Modeling Reaction Mechanism of Cocaine Hydrolysis and Rational Drug Design for Therapeutic Treatment of Cocaine Abuse

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

Abstract

Cocaine is a widely abused heterocyclic drug and there is no available anti-cocaine therapeutic. The disastrous medical and social consequences of cocaine addiction have made the development of an effective pharmacological treatment a high priority. An ideal anti-cocaine medication would accelerate cocaine metabolism producing biologically inactive metabolites. The main metabolic pathway of cocaine in the body is hydrolysis at its benzoyl ester group. State-of-the-art molecular modeling of the reaction mechanism for the hydrolysis of cocaine and the mechanism-based design of anti-cocaine therapeutics will be discussed. First of all, competing reaction pathways and the transition state stabilization of the spontaneous hydrolysis of cocaine in solution will be examined. It will be demonstrated that the information obtained about the transition states and their stabilization has been very useful in the rational design of stable analogs of the transition states of cocaine hydrolysis, in order to elicit anti-cocaine catalytic antibodies. Detailed molecular modeling of the reaction mechanism for cocaine hydrolysis catalyzed by human butyrylcholinesterase (BChE), the primary cocaine-metabolizing enzyme in body, will be examined. Then, we will describe the application of these mechanistic insights to the rational design of human BChE mutants as a new therapeutic treatment of cocaine abuse. Finally, future directions of the mechanism-based design of anti-cocaine therapeutics will be discussed.

Cocaine Hydrolysis mechanism Transition-state simulation Rational enzyme redesign Catalytic antibody 

Abbreviations

ACh

Acetylcholine

AChE

Acetylcholinesterase

BCh

Butyrylcholine

BChE

Butyrylcholinesterase

QM

Quantum mechanics

MM

Molecular mechanics

QM/MM

Quantum mechanics/molecular mechanics

MD

Molecular dynamics

BE

Benzoylecgonine

EME

Ecgonine methyl ester

CNS

Central nervous system

PET

Positron emission tomography

BAC2

Base-catalyzed, acyl-oxygen cleavage, bimolecular

IRC

Intrinsic reaction coordinate

TSA

Transition state analog

TS

Transition state

TS1

Transition state for the first reaction step

TS2

Transition state for the second reaction step

TS3

Transition state for the third reaction step

TS4

Transition state for the fourth reaction step

INT

Intermediate

INT1

First intermediate

INT2

Second intermediate

INT3

Third intermediate

ES

Prereactive enzyme–substrate complex

SCRF

Self-consistent reaction field

SVPE

Surface and volume polarization for electrostatic interactions

FPCM

Fully polarizable continuum model

PCM

Polarizable continuum model

HBR

Hydrogen-bonded reactant complex

NPA

Natural population analysis

HBE

Hydrogen bonding energy

3D

Three-dimensional

ZPVE

Zero-point vibration energy

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Notes

Acknowledgments

The financial support from the National Institute on Drug Abuse (NIDA) of the National Institutes of Health (NIH) (grant R01 DA013930) is gratefully acknowledged.

References

  1. 1.
    Gawin FH, Ellinwood EHN Jr (1988) Eng J Med 318:1173 CrossRefGoogle Scholar
  2. 2.
    Landry DW (1997) Sci Am 276:28 CrossRefGoogle Scholar
  3. 3.
    Singh S (2000) Chem Rev 100:925 Google Scholar
  4. 4.
    Sparenborg S, Vocci F, Zukin S (1997) Drug Alcohol Depend 48:149 Google Scholar
  5. 5.
    Gorelick DA (1997) Drug Alcohol Depend 48:159 Google Scholar
  6. 6.
    Gorelick DA, Gardner EL, Xi ZX (2004) Drugs 64:1547 Google Scholar
  7. 7.
    Baird TJ, Deng SX, Landry DW, Winger G, Woods JH (2000) J Pharmacol Exp Ther 295:1127 Google Scholar
  8. 8.
    Carrera MRA, Ashley JA, Wirsching P, Koob GF, Janda KD (2001) Proc Natl Acad Sci USA 98:1988 Google Scholar
  9. 9.
    Deng SX, de Prada P, Landry DW (2002) J Immunol Methods 269:299 Google Scholar
  10. 10.
    Kantak KM (2003) Expert Opin Pharmacother 4:213 Google Scholar
  11. 11.
    Carrera MRA, Kaufmann GF, Mee JM, Meijler MM, Koob GF, Janda KD (2004) Proc Natl Acad Sci USA 101:10416 Google Scholar
  12. 12.
    Dickerson TJ, Kaufmann GF, Janda KD (2005) Expert Opin Biol Ther 5:773 Google Scholar
  13. 13.
    Meijler MM, Kaufmann GF, Qi LW, Mee JM, Coyle AR, Moss JA, Wirsching P, Matsushita M, Janda KD (2005) J Am Chem Soc 127:2477 Google Scholar
  14. 14.
    Rogers CJ, Mee JM, Kaufmann GF, Dickerson TJ, Janda KD (2005) J Am Chem Soc 127:10016 Google Scholar
  15. 15.
    Carrera MRA, Ashley JA, Parsons LH, Wirsching P, Koob GF, Janda KD (1995) Nature 378:727 Google Scholar
  16. 16.
    Fox BS (1997) Drug Alcohol Depend 100:153 Google Scholar
  17. 17.
    Carrera MRA, Ashley JA, Zhou B, Wirsching P, Koob GF, Janda KD (2000) Proc Natl Acad Sci USA 97:6202 Google Scholar
  18. 18.
    Carrera MRA, Ashley JA, Wirsching P, Koob GF, Janda KD (2001) Proc Natl Acad Sci USA 98:1988 Google Scholar
  19. 19.
    Carrera MRA, Trigo JM, Roberts AJ, Janda KD (2005) Pharmacol Biochem Behav 81:709 Google Scholar
  20. 20.
    Fox BS, Kantak KM, Edwards MA, Black KM, Bollinger BK, Botka AJ, French TL, Thompson TL, Schad VC, Greenstein JL, Gefter ML, Exley MA, Swain PA, Briner TJ (1996) Nat Med 2:1129 Google Scholar
  21. 21.
    Landry DW, Yang GXQ (1997) J Addict Dis 16:1 Google Scholar
  22. 22.
    Landry DW, Zhao K, Yang GXQ, Glickman M, Georgiadis TM (1993) Science 259:1899 Google Scholar
  23. 23.
    Matsushita M, Hoffman TZ, Ashley JA, Zhou B, Wirsching P, Janda KD (2001) Bioorg Med Chem Lett 11:87 Google Scholar
  24. 24.
    Cashman JR, Berkman CE, Underiner GE (2000) J Pharm Exp Ther 293,952:961 Google Scholar
  25. 25.
    Yang G, Chun J, Arakawa-Uramoto H, Wang X, Gawinowicz MA, Zhao K, Landry DW (1996) J Am Chem Soc 118:5881 Google Scholar
  26. 26.
    Kamendulis LM, Brzezinski MR, Pindel EV, Bosron WF, Dean RA (1996) J Pharmacol Exp Ther 279:713 Google Scholar
  27. 27.
    Poet TS, McQueen CA, Halpert JR (1996) Drug Metab Dispos 24:74 Google Scholar
  28. 28.
    Pan WJ, Hedaya MA (1999) J Pharm Sci 88:468 Google Scholar
  29. 29.
    Sukbuntherng J, Martin DK, Pak Y, Mayersohn M (1996) J Pharm Sci 85:567 Google Scholar
  30. 30.
    Browne SP, Slaughter EA, Couch RA, Rudnic EM, McLean AM (1998) Biopharm Drug Dispos 19:309 Google Scholar
  31. 31.
    Carmona GN, Baum I, Schindler CW, Goldberg SR, Jufer R (1996) Life Sci 59:939 Google Scholar
  32. 32.
    Lynch TJ, Mattes CE, Singh A, Bradley RM, Brady RO, Dretchen KL (1997) Toxicol Appl Pharmacol 145:363 Google Scholar
  33. 33.
    Mattes CE, Lynch TJ, Singh A, Bradley RM, Kellaris PA, Brady RO, Dretchen KL (1997) Toxicol Appl Pharmacol 145:372 Google Scholar
  34. 34.
    Mattes CE, Belendiuk GW, Lynch TJ, Brady RO, Dretchen KL (1998) Addict Biol 3:171 Google Scholar
  35. 35.
    Lockridge O, Blong RM, Masson P, Froment M-T, Millard CB, Broomfield CA (1997) Biochemistry 36:786 Google Scholar
  36. 36.
    Gately SJ (1991) Biochem Pharmacol 41:1249 Google Scholar
  37. 37.
    Gately SJ, MacGregor RR, Fowler JS, Wolf AP, Dewey SL, Schlyer DJ (1990) J Neurochem 54:720 Google Scholar
  38. 38.
    Darvesh S, Hopkins DA, Geula C (2003) Nature Rev Neurosci 4:131 Google Scholar
  39. 39.
    Giacobini E (ed) (2003) Butyrylcholinesterase: its function and inhibitors. Dunitz Martin, Great Britain Google Scholar
  40. 40.
    Lerner RA, Benkovic SJ, Schultz PG (1991) Science 252:659 Google Scholar
  41. 41.
    Jones RAY (1979) Physical and Mechanistic organic chemistry. Cambridge University Press, Cambridge Google Scholar
  42. 42.
    McMurry J (1988) Organic chemistry, 2nd edn. Cole, California Google Scholar
  43. 43.
    Lowry TH, Richardson KS (1987) Mechanism and Theory in organic chemistry, 3rd edn. Harper and Row, New York Google Scholar
  44. 44.
    Williams A (1987) In: Page MI, Williams A (eds) Enzyme mechanisms. Burlington, London, p 123 Google Scholar
  45. 45.
    Li P, Zhao K, Deng S, Landry DW (1999) Helvetica Chim Acta 82:85 Google Scholar
  46. 46.
    Zhan CG, Landry DW, Ornstein RL (2000) J Am Chem Soc 122:1522 Google Scholar
  47. 47.
    Zhan CG, Landry DW, Ornstein RL (2000) J Am Chem Soc 122:2621 Google Scholar
  48. 48.
    Zhan CG, Landry DW, Ornstein RL (2000) J Phys Chem A 104:7672 Google Scholar
  49. 49.
    Bender ML, Thomas RJ (1961) J Am Chem Soc 83:4189 Google Scholar
  50. 50.
    Bender ML, Matsui H, Thomas RJ, Tobey SW (1961) J Am Chem Soc 83:4193 Google Scholar
  51. 51.
    Bender ML, Heck HA (1967) J Am Chem Soc 89:1211 Google Scholar
  52. 52.
    Bender ML, Ginger RD, Unik JP (1958) J Am Chem Soc 80:1044 Google Scholar
  53. 53.
    O'Leary MH, Marlier JF (1979) J Am Chem Soc 101:3300 Google Scholar
  54. 54.
    Guthrie JP (1991) J Am Chem Soc 113:3941 Google Scholar
  55. 55.
    Hengge A (1992) J Am Chem Soc 114:6575 Google Scholar
  56. 56.
    Marlier JF (1993) J Am Chem Soc 115:5953 Google Scholar
  57. 57.
    Sherer EC, Turner GM, Lively TN, Landry DW, Shields GC (1996) J Mol Model 2:62 Google Scholar
  58. 58.
    Sherer EC, Yang G, Turner GM, Shields GC, Landry DW (1997) J Phys Chem A 101:8526 Google Scholar
  59. 59.
    Sherer EC, Turner GM, Shields GC (1995) Int J Quantum Chem Quantum Biol Symp 22:83 Google Scholar
  60. 60.
    Turner GM, Sherer EC, Shields GC (1995) Int J Quantum Chem Quantum Biol Symp 22:103 Google Scholar
  61. 61.
    Fairclough RA, Hinshelwood CN (1937) J Chem Soc 538 Google Scholar
  62. 62.
    Rylander PN, Tarbell DS (1950) J Am Chem Soc 72:3021 Google Scholar
  63. 63.
    Zhan CG, Landry DW (2001) J Phys Chem A 105:1296 Google Scholar
  64. 64.
    Becke AD (1993) J Chem Phys 98:5648 Google Scholar
  65. 65.
    Lee C, Yang W, Parr RG (1988) Phys Rev B 37:785 Google Scholar
  66. 66.
    Gonzalez C, Schlegel HB (1989) J Chem Phys 90:2154 Google Scholar
  67. 67.
    Gonzalez C, Schlegel HB (1990) J Phys Chem 94:5523 Google Scholar
  68. 68.
    Tomasi J, Persico M (1994) Chem Rev 94:2027 Google Scholar
  69. 69.
    Cramer CJ, Truhlar DG (1996) In: Tapia O, Bertran J (eds) Solvent effects and chemical reactions. Kluwer, Dordrecht, p 1 Google Scholar
  70. 70.
    Cramer CJ, Truhlar DG (1999) Chem Rev 99:2161 Google Scholar
  71. 71.
    Chipman DM (1997) J Chem Phys 106:10194 Google Scholar
  72. 72.
    Chipman DM (1999) J Chem Phys 110:8012 Google Scholar
  73. 73.
    Schmidt MW, Baldridge KK, Boatz JA, Elbert ST, Gordon MS, Jensen JH, Koseki S, Matsunaga N, Nguyen KA, Su SJ, Windus TL, Dupuis M, Montgomery JA (1993) J Comput Chem 14:1347 Google Scholar
  74. 74.
    Zhan CG, Bentley J, Chipman DM (1998) J Chem Phys 108:177 Google Scholar
  75. 75.
    Zhan CG, Chipman DM (1998) J Chem Phys 109:10543 Google Scholar
  76. 76.
    Zhan CG, Chipman DM (1999) J Chem Phys 110:1611 Google Scholar
  77. 77.
    Zheng F, Zhan CG, Ornstein RL (2001) J Chem Soc Perkin Trans 2 2355 Google Scholar
  78. 78.
    Zheng F, Zhan CG, Ornstein RL (2002) J Phys Chem B 106:717 Google Scholar
  79. 79.
    Zhan CG, Dixon DA, Sabri MI, Kim MS, Spencer PS (2002) J Am Chem Soc 124:2744 Google Scholar
  80. 80.
    Dixon DA, Feller D, Zhan CG, Francisco SF (2002) J Phys Chem A 106:3191 Google Scholar
  81. 81.
    Zhan CG, Norberto de Souza O; Rittenhouse R, Ornstein RL (1999) J Am Chem Soc 121:7279 Google Scholar
  82. 82.
    Zhan CG, Zheng F (2001) J Am Chem Soc 123:2835 Google Scholar
  83. 83.
    Dixon DA, Feller D, Zhan CG, Francisco SF (2003) Int J Mass Spectrom 227:421 Google Scholar
  84. 84.
    Zhan CG, Dixon DA, Spencer PS (2003) J Phys Chem B 107:2853 Google Scholar
  85. 85.
    Zhan CG, Dixon DA, Spencer PS (2004) J Phys Chem B 108:6098 Google Scholar
  86. 86.
    Chen X, Zhan CG (2004) J Phys Chem A 108:3789 Google Scholar
  87. 87.
    Chen X, Zhan CG (2004) J Phys Chem A 108:6407 Google Scholar
  88. 88.
    Xiong Y, Zhan CG (2004) J Org Chem 69:8451 Google Scholar
  89. 89.
    Zhan CG, Deng SX, Skiba JG, Hayes BA, Tschampel SM, Shields GC, Landry DW (2005) J Comput Chem 26:980 Google Scholar
  90. 90.
    Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Zakrzewski VG, Montgomery JA, Stratmann RE, Burant JC, Dapprich S, Millam JM, Daniels AD, Kudin KN, Strain MC, Farkas O, Tomasi J, Barone V, Cossi M, Cammi R, Mennucci B, Pomelli C, Adamo C, Clifford S, Ochterski J, Petersson GA, Ayala PY, Cui Q, Morokuma K, Malick DK, Rabuck AD, Raghavachari K, Foresman JB, Cioslowski J, Ortiz JV, Stefanov BB, Liu G, Liashenko A, Piskorz P, Komaromi I, Gomperts R, Martin RL, Fox DJ, Keith T, Al-Laham MA, Peng CY, Nanayakkara A, Gonzalez C, Challacombe M, Gill PMW, Johnson B, Chen W, Wong MW, Andres JL, Gonzalez AC, Head-Gordon M, Replogle ES, Pople JA (1998) Gaussian 98. Gaussian, Pittsburgh, PA Google Scholar
  91. 91.
    Gu Y, Kar T, Scheiner S (1999) J Am Chem Soc 121:9411 Google Scholar
  92. 92.
    Meadows ES, De Wall SL, Barbour LJ, Fronczek FR, Kim MS, Gokel GW (2000) J Am Chem Soc 122:3325 Google Scholar
  93. 93.
    Vargas R, Garza J, Dixon DA, Hay BP (2000) J Am Chem Soc 122:4750 Google Scholar
  94. 94.
    Deng S, Bharat N, de Prada P, Landry DW (2004) Org Biomol Chem 2:288 Google Scholar
  95. 95.
    Mets B, Winger G, Cabrera C, Seo S, Jamdar S, Yang G, Zhao K, Briscoe RJ, Almonte R, Woods JH, Landry DW (1998) Proc Natl Acad Sci USA 95:10176 Google Scholar
  96. 96.
    Nicolet Y, Lockridge O, Masson P, Fontecilla-Camps JC, Nachon F (2003) J Biol Chem 278:41141 Google Scholar
  97. 97.
    Sun H, Yazal JE, Lockridge O, Schopfer LM, Brimijoin S, Pang YP (2001) J Biol Chem 276:9330 Google Scholar
  98. 98.
    Sun H, Shen ML, Pang YP, Lockridge O, Brimijoin S (2002) J Pharmacol Exp Ther 302:710 Google Scholar
  99. 99.
    Sun H, Pang YP, Lockridge O, Brimijoin S (2002) Mol Pharmacol 62:220 Google Scholar
  100. 100.
    Zhan CG, Zheng F, Landry DW (2003) J Am Chem Soc 125:2462 Google Scholar
  101. 101.
    Hamza A, Cho H, Tai HH, Zhan CG (2005) J Phys Chem B 109:4776 Google Scholar
  102. 102.
    Bruice TC, Lightstone FC (1999) Acc Chem Res 32:127 Google Scholar
  103. 103.
    Shurki A, Štrajbl M, Villá J, Warshel A (2002) J Am Chem Soc 124:4097 Google Scholar
  104. 104.
    Masson P, Legrand P, Bartels CF, Froment M-T, Schopfer LM, Lockridge O (1997) Biochemistry 36:2266 Google Scholar
  105. 105.
    Ekholm M, Konschin H (1999) J Mol Struct (THEOCHEM) 467:161 Google Scholar
  106. 106.
    Harel M, Sussman JL, Krejci E, Bon S, Chanal P, Massoulie J, Silman I (1992) Proc Natl Acad Sci USA 89:10827 Google Scholar
  107. 107.
    Masson P, Xie W, Froment MT, Levitsky V, Fortier PL, Albaret C, Lockridge O (1999) Biochim Biophys Acta 1433:281 Google Scholar
  108. 108.
    Hu C-H, Brinck T, Hult K (1998) Int J Quantum Chem 69:89 Google Scholar
  109. 109.
    Wlodek ST, Clark TW, Scott L, McCammon JA (1997) J Am Chem Soc 119:9513 Google Scholar
  110. 110.
    Wlodek ST, Antosiewicz J, Briggs JM (1997) J Am Chem Soc 119:8159 Google Scholar
  111. 111.
    Zhou HX, Wlodek ST, McCammon JA (1998) Proc Natl Acad Sci USA 95:9280 Google Scholar
  112. 112.
    Malany S, Sawai M, Sikorski RS, Seravalli J, Quinn DM, Radic Z, Taylor P, Kronman C, Velan B, Shafferman A (2000) J Am Chem Soc 122:2981 Google Scholar
  113. 113.
    Zhan CG, Gao D (2005) Biophys J 89:3863 Google Scholar
  114. 114.
    Gao Y, Atanasova E, Sui N, Pancook JD, Watkins JD, Brimijoin S (2005) Mol Pharmacol 67:204 Google Scholar
  115. 115.
    Gao D, Zhan CG (2006) Proteins 62:99 Google Scholar
  116. 116.
    Gao D, Zhan CG (2005) J Phys Chem B 109:23070 Google Scholar
  117. 117.
    Pan Y, Gao D, Yang W, Cho H, Yang GF, Tai HH, Zhan CG (2005) Proc Natl Acad Sci USA 102:16656 Google Scholar
  118. 118.
    Gao D, Cho H, Yang W, Pan Y, Yang GF, Tai HH, Zhan CG (2006) Angew Chem Int Ed 45:653 Google Scholar
  119. 119.
    Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, Olson AJ (1998) J Comput Chem 19:1639 Google Scholar
  120. 120.
    Zhang Y, Kua J, McCammon JA (2002) J Am Chem Soc 124:10572 Google Scholar
  121. 121.
    Tai K, Shen T, Börjesson U, Philippopoulos M, McCammon JA (2001) Biophys J 81:715 CrossRefGoogle Scholar
  122. 122.
    Kua J, Zhang YK, Eslami AC, Butler JR, McCammon JA (2003) Protein Science 12:2675 Google Scholar
  123. 123.
    Bernstein FC, Koetzle TF, Williams GJ, Meyer EF, Brice MD, Rodgers JR, Kennard O, Shimanouchi T, Tasumi M (1977) J Mol Biol 112:535 Google Scholar
  124. 124.
    Rosenberry TL (1975) Proc Nat Acad Sci USA 72:3834 Google Scholar
  125. 125.
    Alvarez-Idaboy JR, Galano A, Bravo-Pérez G, Ruíz ME (2001) J Am Chem Soc 123:8387 Google Scholar

Authors and Affiliations

  1. 1.Department of Pharmaceutical Sciences, College of PharmacyUniversity of KentuckyLexingtonUSA

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