis E, Wang YF, Wu BQ, Ye F, Zhang N (2000) J Med Chem 43:3244–3256

    Article  CAS  Google Scholar 

  152. Chipot C, Pohorille A (2007) Free Energy Calculations: Theory and Applications in Chemistry and Biology. Heidelberg, Berlin

    Book  Google Scholar 

  153. Deng YQ, Roux B (2009) J Phys Chem B 113:2234–2246

    Article  CAS  Google Scholar 

  154. Goodford PJ (1985) J Med Chem 28:849–857

    Article  CAS  Google Scholar 

  155. Helms V, Wade RC (1998) J Am Chem Soc 120:2710–2713

    Article  CAS  Google Scholar 

  156. MCPRO + version 2.6 (2009) Schrödinger. LLC, New York, NY

    Google Scholar 

  157. Bowers KJ, Chow E, Xu E, Drorr RO, Eastwood MP, Gregerson BA, Klepeis JL, Kollossvary I, Moraes MA, Sacerdoti FD, Salmon JK, Shan Y, Shaw DE (2006) Proceedings of the ACM/IEEE Conference on Supercomputing (SC06), Tampa, Floria

  158. Newman J, Fazio VJ, Caradoc-Davies TT, Branson K, Peat TS (2009) J Biomol Screen 14:1245–1250

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This research was partially supported (J.M.) by a Marie Curie International Outgoing Fellowship within the 7th European Community Framework Programme (FP7-PEOPLE-2008-4-1-IOF, 234796-PPIdesign).

Author information

Authors and Affiliations

  1. Institute of Structural and Molecular Biology, The University of Edinburgh, Edinburgh, EH9 3JR, UK

    Julien Michel

  2. Department of Chemistry, Yale University, New Haven, CT, 06520, USA

    Julien Michel

  3. School of Chemistry, University of Southampton, Highfield, Southampton, SO17 1BJ, UK

    Jonathan W. Essex

Authors
  1. Julien Michel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jonathan W. Essex
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Julien Michel.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Michel, J., Essex, J.W. Prediction of protein–ligand binding affinity by free energy simulations: assumptions, pitfalls and expectations. J Comput Aided Mol Des 24, 639–658 (2010). https://doi.org/10.1007/s10822-010-9363-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10822-010-9363-3

Keywords

Search

Navigation