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Challenges for Computer Simulations in Drug Design

  • Hannes G. Wallnoefer
  • Thomas Fox
  • Klaus R. Liedl
Chapter
Part of the Challenges and Advances in Computational Chemistry and Physics book series (COCH, volume 12)

Abstract

Many computational methods have become standard techniques in modern drug discovery. However, approaches which employ explicit molecular dynamics simulations still are restricted to special applications, as their extensive computational requirements make it difficult to obtain results within the necessary time scale of industrial drug development projects. Moreover, a high expertise is needed to analyze and interpret the enormous amount of resulting data. Nevertheless, both the increasing computational power, and theawareness that it is important to use not static, but flexible models of biomolecules to represent the properties of the system of interest, have brought computer simulations back into the focus of interest: they are the most straightforward method to include flexibility into the in silico description of molecules. Here, state-of-the-art methods, applications, and arising challenges of molecular dynamics simulations to support drug discovery are discussed.

Keywords

Simulations Molecular dynamics flexibility Structure-based drug design Virtual screening Docking Pharmacophore modelling Free energy prediction MM/PBSA MM/GBSA Linear interaction energy FEP/TI Water in proteins GPCR simulations 

References

  1. 1.
    Greer J, Erickson JW, Baldwin JJ et al (2002) J Med Chem 37:1035–1054Google Scholar
  2. 2.
    Jorgensen WL (2004) Science 303:1813–1818Google Scholar
  3. 3.
    Chand P, Kotian PL, Dehghani A et al (2001) J Med Chem 44:4379–4392Google Scholar
  4. 4.
    Gubernator K, Böhm H-J (1998) structure-based ligand design. Wiley-VCH Verlag GmbH, WeinheimGoogle Scholar
  5. 5.
    Hazuda DJ, Anthony NJ, Gomez RP et al (2004) Proc Natl Acad Sci USA 101:11233–11238Google Scholar
  6. 6.
    Schames JR, Henchman RH, Siegel JS et al (2004) J Med Chem 47:1879–1881Google Scholar
  7. 7.
    Liverton NJ, Holloway MK, McCauley JA et al (2008) J Am Chem Soc 130:4607–4609Google Scholar
  8. 8.
    Thomson JA, Perni RB (2006) Curr Opin Drug Disc Dev 9:606–617Google Scholar
  9. 9.
    Stauffer SR, Stanton MG, Gregro AR et al (2007) Bioorg Med Chem Lett 17:1788–1792Google Scholar
  10. 10.
    Hop CECA, Cole MJ, Davidson RE et al (2008) Curr Drug Metab 9:847–853Google Scholar
  11. 11.
    Jamei M, Marciniak S, Feng KR et al (2009) Expert Opin Drug Metab Toxicol 5:211–223Google Scholar
  12. 12.
    Nogueira RC, Oliveira-Costa JF, De Sa MS et al (2009) Curr Drug Targets 10:291–298Google Scholar
  13. 13.
    Selick HE, Beresford AP, Tarbit MH (2002) Drug Disc Today 7:109–116Google Scholar
  14. 14.
    van de Waterbeemd H, Gifford E (2003) Nat Drug Disc 2:192–204Google Scholar
  15. 15.
    Wang J, Hou T (2009) Annu Rep Comput Chem 5:101–103Google Scholar
  16. 16.
    Bolton V, Perutz M (1970) Nature 228:551–552Google Scholar
  17. 17.
    Fermi G, Perutz M, Shaanan B et al (1984) J Mol Biol 175:159–174Google Scholar
  18. 18.
    Kendrew J, Bodo GR, Dintzis H et al (1958) Nature 181:662–666Google Scholar
  19. 19.
    Watson H (1969) Prog Stereochem 4:299–333Google Scholar
  20. 20.
    Safo MK, Abraham DJ (2005) Biochemistry 44:8347–8359Google Scholar
  21. 21.
    Wolf-Watz M, Thai V, Henzler-Wildman K et al (2004) Nat Struct Mol Biol 11:945–949Google Scholar
  22. 22.
    Vonrhein C, Schlauderer GJ, Schulz GE (2009) Structure 3:483–490Google Scholar
  23. 23.
    Henzler-Wildman KA, Lei M, Thai V et al (2007) Nature 450:913–916Google Scholar
  24. 24.
    Hu X, Lazar MA (2000) Trends Endocrinol Metab 11:6–10Google Scholar
  25. 25.
    Hellal-Levy C, Fagart J, Souque A et al (2000) Mol Endocrinol 14:1210–1221Google Scholar
  26. 26.
    Henzler-Wildman K, Kern D (2007) Nature 450:964–972Google Scholar
  27. 27.
    Bahar I, Chennubhotla C, Tobi D (2007) Curr Opin Struct Biol 17:633–640Google Scholar
  28. 28.
    Cozzini P, Kellogg GE, Spyrakis F et al (2008) J Med Chem 51:6237–6255Google Scholar
  29. 29.
    Lee GM, Craik CS (2009) Science 324:213–215Google Scholar
  30. 30.
    Tsai CJ, Ma B, Nussinov R (1999) Proc Natl Acad Sci USA 96:9970–9972Google Scholar
  31. 31.
    Koshland DE, Nemethy G, Filmer D (2002) Biochemistry 5:365–385Google Scholar
  32. 32.
    Monod J, Wyman J, Changeux JP (1965) J Mol Biol 12:88–118Google Scholar
  33. 33.
    Weber G (2002) Biochemistry 11:864–878Google Scholar
  34. 34.
    Tsai CJ, Kumar S, Ma B et al (1999) Protein Sci 8:1181–1190Google Scholar
  35. 35.
    Berman HM, Westbrook J, Feng Z et al (2000) Nucl Acid Res 28:235–242Google Scholar
  36. 36.
    Tompa P (2002) Trends Biochem Sci 27:527–533Google Scholar
  37. 37.
    Zheng Q, Kyle DJ (1997) Drug Disc Today 2:229–234Google Scholar
  38. 38.
    Walters WP, Stahl MT, Murcko MA (1998) Drug Disc Today 3:160–178Google Scholar
  39. 39.
    Ma B, Kumar S, Tsai CJ et al (1999) Protein Eng 12:713–720Google Scholar
  40. 40.
    Freire E (1998) In: Richards FM (ed) Advances in protein chemistry – linkage thermodynamics of macromolecular interactions. Academic, San Diego, CAGoogle Scholar
  41. 41.
    Onuchic JN (1997) Proc Natl Acad Sci USA 94:7129–7131Google Scholar
  42. 42.
    Shoemaker B, Wang J, Wolynes P (1997) Proc Natl Acad Sci USA 94:777–782Google Scholar
  43. 43.
    Rejto PA, Freer ST (1996) Prog Biophys Mol Biol 66:167–196Google Scholar
  44. 44.
    Brem R, Dill KA (1999) Protein Sci 8:1134–1143Google Scholar
  45. 45.
    Boehr DD, Dyson HJ, Wright PE (2006) Chem Rev 106:3055–3079Google Scholar
  46. 46.
    Wüthrich K (2003) J Biomol NMR 27:13–39Google Scholar
  47. 47.
    Mulder FAA, Mittermaier A, Hon B et al (2001) Nat Struct Mol Biol 8:932–935Google Scholar
  48. 48.
    Ishima R, Torchia DA (2000) Nat Struct Mol Biol 7:740–743Google Scholar
  49. 49.
    Eisenmesser EZ, Millet O, Labeikovsky W et al (2005) Nature 438:117–121Google Scholar
  50. 50.
    Horst R, Wider G, Fiaux J et al (2006) Proc Natl Acad Sci USA 103:15445–15450Google Scholar
  51. 51.
    Grishaev A, Tugarinov V, Kay L et al (2008) J Biomol NMR 40:95–106Google Scholar
  52. 52.
    Sprangers R, Velyvis A, Kay LE (2007) Nat Meth 4:697–703Google Scholar
  53. 53.
    Liang B, Tamm LK (2007) Proc Natl Acad Sci USA 104:16140–16145Google Scholar
  54. 54.
    Cioffi M, Hunter CA, Packer MJ et al (2008) J Med Chem 51:2512–2517Google Scholar
  55. 55.
    Ramos CRR, Figueredo RCR, Pertinhez TA et al (2003) J Biol Chem 278:12745–12751Google Scholar
  56. 56.
    Pertinhez T, Sforça M, Alves A et al (2004) J Biomol NMR 29:553–554Google Scholar
  57. 57.
    Vitkup D, Ringe D, Karplus M et al (2002) Proteins 46:345–354Google Scholar
  58. 58.
    Merritt E (1999) Acta Cryst Sect D 55:1109–1117Google Scholar
  59. 59.
    Schmidt A, Lamzin V (2007) Cell Mol Life Sci 64:1959–1969Google Scholar
  60. 60.
    Bossi RT, Aliverti A, Raimondi D et al (2002) Biochemistry 41:8807–8818Google Scholar
  61. 61.
    Ringe D, Petsko GA (1985) Prog Biophys Mol Biol 45:197–235Google Scholar
  62. 62.
    Bourgeois D, Royant A (2005) Curr Opin Struct Biol 15:538–547Google Scholar
  63. 63.
    Somogyi B, Lakos Z, Szarka A et al (2000) J Photochem Photobiol B: Biol 59:26–32Google Scholar
  64. 64.
    Hubbell WL, Cafiso DS, Altenbach C (2000) Nat Struct Mol Biol 7:735–739Google Scholar
  65. 65.
    Lipfert J, Doniach S (2007) Annu Rev Biophys Biomol Struct 36:307–327Google Scholar
  66. 66.
    Katona G, Carpentier P, Niviere V et al (2007) Science 316:449–453Google Scholar
  67. 67.
    McCammon JA, Gelin BR, Karplus M (1977) Nature 267:585–590Google Scholar
  68. 68.
    Freddolino PL, Liu F, Gruebele M et al (2008) Biophys J 94:L75–L77Google Scholar
  69. 69.
    Klepeis JL, Lindorff-Larsen K, Dror RO et al (2009) Curr Opin Struct Biol 19:120–127Google Scholar
  70. 70.
    Maragakis P, Lindorff-Larsen K, Eastwood MP et al (2008) J Phys Chem B 112:6155–6158Google Scholar
  71. 71.
    Perez A, Luque FJ, Orozco M (2007) J Am Chem Soc 129:14739–14745Google Scholar
  72. 72.
    Romo TD, Grossfield A, Pitman MC et al (2009) Biophys J 96:340a–340aGoogle Scholar
  73. 73.
    Vaiana AC, Sanbonmatsu KY (2009) J Mol Biol 386:648–661Google Scholar
  74. 74.
    McCammon JA, Wolynes PG, Karplus M (2002) Biochemistry 18:927–942Google Scholar
  75. 75.
    van Gunsteren WF, Karplus M (1981) Nature 293:677–678Google Scholar
  76. 76.
    Lin H, Truhlar DG (2007) Theor Chem Acc 117:185–199Google Scholar
  77. 77.
    Gleeson MP, Gleeson D (2009) J Chem Inf Model 49:1437–1448Google Scholar
  78. 78.
    Senn HM, Thiel W (2009) Angew Chem Int Ed 48:1198–1229Google Scholar
  79. 79.
    Bakowies D, Thiel W (1996) J Phys Chem 100:10580–10594Google Scholar
  80. 80.
    Gogonea V, Suβrez D, Avd V et al (2001) Curr Opin Struct Biol 11:217–223Google Scholar
  81. 81.
    Case DA, Darden TE, Cheatham TE et al (2008) AMBER 10. University of California, San Francisco, CAGoogle Scholar
  82. 82.
    Brooks BR, Bruccoleri RE, Olafson BD et al (1983) J Comput Chem 4:187–217Google Scholar
  83. 83.
    Van Der Spoel D, Lindahl E, Hess B et al (2005) J Comput Chem 26:1701–1718Google Scholar
  84. 84.
    Phillips JC, Braun R, Wang W et al (2005) J Comput Chem 26:1781–1802Google Scholar
  85. 85.
    Berendsen HJC, Postma J, van Gunsteren W et al (1981) In: Pullman B (ed) Intermolecular Forces. D.Reidel, Dordrecht, The NederlandsGoogle Scholar
  86. 86.
    Jorgensen WL, Maxwell DS, Tirado-Rives J (1996) J Am Chem Soc 118:11225–11236Google Scholar
  87. 87.
    Mongan J (2004) J Comput Aided Mol Des 18:433–436Google Scholar
  88. 88.
    Hess B (2000) Phys Rev E 62:8438Google Scholar
  89. 89.
    Hess B (2002) Phys Rev E 65:031910Google Scholar
  90. 90.
    Gund P (1977) Prog Mol Subcell Biol 5:117–143Google Scholar
  91. 91.
    Mallik B, Morikis D (2005) J Am Chem Soc 127:10967–10976Google Scholar
  92. 92.
    Bernard D, Coop A, MacKerell AD (2003) J Am Chem Soc 125:3101–3107Google Scholar
  93. 93.
    Deng J, Taheri L, Grande F et al (2008) Chem Med Chem 3:1677–1686Google Scholar
  94. 94.
    Meagher KL, Carlson HA (2004) J Am Chem Soc 126:13276–13281Google Scholar
  95. 95.
    Meagher KL, Lerner MG, Carlson HA (2006) J Med Chem 49:3478–3484Google Scholar
  96. 96.
    Carlson HA, Masukawa KM, Rubins K et al (2000) J Med Chem 43:2100–2114Google Scholar
  97. 97.
    Deng J, Sanchez T, Neamati N et al (2006) J Med Chem 49:1684–1692Google Scholar
  98. 98.
    Bowman AL, Lerner MG, Carlson HA (2007) J Am Chem Soc 129:3634–3640Google Scholar
  99. 99.
    Damm KL, Carlson HA (2007) J Am Chem Soc 129:8225–8235Google Scholar
  100. 100.
    Kuntz ID, Blaney JM, Oatley SJ et al (1982) J Mol Biol 161:269–288Google Scholar
  101. 101.
    Goodsell DS, Olson AJ (1990) Proteins 8:195–202Google Scholar
  102. 102.
    Morris GM, Goodsell DS, Huey R et al (1996) J Comput Aided Mol Des 10:293–304Google Scholar
  103. 103.
    Morris GM, Goodsell DS, Halliday RS et al (1998) J Comput Chem 19:1639–1662Google Scholar
  104. 104.
    Rarey M, Kramer B, Lengauer T et al (1996) J Mol Biol 261:470–489Google Scholar
  105. 105.
    Cavasotto CN, Abagyan RA (2004) J Mol Biol 337:209–225Google Scholar
  106. 106.
    Claussen H, Buning C, Rarey M et al (2001) J Mol Biol 308:377–395Google Scholar
  107. 107.
    Huey R, Morris GM, Olson AJ et al (2007) J Comput Chem 28:1145–1152Google Scholar
  108. 108.
    Jain A (2007) J Comput Aided Mol Des 21:281–306Google Scholar
  109. 109.
    Österberg F, Morris GM, Sanner MF et al (2002) Proteins 46:34–40Google Scholar
  110. 110.
    Verdonk ML, Cole JC, Hartshorn MJ et al (2003) Proteins 52:609–623Google Scholar
  111. 111.
    Wei BQ, Weaver LH, Ferrari AM et al (2004) J Mol Biol 337:1161–1182Google Scholar
  112. 112.
    Jones G, Willett P, Glen RC (1995) J Mol Biol 245:43–53Google Scholar
  113. 113.
    Schnecke V, Swanson CA, Getzoff ED et al (1998) Proteins 33:74–87Google Scholar
  114. 114.
    Leach AR (1994) J Mol Biol 235:345–356Google Scholar
  115. 115.
    Schaffer L, Verkhivker GM (1998) Proteins 33:295–310Google Scholar
  116. 116.
    Zavodszky MI, Kuhn LA (2005) Protein Sci 14:1104–1114Google Scholar
  117. 117.
    Zavodszky MI, Lei M, Thorpe MF et al (2004) Proteins 57:243–261Google Scholar
  118. 118.
    Cavasotto CN, Kovacs JA, Abagyan RA (2005) J Am Chem Soc 127:9632–9640Google Scholar
  119. 119.
    Kallblad P, Dean PM (2003) J Mol Biol 326:1651–1665Google Scholar
  120. 120.
    Nabuurs SB, Wagener M, de Vlieg J (2007) J Med Chem 50:6507–6518Google Scholar
  121. 121.
    Kuhn LA (2008) In: Stroud RM, Finer-Moore J (eds) Computational and structural approaches to drug discovery: ligand-protein interactions. RSC Publishing, CambridgeGoogle Scholar
  122. 122.
    McCammon JA (2005) Biochim Biophys Acta 1754:221–224Google Scholar
  123. 123.
    Lin JH, Perryman AL, Schames JR et al (2002) J Am Chem Soc 124:5632–5633Google Scholar
  124. 124.
    Lin J-H, Perryman AL, Schames JR et al (2003) Biopolymers 68:47–62Google Scholar
  125. 125.
    Knegtel RMA, Kuntz ID, Oshiro CM (1997) J Mol Biol 266:424–440Google Scholar
  126. 126.
    Macchiarulo A, Nobeli I, Thornton JM (2004) Nat Biotech 22:1039–1045Google Scholar
  127. 127.
    Sotriffer CA, Dramburg I (2005) J Med Chem 48:3122–3125Google Scholar
  128. 128.
    Klebe G, Krämer O, Sotriffer CA (2004) Cell Mol Life Sci 61:783–793Google Scholar
  129. 129.
    Sotriffer CA, Krämer O, Klebe G (2004) Proteins 56:52–66Google Scholar
  130. 130.
    Steuber H, Zentgraf M, Gerlach C et al (2006) J Mol Biol 363:174–187Google Scholar
  131. 131.
    Steuber H, Zentgraf M, Podjarny A et al (2006) J Mol Biol 356:45–56Google Scholar
  132. 132.
    Da Settimo F, Primofiore G, La Motta C et al (2005) J Med Chem 48:6897–6907Google Scholar
  133. 133.
    Zentgraf M, Steuber H, Koch C et al (2007) Angew Chem Int Ed 46:3575–3578Google Scholar
  134. 134.
    Hamelberg D, Mongan J, McCammon JA (2004) J Chem Phys 120:11919–11929Google Scholar
  135. 135.
    Egbertson MS (2007) Curr Top Med Chem 7:1251–1272Google Scholar
  136. 136.
    Keskin O, Gursoy A, Ma B et al (2008) Chem Rev 108:1225–1244Google Scholar
  137. 137.
    Król M, Tournier AL, Bates PA (2007) Proteins 68:159–169Google Scholar
  138. 138.
    Gottschalk KE, Neuvirth H, Schreiber G (2004) Protein Eng 17:183–189Google Scholar
  139. 139.
    Duan Y, Reddy BVB, Kaznessis YN (2005) Protein Sci 14:316–328Google Scholar
  140. 140.
    Smith GR, Sternberg MJE, Bates PA (2005) J Mol Biol 347:1077–1101Google Scholar
  141. 141.
    Burlingham BT, Widlanski TS (2003) J Chem Educ 80:214–218Google Scholar
  142. 142.
    Yung-Chi C, Prusoff WH (1973) Biochem Pharmacol 22:3099–3108Google Scholar
  143. 143.
    Cheluvaraja S, Meirovitch H (2008) J Chem Theor Comput 4:192–208Google Scholar
  144. 144.
    Cheluvaraja S, Mihailescu M, Meirovitch H (2008) J Phys Chem B 112:9512–9522Google Scholar
  145. 145.
    Deng Y, Roux B (2009) J Phys Chem B 113:2234–2246Google Scholar
  146. 146.
    Meirovitch H, Cheluvaraja S, White RP (2009) Curr Protein Pept Sci 10:229–243Google Scholar
  147. 147.
    Mihailescu M, Meirovitch H (2009) J Phys Chem B 113:7950–7964Google Scholar
  148. 148.
    Miyamoto S, Kollman PA (1993) Proteins 16:226–245Google Scholar
  149. 149.
    Zhang X, Mamonov AB, Zuckerman DM (2009) J Comput Chem 30:1680–1691Google Scholar
  150. 150.
    Kirkwood JG (1935) J Chem Phys 3:300–313Google Scholar
  151. 151.
    Zwanzig RW (1954) I Nonpolar Gases J Chem Phys 22:1420–1426Google Scholar
  152. 152.
    Åqvist J, Medina C, Samuelsson JE (1994) Protein Eng 7:385–391Google Scholar
  153. 153.
    Lee MS, Olson MA (2006) Biophys J 90:864–877Google Scholar
  154. 154.
    Kollman P (1993) Chem Rev 93:2395–2417Google Scholar
  155. 155.
    Huang N, Jacobson MP (2007) Curr Opin Drug Disc Dev 10:325–331Google Scholar
  156. 156.
    Gilson MK, Zhou HX (2007) Annu Rev Biophys Biomol Struct 36:21Google Scholar
  157. 157.
    Foloppe N, Hubbard RE (2006) Curr Med Chem 13:3583–3608Google Scholar
  158. 158.
    Honig B, Nicholls A (1995) Science 268:1144–1149Google Scholar
  159. 159.
    Still WC, Tempczyk A, Hawley RC et al (1990) J Am Chem Soc 112:6127–6129Google Scholar
  160. 160.
    Bryce RA, Hillier IH, Naismith JH (2001) Biophys J 81:1373–1388Google Scholar
  161. 161.
    Bashford D, Case DA (2000) Annu Rev Phys Chem 51:129–152Google Scholar
  162. 162.
    Kuhn B, Kollman PA (2000) J Med Chem 43:3786–3791Google Scholar
  163. 163.
    Gouda H, Kuntz ID, Case DA et al (2003) Biopolymers 68:16–34Google Scholar
  164. 164.
    Barril X, Gelpi JL, Lopez JM et al (2001) Theor Chem Acc 106:2–9Google Scholar
  165. 165.
    Masukawa KM, Kollman PA, Kuntz ID (2003) J Med Chem 46:5628–5637Google Scholar
  166. 166.
    Bea I, Cervello E, Kollman PA et al (2001) Comb Chem High Throughput Screen 4:605–611Google Scholar
  167. 167.
    Cox SR, Williams DE (1981) J Comput Chem 2:304–323Google Scholar
  168. 168.
    Pearlman DA (2005) J Med Chem 48:7796–7807Google Scholar
  169. 169.
    Swanson JMJ, Henchman RH, McCammon JA (2004) Biophys J 86:67–74Google Scholar
  170. 170.
    Gilson MK, Honig B (1988) Proteins 4:7–18Google Scholar
  171. 171.
    Scarsi M, Caflisch A (1999) J Comput Chem 20:1533–1536Google Scholar
  172. 172.
    Sharp KA (1994) Curr Opin Struct Biol 4:234–239Google Scholar
  173. 173.
    Holst M, Saied F (1993) J Comput Chem 14:105–113Google Scholar
  174. 174.
    Warwicker J, Watson HC (1982) J Mol Biol 157:671–679Google Scholar
  175. 175.
    Honig B, Nicholls A (1995) Science 268:1144–1149Google Scholar
  176. 176.
    Gilson MK, Sharp KA, Honig BH (1988) J Comput Chem 9:327–335Google Scholar
  177. 177.
    Shen J, Wendoloski J (1996) J Comput Chem 17:350–357Google Scholar
  178. 178.
    Baker NA, Sept D, Joseph S et al (2001) Proc Natl Acad Sci USA 98:10037–10041Google Scholar
  179. 179.
    Bashford D, Gerwert K (1992) J Mol Biol 224:473–486Google Scholar
  180. 180.
    Im W, Beglov D, Roux B (1998) Comput Phys Commun 111:59–75Google Scholar
  181. 181.
    Ma C, Baker NA, Joseph S et al (2002) J Am Chem Soc 124:1438–1442Google Scholar
  182. 182.
    Madura JD, Briggs JM, Wade RC et al (1995) Comput Phys Commun 91:57–95Google Scholar
  183. 183.
    Gilson MK, Honig BH (1986) Biopolymers 25:2097–2119Google Scholar
  184. 184.
    Sharp KA, Honig B (1990) Annu Rev Biophys Biophys Chem 19:301–332Google Scholar
  185. 185.
    Simonson T, Perahia D (1995) Proc Natl Acad Sci USA 92:1082–1086Google Scholar
  186. 186.
    Simonson T, Perahia D (1995) Comput Phys Commun 91:291–303Google Scholar
  187. 187.
    Antosiewicz J, McCammon JA, Gilson MK (1994) J Mol Biol 238:415–436Google Scholar
  188. 188.
    Demchuk E, Wade RC (1996) J Phys Chem 100:17373–17387Google Scholar
  189. 189.
    Demchuk E, Genick UK, Woo TT et al (2000) Biochemistry 39:1100–1113Google Scholar
  190. 190.
    Foloppe N, Sagemark J, Nordstrand K et al (2001) J Mol Biol 310:449–470Google Scholar
  191. 191.
    Grant JA, Pickup BT, Nicholls A (2001) J Comput Chem 22:608–640Google Scholar
  192. 192.
    Richards FM (1977) Annu Rev Biophys Bioeng 6:151–176Google Scholar
  193. 193.
    Swanson JMJ, Mongan J, McCammon JA (2005) J Phys Chem B 109:14769–14772Google Scholar
  194. 194.
    Nina M, Beglov D, Roux B (1997) J Phys Chem B 101:5239–5248Google Scholar
  195. 195.
    Nina M, Im W, Roux B (1999) Biophys Chem 78:89–96Google Scholar
  196. 196.
    Sitkoff D, Sharp KA, Honig B (1994) J Phys Chem 98:1978–1988Google Scholar
  197. 197.
    Swanson JMJ, Adcock SA, McCammon JA (2005) J Chem Theory Comput 1:484–493Google Scholar
  198. 198.
    Wang J, Morin P, Wang W et al (2001) J Am Chem Soc 123:5221–5230Google Scholar
  199. 199.
    Froloff N, Windemuth A, Honig B (1997) Protein Sci 6:1293–1301Google Scholar
  200. 200.
    Huo S, Wang J, Cieplak P et al (2002) J Med Chem 45:1412–1419Google Scholar
  201. 201.
    Schwarzl SM, Tschopp TB, Smith JC et al (2002) J Comput Chem 23:1143–1149Google Scholar
  202. 202.
    Tanford C (1978) Science 200:1012–1018Google Scholar
  203. 203.
    Blokzijl W, Engberts JBFN (1993) Angew Chem Int Ed 32:1545–1579Google Scholar
  204. 204.
    Gao J, Qiao S, Whitesides GM (1995) J Med Chem 38:2292–2301Google Scholar
  205. 205.
    Hunenberger PH, Helms V, Narayana N et al (1999) Biochemistry 38:2358–2366Google Scholar
  206. 206.
    Janin J, Chothia C (1978) Biochemistry 17:2943–2948Google Scholar
  207. 207.
    Scarsi M, Majeux N, Caflisch A (1999) Proteins 37:565–575Google Scholar
  208. 208.
    Hermann RB (1972) J Phys Chem 76:2754–2759Google Scholar
  209. 209.
    Reynolds JA, Gilbert DB, Tanford C (1974) Proc Natl Acad Sci USA 71:2925–2927Google Scholar
  210. 210.
    Sims PA, Wong CF, McCammon JA (2003) J Med Chem 46:3314–3325Google Scholar
  211. 211.
    Shen J, Wendoloski J (1995) Protein Sci 4:373–381Google Scholar
  212. 212.
    Sharp KA, Nicholls A, Fine RF et al (1991) Science 252:106–109Google Scholar
  213. 213.
    Doyle ML (1997) Curr Opin Biotechnol 8:31–35Google Scholar
  214. 214.
    Leavitt S, Freire E (2001) Curr Opin Struct Biol 11:560–566Google Scholar
  215. 215.
    Weber PC, Salemme FR (2003) Curr Opin Struct Biol 13:115–121Google Scholar
  216. 216.
    Finkelstein AV, Janin J (1989) Protein Eng 3:1–3Google Scholar
  217. 217.
    Murray CW, Verdonk ML (2002) J Comput Aided Mol Des 16:741–753Google Scholar
  218. 218.
    Page MI, Jencks WP (1971) Proc Natl Acad Sci USA 68:1678–1683Google Scholar
  219. 219.
    Gidofalvi G, Wong CF, McCammon JA (2002) J Chem Educ 79:1122–1126Google Scholar
  220. 220.
    Sirockin F, Sich C, Improta S et al (2002) J Am Chem Soc 124:11073–11084Google Scholar
  221. 221.
    Searle MS, Williams DH (1992) J Am Chem Soc 114:10690–10697Google Scholar
  222. 222.
    Bonnet P, Bryce RA (2004) Protein Sci 13:946–957Google Scholar
  223. 223.
    Foloppe N, Fisher LM, Howes R et al (2005) J Med Chem 48:4332–4345Google Scholar
  224. 224.
    Steinbrecher T, Case DA, Labahn A (2006) J Med Chem 49:1837–1844Google Scholar
  225. 225.
    Zhou Z, Madura JD (2004) Proteins 57:493–503Google Scholar
  226. 226.
    Kollman PA, Massova I, Reyes C et al (2000) Acc Chem Res 33:889–897Google Scholar
  227. 227.
    Hou T, Guo S, Xu X (2002) J Phys Chem B 106:5527–5535Google Scholar
  228. 228.
    Karplus M, Kushick JN (1981) Macromolecules 14:325–332Google Scholar
  229. 229.
    Ferrara P, Gohlke H, Price DJ et al (2004) J Med Chem 47:3032–3047Google Scholar
  230. 230.
    Huang D, Caflisch A (2004) J Med Chem 47:5791–5797Google Scholar
  231. 231.
    Kuhn B, Gerber P, Schulz-Gasch T et al (2005) J Med Chem 48:4040–4048Google Scholar
  232. 232.
    Zou X, Sun Y, Kuntz ID (1999) J Am Chem Soc 121:8033–8043Google Scholar
  233. 233.
    Barril X, Aleman C, Orozco M et al (1998) Proteins 32:67–79Google Scholar
  234. 234.
    Woods CJ, King MA, Essex JW (2001) J Comput Aided Mol Des 15:129–144Google Scholar
  235. 235.
    Rizzo RC, Toba S, Kuntz ID (2004) J Med Chem 47:3065–3074Google Scholar
  236. 236.
    Donini OAT, Kollman PA (2000) J Med Chem 43:4180–4188Google Scholar
  237. 237.
    Kuhn B, Kollman PA (2000) J Med Chem 43:3786–3791Google Scholar
  238. 238.
    Mardis KL, Luo R, Gilson MK (2001) J Mol Biol 309:507–517Google Scholar
  239. 239.
    Zhou R, Friesner RA, Ghosh A et al (2001) J Phys Chem B 105:10388–10397Google Scholar
  240. 240.
    Resat H, McCammon JA (1996) J Chem Phys 104:7645–7651Google Scholar
  241. 241.
    Simonson T, Archontis G, Karplus M (2002) Acc Chem Res 35:430–437Google Scholar
  242. 242.
    Åqvist J (1996) J Comput Chem 17:1587–1597Google Scholar
  243. 243.
    Åqvist J, Marelius J (2001) Comb Chem High Throughput Screen 4:613–626Google Scholar
  244. 244.
    Åqvist J, Luzhkov VB, Brandsdal BO (2002) Acc Chem Res 35:358–365Google Scholar
  245. 245.
    Jones-Hertzog DK, Jorgensen WL (1997) J Med Chem 40:1539–1549Google Scholar
  246. 246.
    Hansson T, Marelius J, Åqvist J (1998) J Comput Aided Mol Des 12:27–35Google Scholar
  247. 247.
    Essex JW, Jorgensen WL (1995) J Comput Chem 16:951–972Google Scholar
  248. 248.
    Pierce AC, Jorgensen WL (2001) J Med Chem 44:1043–1050Google Scholar
  249. 249.
    Wall ID, Leach AR, Salt DW et al (1999) J Med Chem 42:5142–5152Google Scholar
  250. 250.
    Wang J, Dixon R, Kollman PA (1999) Proteins 34:69–81Google Scholar
  251. 251.
    Zoete V, Michielin O, Karplus M (2003) J Comput Aided Mol Des 17:861–880Google Scholar
  252. 252.
    Ljungberg KB, Marelius J, Musil D et al (2001) Eur J Pharm Sci 12:441–446Google Scholar
  253. 253.
    Hansson T, Åqvist J (1995) Protein Eng 8:1137–1144Google Scholar
  254. 254.
    Tounge BA, Reynolds CH (2003) J Med Chem 46:2074–2082Google Scholar
  255. 255.
    Rizzo RC, Tirado-Rives J, Jorgensen WL (2001) J Med Chem 44:145–154Google Scholar
  256. 256.
    Svab I, Alexandru D, Vitos G et al (2004) J Cell Mol Med 8:551–562Google Scholar
  257. 257.
    Dey I (1999) J Biomol Struct Dyn 16:891–900Google Scholar
  258. 258.
    Lamb ML, Tirado-Rives J, Jorgensen WL (1999) Bioorg Med Chem 7:851–860Google Scholar
  259. 259.
    Smith RH Jr, Jorgensen WL, Tirado-Rives J et al (1998) J Med Chem 41:5272–5286Google Scholar
  260. 260.
    Pierce KL, Premont RT, Lefkowitz RJ (2002) Nat Rev Mol Cell Biol 3:639–650Google Scholar
  261. 261.
    Hulten J, Bonham NM, Nillroth U et al (1997) J Med Chem 40:885–897Google Scholar
  262. 262.
    Graffner-Nordberg M, Kolmodin K, Åqvist J et al (2001) J Med Chem 44:2391–2402Google Scholar
  263. 263.
    Singh P, Mhaka AM, Christensen SB et al (2005) J Med Chem 48:3005–3014Google Scholar
  264. 264.
    Paulsen MD, Ornstein RL (1996) Protein Eng 9:567–571Google Scholar
  265. 265.
    Chen J, Wang R, Taussig M et al (2001) J Org Chem 66:3021–3026Google Scholar
  266. 266.
    Wang W, Wang J, Kollman PA (1999) Proteins 34:395–402Google Scholar
  267. 267.
    Chipot C (2003) J Comput Chem 24:409–415Google Scholar
  268. 268.
    Carlson HA, Jorgensen WL (1995) J Phys Chem 99:10667–10673Google Scholar
  269. 269.
    Rizzo RC, Udier-Blagovic M, Wang DP et al (2002) J Med Chem 45:2970–2987Google Scholar
  270. 270.
    Jorgensen WL, Ravimohan C (1985) J Chem Phys 83:3050–3054Google Scholar
  271. 271.
    Jorgensen WL, Tirado-Rives J (2005) Proc Natl Acad Sci USA 102:6665–6670Google Scholar
  272. 272.
    Bennett CH (1976) J Comput Phys 22:245–268Google Scholar
  273. 273.
    Lawrenz M, Baron R, McCammon JA (2009) J Chem Theor Comput 5:1106–1116Google Scholar
  274. 274.
    Adcock SA, McCammon JA (2006) Chem Rev 106:1589–1615Google Scholar
  275. 275.
    Zagrovic B, van Gunsteren WF (2006) J Chem Theor Comput 3:301–311Google Scholar
  276. 276.
    Fujitani H, Tanida Y, Ito M et al (2005) J Chem Phys 123:084108–5Google Scholar
  277. 277.
    Reinhardt WP, Miller MA, Amon LM (2001) Acc Chem Res 34:607–614Google Scholar
  278. 278.
    Fajer M, Hamelberg D, McCammon JA (2008) J Chem Theor Comput 4:1565–1569Google Scholar
  279. 279.
    Woods CJ, Essex JW, King MA (2003) J Phys Chem B 107:13703–13710Google Scholar
  280. 280.
    de Oliveira CA, Hamelberg D, McCammon JA (2008) J Chem Theor Comput 4:1516–1525Google Scholar
  281. 281.
    Hamelberg D, de Oliveira CA, McCammon JA (2007) J Chem Phys 127:155102–155109Google Scholar
  282. 282.
    Steinbrecher T, Hrenn A, Dormann KL et al (2008) Bioorg Med Chem 16:2385–2390Google Scholar
  283. 283.
    Lundstrom K (2006) Curr Protein Pept Sci 7:465–470Google Scholar
  284. 284.
    Palczewski K (2006) Annu Rev Biochem 75:743Google Scholar
  285. 285.
    Fanelli F, De Benedetti PG (2005) Chem Rev 105:3297–3351Google Scholar
  286. 286.
    Cherezov V, Rosenbaum DM, Hanson MA et al (2007) Science 318:1258–1265Google Scholar
  287. 287.
    Rasmussen SGF, Choi HJ, Rosenbaum DM et al (2007) Nature 450:383–387Google Scholar
  288. 288.
    Warne T, Serrano-Vega MJ, Baker JG et al (2008) Nature 454:486–491Google Scholar
  289. 289.
    Kenakin T (2002) Nat Rev Drug Discov 1:103–110Google Scholar
  290. 290.
    Cremades N, Sancho J, Freire E (2006) Trends Biochem Sci 31:494–496Google Scholar
  291. 291.
    Barnett-Norris J, Lynch D, Reggio PH (2005) Life Sci 77:1625–1639Google Scholar
  292. 292.
    Fanelli F, De Benedetti PG (2006) J Comput Aided Mol Des 20:449–461Google Scholar
  293. 293.
    Feng X, Muller T, Mizrachi D et al (2008) Endocrinol 149:1705–1717Google Scholar
  294. 294.
    Angelova K, Fanelli F, Puett D (2008) Mol Endocrinol 22:126–138Google Scholar
  295. 295.
    Raimondi F, Seeber M, De Benedetti PG et al (2008) J Am Chem Soc 130:4310–4325Google Scholar
  296. 296.
    Seeber M, De Benedetti PG, Fanelli F (2003) J Chem Inf Model 43:1520–1531Google Scholar
  297. 297.
    Vitale RM, Pedone C, De Benedetti PG et al (2004) Proteins 56:430–448Google Scholar
  298. 298.
    Yan F, Mosier PD, Westkaemper RB et al (2008) Biochemistry 47:1567–1578Google Scholar
  299. 299.
    Ballesteros JA, Jensen AD, Liapakis G et al (2001) J Biol Chem 276:29171–29177Google Scholar
  300. 300.
    Dror RO, Arlow DH, Borhani DW et al (2009) Proc Natl Acad Sci USA 106:4689–4694Google Scholar
  301. 301.
    Wolf S, Böckmann M, Höweler U et al (2008) FEBS lett 582:3335–3342Google Scholar
  302. 302.
    Hamelberg D, McCammon JA (2004) J Am Chem Soc 126:7683–7689Google Scholar
  303. 303.
    Lu YP, Yang CY, Wang SM (2006) J Am Chem Soc 128:11830–11839Google Scholar
  304. 304.
    Zhang L, Hermans J (1996) Proteins 24:433–438Google Scholar
  305. 305.
    Olano LR, Rick SW (2004) J Am Chem Soc 126:7991–8000Google Scholar
  306. 306.
    Lounnas V, Pettitt BM (1994) Proteins 18:133–147Google Scholar
  307. 307.
    Bizzarri AR, Cannistraro S (2002) J Phys Chem B 106:6617–6633Google Scholar
  308. 308.
    Luise A, Falconi M, Desideri A (2000) Proteins 39:56–67Google Scholar
  309. 309.
    Otting G, Liepinsh E, Wüthrich K (1991) Science 254:974–980Google Scholar
  310. 310.
    Henchman RH, McCammon JA (2002) J Comput Chem 23:861–869Google Scholar
  311. 311.
    Huang HC, Jupiter D, Qiu M et al (2008) Biopolymers 89:210–219Google Scholar
  312. 312.
    Brunne RM, Liepinsh E, Otting G et al (1993) J Mol Biol 231:1040–1048Google Scholar
  313. 313.
    Barillari C, Taylor J, Viner R et al (2007) J Am Chem Soc 129:2577–2587Google Scholar
  314. 314.
    Abel R, Young T, Farid R et al (2008) J Am Chem Soc 130:2817–2831Google Scholar
  315. 315.
    Lazaridis T (1998) The Journal of Physical Chemistry B 102:3531–3541Google Scholar
  316. 316.
    Van Drie J (2007) J Comput Aided Mol Des 21:591–601Google Scholar
  317. 317.
    Moore GE (1965) Electronics 38:114–117Google Scholar
  318. 318.
    Mitsutake A, Sugita Y, Okamoto Y (2001) Biopolymers 60:86–123Google Scholar
  319. 319.
    Okabe T, Kawata M, Okamoto Y et al (2001) Chem Phys Lett 335:435–439Google Scholar
  320. 320.
    Berg BA, Neuhaus T (1992) Phys RevLett 68:9–12Google Scholar
  321. 321.
    Kubitzki MB, de Groot BL (2007) Biophys J 92:4262–4270Google Scholar
  322. 322.
    Shaw, DE, Deneroff, MM, Dror, RO et al (2007) Anton, a special-purpose machine for molecular dynamics simulation. Proceedings of the 34th annual international symposium on computer architecture, San Diego, CaliforniaGoogle Scholar
  323. 323.
    Miller BT, Singh RP, Klauda JB et al (2008) J Chem Inf Model 48:1920–1929Google Scholar
  324. 324.
    Stjernschantz E, Marelius J, Medina C et al (2006) J Chem Inf Model 46:1972–1983Google Scholar

Copyright information

© Springer Netherlands 2010

Authors and Affiliations

  • Hannes G. Wallnoefer
    • 1
    • 2
  • Thomas Fox
    • 1
  • Klaus R. Liedl
    • 2
  1. 1.Computational Chemistry, Department of Lead DiscoveryBoehringer Ingelheim Pharma GmbH & Co. KGBiberachGermany
  2. 2.Institute of General, Inorganic and Theoretical ChemistryUniversity of InnsbruckInnsbruckAustria

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