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QSAR and Molecular Modeling Studiesof Factor Xa and Thrombin Inhibitors

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QSAR and Molecular Modeling Studies in Heterocyclic Drugs II

Part of the book series: Topics in Heterocyclic Chemistry ((TOPICS,volume 4))

Abstract

Thrombotic disorders remain the major cause of death and disability in Western society. Many approaches to develop antithrombotic drugs that interfere with enzymes in the coagulation system have been pursued over the past few decades. Factor FXa and thrombin are both bound to and are enzymatically active in blood clots. In this article, a brief review is presented on the QSAR and molecular modelling studies on FXa and thrombin inhibitors reported during the last decade. The results from the widely used CoMFA and CoMSIA methods have been included. Analogues with various heterocyclic rings, isoquinoline derivatives, five- or six-membered heteroaryl derivatives, benzoxazinones, and tetrazoles are included in the discussion. Hydrophobic property of molecules is shown to play a significant role. In most of the cases, CMR/MR as well as Sterimol parameters have been shown to be important. Electronic factors, with the exception of the Hammett's constant, have not been found to be of much importance.

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Abbreviations

AFMoC:

Adaptation of fields for molecular comparison

Å:

Angstrom

AVRES:

Average of absolute values of residuals

C log P:

Lipophilicity values calculated theoretically according to Hansch and Leo

CoMSIA:

Comparative molecular similarity index analysis

CoMFA:

Comparative molecular field analysis

COMBINE:

Comparative binding energy

Df:

Degrees of freedom

LFER:

Free energy related

LMWS:

Low molecular weight heparins

GA-MLR:

Genetic algorithm multiple linear regression

MLR:

Multiple linear regression

PLS:

Partial least squares

PDB:

Protein data bank

QSAR:

Quantitative structure activity relationships

QSPR:

Quantitative structure property relationships

PRESS:

Sum of the squared errors of prediction

r2 a :

Adjusted correlation coefficient

r2 bs :

Bootstrapped correlation coefficient

r2 pred :

(SD-PRESS)/SD

RMS:

Root mean square

RMSE:

Root mean square error

S press :

Standard deviation sum of the squared errors of prediction

SDEP:

Standard deviation sum of the error of prediction

SlogP:

Program for the estimation of logP using the atom – weighted solvent accessible surface areas

tPA:

Tissue-type plasminogen activator

TScore:

Tailored scored function

uPA:

Urokinase-type plasminogen activator

References

  1. Babine RE, Bender SL (1997) Chem Rev 97:1359

    CAS  Google Scholar 

  2. Ripka AS, Rich DH (1998) Curr Opin Chem Biol 2:441

    CAS  Google Scholar 

  3. Shaw E (1990) Adv Enzymol Relat Areas Mol Biol 63:271

    CAS  Google Scholar 

  4. Leung D, Abbenante G, Fairlie DP (2000) J Med Chem 43:305

    CAS  Google Scholar 

  5. Schechter I, Berger A (1967) Biochem Biophys Res Commun 27:157

    CAS  Google Scholar 

  6. Hedstrom L (2002) Chem Rev 102:4501

    CAS  Google Scholar 

  7. Stubbs MT, Bode W (1994) Curr Opin Struct Biol 4:823

    CAS  Google Scholar 

  8. Claeson G (1994) Blood Coag Fibrinolysis 5:411

    CAS  Google Scholar 

  9. Prager NA, Abenschein DR, McKenzie CR, Einsanberg PR (1995) Circulation 92:962

    CAS  Google Scholar 

  10. Furie B, Furie BC (1988) Cell 53:505

    CAS  Google Scholar 

  11. Hammer RH (1995) Anticoagulants, Coagulants and Plasma Extenders. In: Foye WO, Lemke TL, Williams DA (eds) Principles of Medicinal Chemistry. Waverly BI PVt. Ltd., New Delhi, p 388

    Google Scholar 

  12. Davie EW, Fujikawa K, Kisiel W (1991) Biochemistry 30:10363

    CAS  Google Scholar 

  13. Vaz RJ, McLean LR, Pelton JT (1998) J Comp Aid Mol Des 12:99

    CAS  Google Scholar 

  14. Leadley RJ Jr (2001) Curr Top Med Chem 1:151

    CAS  Google Scholar 

  15. Turk D, Stürzebecher J, Bode W (1991) FEBS 287:133

    CAS  Google Scholar 

  16. Narasimhan LS, Rubin JR, Holland DR, Plummer JS, Rapundalo ST, Edmunds JE, St-Denis Y, Siddiqui MA, Humblet C (2000) J Med Chem 43:361

    CAS  Google Scholar 

  17. Linusson A, Gottfries J, Olsson T, Örnskov E, Folestad S, Norden B, Wold S (2001) J Med Chem 44:3424

    CAS  Google Scholar 

  18. Bode W, Mayr I, Baumann U, Huber R, Stone SR, Hofskeenge J (1989) EMBO J 8:3467

    CAS  Google Scholar 

  19. Padmanahan K, Padmanahan KP, Tulinsky A, Park CH, Bode W, Huber R, Blakenship DT, Cardin AD, Kisiel W (1993) J Mol Biol 232:947

    Google Scholar 

  20. Brandstetter H, Kuhne A, Bode W, Huber R, Von der Saal, Wirthensohn K, Engh RA (1996) J Biol Chem 271:29988

    CAS  Google Scholar 

  21. Maignan S, Guilloteau JP, Pouzieux S, Choi-Sledeski YM, Becker MR, Klein SI, Ewing WR, Pauls HW, Spada AP, Mikol V (2000) J Med Chem 43:3226

    CAS  Google Scholar 

  22. Dougherty DA (1996) Science 271:163

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  24. Matter H, Defossa E, Heinelt U, Blohm PM, Schneider D, Müller A, Herok S, Schreuder H, Liesum A, Brachvogel V, Lonze P, Walser A, Al-Obeidi F, Wildgoose P (2002) J Med Chem 45:2749

    CAS  Google Scholar 

  25. Yee YK, Tebbe AI, Linebarger JH, Beight DW, Craft TJ, Gifford-Moore D, Goodson T, Herron DK, KlimKowski VJ, Kyle JA, Sawyer JS, Smith GF, Tinsley JM, Towner RD, Weir L, Wiley MR (2000) J Med Chem 43:873

    CAS  Google Scholar 

  26. Buckman BO, Mohan R, Koovakkat S, Liang A, Trinh L, Morrissey MM (1998) Bioorg Med Chem Lett 8:2235

    CAS  Google Scholar 

  27. Maignan S, Mikol V (2001) Curr Top Med Chem 1:161

    CAS  Google Scholar 

  28. Ewing WR, Pauls HW, Spada AP (1999) Drugs Future 24:771

    CAS  Google Scholar 

  29. Choi-Sledeski YM, MCGarry DG, Green DM, Mason HJ, Rewcker MR, Davis RS (1999) J Med Chem 42:3572

    CAS  Google Scholar 

  30. Shaw KJ, Guilford WJ, Dallas JL, Koovakkat SK, Mc Carrick MA, Liang A, Light DR, Morrisey MM (1998) J Med Chem 41:3551

    CAS  Google Scholar 

  31. Daura X, Haaksma E, Van Gunsteren WF (2000) J Comput Aided Mol Des 14:507

    CAS  Google Scholar 

  32. Koshland DE (1958) Proc Natl Acad Sci USA 44:98

    CAS  Google Scholar 

  33. Jorgensen WL (1991) Science 254:951

    Google Scholar 

  34. Morton A, Matthews BW (1995) Biochemistry 34:8576

    CAS  Google Scholar 

  35. Andrews PR, Craik DJ, Martin JL (1984) J Med Chem 27:1648

    CAS  Google Scholar 

  36. Cohen NC (1996) Guidebook on Molecular Modeling in Drug Design. Academic, New York

    Google Scholar 

  37. Cooper DN, Millar DS, Wacey A, Pemberto S, Tuddenham EGD (1997) Thromb Haemost 78:161

    CAS  Google Scholar 

  38. Lapatto R, Krengel U, Schreuder HA, Arkema A, De Boer B, Kalk KH, Hol WG, Grootenhuis PDJ, Mulders JW, Dijkema R, Theunissen HJ, Dijkstra BW (1997) EMBO J 16:5151

    CAS  Google Scholar 

  39. Al-Obeidi F, Ostrem JA (1999) Expert Opin Ther Pat 74:635

    Google Scholar 

  40. Morishima Y, Tanabe K, Terada Y, Hara T, Kunitada S (1997) Thromb Haemost 78:1366

    CAS  Google Scholar 

  41. Wong PC, Crain EJ, Nguan O, Watson CA, Racanelli A (1996) Thromb Res 83:117

    CAS  Google Scholar 

  42. Lamba D, Bauer M, Huber R, Fischer S, Rudolph R, Kohert U, Bode W (1996) J Mol Biol 258:117

    CAS  Google Scholar 

  43. Spraggon G, Phillips C, Nowak UK, Ponting CP, Saunders D, Dobson CM, Stuart DI, Jones EY (1995) Structure 3:681

    CAS  Google Scholar 

  44. Katz BA, Mackman R, Luong C, Radika K, Martelli A, Sprengeler PA, Wang J, Chan H, Wong L (2000) Chem Biol 7:299

    CAS  Google Scholar 

  45. Rai R, Sprengeler PA, Elrod KC, Young WB (2000) Curr Med Chem 1:35

    Google Scholar 

  46. Katakura S, Nagahara T, Hara T, Iwamoto MA (1993) Biochem Biophys Res Commun 197:965

    CAS  Google Scholar 

  47. Katakura S, Nagahara T, Hara T, Kumitada S, Iwamoto MA (1995) Eur J Med Chem 30:387

    CAS  Google Scholar 

  48. Lin Z, Johnson ME (1995) FEBS Lett 370:1

    CAS  Google Scholar 

  49. Stubbs MT, Huber R, Bode W (1995) FEBS Lett 375:103

    CAS  Google Scholar 

  50. Böhm M, Stürzebecher J, Klebe G (1999) J Med Chem 42:458

    Google Scholar 

  51. Stürzebecher J, Vieweg H, Wilkström P (1991) WO 92/08709

    Google Scholar 

  52. Stürzebecher J, Vieweg H, Wilkström P (1993) WO 94/18185

    Google Scholar 

  53. Stürzebecher J, Prasa D, Vieweg H, Wilkström P (1995) J Enzyme Inhib 9:87

    Google Scholar 

  54. Stürzebecher J, Prasa D, Hauptmann J, Vieweg H, Wilkström P (1997) J Med Chem 40:3091

    Google Scholar 

  55. Labute P (2000) J Mol Graph Model 18:464

    CAS  Google Scholar 

  56. Murcia M, Ortiz AR (2004) J Med Chem 47:805

    CAS  Google Scholar 

  57. Matter H, Will DW, Nazare M, Schreuder H, Lax V, Wehner V (2005) J Med Chem 48:3290

    CAS  Google Scholar 

  58. Maignan S, Guilloteau JP, Choi-Sledeski YM, Becker MR, Ewing WR, Pauls HW, Spada AP, Mikol V (2003) J Med Chem 46:685

    CAS  Google Scholar 

  59. Adler M, Kochanny MJ, Ye B, Rumnenik G, Light DR, Biancalana S, Whitlow M (2002) Biochemistry 41:15514

    CAS  Google Scholar 

  60. Kamata K, Kawamoto H, Honma T, Iwama T, Kim SH (1998) Proc Natl Acad Sci USA 95:6630

    CAS  Google Scholar 

  61. Nar H, Bauer M, Schmid A, Stassen JM, Wiennen W, Priepke HWM, Kaufmann IK, Rise UJ, Hauel NH (2001) Structure 9:29

    CAS  Google Scholar 

  62. Adler M, Davey DD, Philips GB, Kim SH, Jancarik J, Rumennik G, Light DR, Whitlow R (2000) Biochemistry 39:12534

    CAS  Google Scholar 

  63. Cramer RD, Patterson DE, Bunce JE (1988) J Am Chem Soc 110:5959

    CAS  Google Scholar 

  64. Clark M, Cramer RD, Jones DM, Patterson DE, Simeroth PE (1990) Tetrahedron Comput Methodol 3:47

    CAS  Google Scholar 

  65. Kubinyi H (ed) (1993) 3D-QSAR in Drug Design: Theory, Methods and Applications. ESCOM, Leiden, The Netherlands

    Google Scholar 

  66. Klebe G, Abraham U, Mietzner T (1994) J Med Chem 37:4130

    CAS  Google Scholar 

  67. Roy K, De AU, Sengupta C (2002) Drug Des Disc 18:23

    CAS  Google Scholar 

  68. Roy K, De AU, Sengupta C (2002) Drug Des Disc 18:33

    CAS  Google Scholar 

  69. Bhongade BA, Gouripur VV, Gadad AK (2005) Bioorg Med Chem 13:2773

    CAS  Google Scholar 

  70. Taha MO, Qandil AA, Zaki DD, AlDamen MA (2005) Eur J Med Chem 40:701

    CAS  Google Scholar 

  71. Phillips G, Guilford WJ, Buckman BO, Davey DD, Eagen KA, Koovakkat S, Liang A, McCarrick M, Mohan R, Ng HP, Pinkerton M, Subramanyam B, Ho E, Trinh L, Whitlow M, Wu S, Xu W, Morrisey MM (2002) J Med Chem 45:2484

    CAS  Google Scholar 

  72. Kontogiorgis CA, Hadjipavlou-Litina D (2004) Med Res Rev 24:687

    CAS  Google Scholar 

  73. Wu S, Guilford WJ, Chou Y-L, Griedel BD, Liang A, Sakata S, Shaw KJ, Trinh l, Xu W, Zhao Z, Morrisey MM (2002) Bioorg Med Chem Lett 12:1307

    CAS  Google Scholar 

  74. Quan ML, LiauwAY, Ellis CD, Pruit JR, Carini DJ, Bostrom LL, Huang P, Harrison K, Knabb RM, Thoolen MJ,Wong PC, Wexler RR (1999) J Med Chem 42:2752

    CAS  Google Scholar 

  75. Quan ML, Ellis CD, Liauw AY, Alexander RS, Knabb RM, Lam GN, Wright MM, Wong PC, Wexler RR (1999) J Med Chem 42:2760

    CAS  Google Scholar 

  76. Pinto DJP, Orwat MJ, Wang S, Fevig JM, Quan ML, Amparo E, Cacciola J, Rossi KA, Alexander RS, Smallwodd AM, Luettgen JM, Liang L, Aungst BJ, Wright BR, Knabb RM, Wong PC, Wexler PP, Lam PYS (2001) J Med Chem 44:566

    CAS  Google Scholar 

  77. Smith GF, Shuman RT, Craft TJ, Gifford DS, Kurz KD, Jones ND, Chirgadze N, Hermann RB, Coffman WJ, Sandusky GE, Roberts E, Jackson CVA(1996) Semin Thromb Hemostasis 22:173

    Article  CAS  Google Scholar 

  78. Hirsh J (1991) New Engl J Med 324:1865

    Article  CAS  Google Scholar 

  79. Pruitt JR, Pinto DJ, Quan ML, Estrella MJ, Bostrom LL, Knabb RM, Wong PC, Wexler RR (2000) Bioorg Med Chem Lett 10:685

    CAS  Google Scholar 

  80. Stein PD, Grandison D, Hua TA (1994) Postgrad Med J 70 Suppl 1:S72

    Google Scholar 

  81. Fevig JM, Pinto DJ, Han Qi, Quan ML, Pruitt JR, Jacobson IC, Galemmo RA Jr, Wang S, Orwat MJ, Bostrom LL, Knabb RM, Wong PC, Lam PYS, Wexler RR (2001) Bioorg Med Chem Lett 11:641

    CAS  Google Scholar 

  82. Masters JJ, Franciskovich JB, Tinsley JM, Cambell JB, Craft TJ, Froelich LL, Gifford-Moore DS, Herron DK, Klimkowski VJ, Kurz KD, Metz JT, Ratz AM, Shuman RT, Smith GF, Towner RD, Wiley MR, Wilson A, Yee YK (2000) J Med Chem 43:2087

    CAS  Google Scholar 

  83. Hirsh J, Poller L (1994) Arch Int Med 154:282

    CAS  Google Scholar 

  84. Kurczierz R, Grams F, Leinert H, Marzenell K, Engh RA, Von der Saal RA (1998) J Med Chem 41:4983

    Google Scholar 

  85. Brandstetter H, Kühne A, Bode W, Huber R, Von der Saal W, Wirthensohn K, Engh RA (1996) J Biol Chem 271:29988.

    CAS  Google Scholar 

  86. Feng DM, Gardell SJ, Lewis SD, Bock MG, Chen Z, Freidinger RM, Naylor-Olsen AM, Ramjit HG, Woltmann R, Baskin EP, Lynch JL, Lucas R, Shafer JA, Dancheck BK, Chen W, Mao S, Krueger JL, Hare TR, Mulichak AM, Vacca JP (1997) J Med Chem 40:3726

    CAS  Google Scholar 

  87. Gong Y, Pauls HW, Spada AP, Chekaj M, Liang G, Chu V, Colussi DJ, Brown KD, Gao J (2000) Bioorg Med Chem Lett 10:217

    CAS  Google Scholar 

  88. Dudley DA, Bucker AM, Chi L, Cody WL, Holland DR, Ingasiak DP, Janiczek-Dolphin N, McClanahan TB, Mertz TE, Narasimhan LS, Rapundalo ST, Trautschold JA, Van Huis CA, Edmunds JJ (2000) J Med Chem 43:4063

    CAS  Google Scholar 

  89. Zhang P, Zuckett JF, Woolfrey J, Tran K, Huang B, Wong P, Sinha U, Park G, Reed A, Malinowski J, Hollenbach S, Scarborough RM, Zhu B-Y (2002) Bioorg Med Chem Lett 12:1657.

    CAS  Google Scholar 

  90. Hirayama F, Koshio H, Ishihara T, Watanuki S, Hachiya S, Kaizawa H, Kuramochi T, Katayama N, Kurihar H, Taniuchi Y, Sato K, Sakai-Moritani Y, Kaku S, Kawasaki T, Matsumoto Y, Sakumoto S, Tsukamoto S (2002) Bioorg Med Chem 10:2597

    CAS  Google Scholar 

  91. Quan ML, Ellis CD, He MY, Liauw AY, Woerner FJ, Alexander RS, Knabb RM, Lam PYS, Luettgen JM, Wong PC, Wright MR, Wexler RR (2003) Bioorg Med Chem Lett 13:369

    CAS  Google Scholar 

  92. Kurihara H, Taniuchi Y, Sato K, Sakai-Moritani Y, Kaku S, Kawasaki T, Matsumoto Y, Sakamoto S, Tsukamoto S (2002) Bioorg Med Chem 10:2597

    Google Scholar 

  93. Su T, WuY, Doughan B, Kane-Maguire K, Morlowe CK, Kanter JP, Woolfrey J, Huang B, Wong P, Sinha U, Park G, Malinowski J, Hollenbach S, Scarborough RM, Zhu B-Y (2001) Bioorg Med Lett 11:2279

    CAS  Google Scholar 

  94. Hansch C, Leo AJ (1995) Exploring QSAR: Fundamentals and applications in chemistry and biology. American Chemical Society, Washington, DC

    Google Scholar 

  95. Hansch C, Caldwell J (1991) J Comp Aid Mol Des 5:441

    CAS  Google Scholar 

  96. Yoshimoto M, Hansch C (1976) J Org Chem 41:2269

    CAS  Google Scholar 

  97. Guinto ER, Vindigni A, Ayala YM, Dang QD, Di Cera E (1995) Proc Natl Acad Sci USA 92:1185

    Google Scholar 

  98. Goodwin CA, Deadman JJ, Le Bonniec BF, Elgendy S, Kakkar VV, Scully MF (1996) Biochem J 315:77

    CAS  Google Scholar 

  99. Bursi R, Grootenhuis PD (1999) J Comput Aided Mol Design 13:221

    CAS  Google Scholar 

  100. Greenidge AP, Merette SAM, Beck R, Dodson G, Goodwin CA, Scully M, Spencer J, Weiser J, Deadman J (2003) J Med Chem 46:1293

    CAS  Google Scholar 

  101. Merops database, http://www.MEROPS.Sanger.Ac.Uk.code S01.217

  102. Dixit A, Kashaw SK, Gaur S, Saxena AK (2004) Bioorg Med Chem 12:3591

    CAS  Google Scholar 

  103. Riester D, Wirsching F, Salinas G, Keller M, Gebinoga M, Kamphausen S, Merwirth C, Goetz R, Wiesenfeldt M, Stürzebecher J, Bode W, Friedrich R, Thürk M, Schwienhorst A (2005) Proc Natl Acad Sci (USA) 12:8597

    Google Scholar 

  104. Sanderson PEJ, Naylor-Olsen AM (19980 Curr Med Chem 5:289

    Google Scholar 

  105. Kikumoto R, Tamao Y, Ohkubo K, Tezuka T, Tonomura S (1980) J Med Chem 23:830

    CAS  Google Scholar 

  106. Kikumoto R, Tamao Y, Ohkubo K, Tezuka T, Tonomura S (1980) J Med Chem 23:1293

    CAS  Google Scholar 

  107. Gupta SP (1987) Chem Rev 87:1183

    CAS  Google Scholar 

  108. Gupta SP, Prahhankar YS, Handa A (1984) In: QSAR in design of Bioactive compounds. Prous, Barcelona, p 175

    Google Scholar 

  109. Fujita T (1973) J Med Chem 16:923

    CAS  Google Scholar 

  110. Shuman TR, Rothenberger RB, Cambell CS, Smith GF, Gillford-Moore DS, Gesellchen PD (1993) J Med Chem 36:314

    CAS  Google Scholar 

  111. Vacca JP (1998) Annual Report in Medicinal Chemistry 33:81

    Article  CAS  Google Scholar 

  112. Kontogiorgis CA, Hadjipavlou-Litina D (2003) Curr Med Chem 10:1241

    Google Scholar 

  113. Hilpert K, Ackermann J, Banner DW, Gaxt A, Gubernator K, Hadvary P, Labler L, Müller K, Schmid G, Tschopp TP, Van der Waterbeemd (1994) J Med Chem 37:3889

    CAS  Google Scholar 

  114. Bajusz S, Szell E, Bagdy D, Bardas E, Howarth G, Dioszegi M, Fittler Z, Szabo G, Juhasz A, Tomori E (1998) Biochem 37:12094

    Google Scholar 

  115. Sall DJ, Bastian JA, Brigga SI, Buben JA, Chirgadze NY, Clawson DK, Denney ML (1997) Structure-Activity Relationships and Binding Orientation 40:3489

    CAS  Google Scholar 

  116. Salemme FR, Spurlino J, Bone R (1997) 5:319

    Google Scholar 

  117. Lewis SD, Ng AS, Lyle EA, Mellott MJ, Appledy SD, Brady SF, Stauffer KJ, Sisko JT, Mao SS, Veber DF (1995) Thromb Haemostasis 74:1107

    CAS  Google Scholar 

  118. Markwardt F, Wagner G, Stürzebecher J, Walshmann P (1980) Thromb Res 17:425

    CAS  Google Scholar 

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  1. Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece

    Dimitra Hadjipavlou-Litina

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  1. Dimitra Hadjipavlou-Litina
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Satya Prakash Gupta

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Hadjipavlou-Litina, D. QSAR and Molecular Modeling Studiesof Factor Xa and Thrombin Inhibitors. In: Gupta, S.P. (eds) QSAR and Molecular Modeling Studies in Heterocyclic Drugs II. Topics in Heterocyclic Chemistry, vol 4. Springer, Berlin, Heidelberg. https://doi.org/10.1007/7081_017

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