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Hydration Structure of Cocaine and its Metabolites: A Molecular Dynamics Study

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Abstract

We present molecular dynamics simulations of solvated cocaine and its metabolites in water, using both the Optimized Potentials for Liquid Simulations (OPLS) force field and the same force field but with Quantum Theory of Atoms In Molecules (QTAIM) atomic charges. We focus on the microscopic aspects of solvation, e.g. hydrogen bonds, and investigate influence of partial charges applied. Hydrophobicity or hydrophicility of these molecules were analyzed in terms of solute–solvent radial distribution functions and, for their most hydrophilic atoms, by spatial density functions. These hydration studies allowed us to classify these molecules according to their total coordination numbers, from the most hydrated metabolite to least hydrated, and this trend matches the degree of each metabolite is excreted in urine of patients with a high consumption of cocaine. Finally, we observed that QTAIM charges provide a more physically reasonable description of electrostatic environment of these solvated molecules than those of OPLS charges.

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References

  1. Singh, S.: Chemistry, design, and structure–activity relationship of cocaine antagonists. Chem. Rev. 100, 925–1024 (2000)

    Article  CAS  Google Scholar 

  2. Jeffcoat, A.R., Perez-Reyes, M., Hill, J.M., Sadler, B.M., Cook, C.E.: Cocaine disposition in humans after intravenous injection, nasal insufflation (snorting), or smoking. Drug Metab. Dispos. 17, 153–159 (1989)

    CAS  Google Scholar 

  3. Zhan, C.-G., Landry, D.W.: Theoretical studies of competing reaction pathways and energy barriers for alkaline ester hydrolysis of cocaine. J. Phys. Chem. A 105, 1296–1301 (2001)

    CAS  Google Scholar 

  4. Laizure, S.C., Mandrell, T., Gades, N.M., Parker, R.B.: Cocaethylene metabolism and interaction with cocaine and ethanol: role of carboxylesterases. Drug Metab. Dispos. 31, 16–20 (2003)

    Article  CAS  Google Scholar 

  5. Zhan, C.G., Zheng, F., Landry, D.W.: Fundamental reaction mechanism for cocaine hydrolysis in human butyrylcholinesterase. J. Am. Chem. Soc. 125, 2462–2474 (2003)

    Article  CAS  Google Scholar 

  6. Gao, D., Zhan, C.G.: Modeling evolution of hydrogen bonding and stabilization of transition states in the process of cocaine hydrolysis catalyzed by human butyrylcholinesterase. Proteins 62, 99–110 (2006)

    Article  CAS  Google Scholar 

  7. Sun, H., Shen, M.L., Pang, Y.P., Lockridge, O., Brimijoin, S.: Cocaine metabolism accelerated by a re-engineered human butyrylcholinesterase. J. Pharmacol. Exp. Ther. 302, 710–716 (2002)

    Article  CAS  Google Scholar 

  8. Gorelick, D.A.: Enhancing cocaine metabolism with butyrylcholinesterase as a treatment strategy. Drug Alcohol Depend. 48, 159–165 (1997)

    Article  CAS  Google Scholar 

  9. Bornheim, L.M.: Effect of cytochrome P450 inducers on cocaine-mediated hepatotoxicity. Toxicol. Appl. Pharmacol. 150, 158–165 (1998)

    Article  CAS  Google Scholar 

  10. Ascenzi, P., Clementi, E., Polticelli, F.: The Rhodococcus sp. cocaine esterase: a bacterial candidate for novel pharmacokinetic-based therapies for cocaine abuse. IUBMB Life 55, 397–402 (2003)

    Article  CAS  Google Scholar 

  11. Redinbo, M.R., Bencharit, S., Potter, P.M.: Human carboxylesterase. 1. From drug metabolism to drug discovery. Biochem. Soc. Trans. 31, 620–624 (2003)

    Article  CAS  Google Scholar 

  12. Turner, J.M., Larsen, N.A., Basran, A., Barbas, C.F., Bruce, N.C., Wilson, I.A., Lerner, R.A.: Biochemical characterization and structural analysis of a highly proficient cocaine esterase. Biochemistry 41, 12297–12307 (2002)

    Article  CAS  Google Scholar 

  13. Isenschmid, D.S.: Cocaine—effects on human performance and behavior. Forensic Sci. Rev. 14, 61–100 (2002)

    Google Scholar 

  14. Moriya, F., Hashimoto, Y., Ishizu, H.: Effects of cocaine administration route on the formation of cocaethylene in drinkers: an experiment using rats. Forensic Sci. Int. 76, 189–197 (1995)

    Article  CAS  Google Scholar 

  15. Brzezinski, M.R., Spink, B.J., Dean, R.A., Berkman, C.E., Cashman, J.R., Bosron, W.F.: Human liver carboxylesterase hCE-1: binding specificity for cocaine, heroin, and their metabolites and analogs. Drug Metab. Dispos. 25, 1089–1096 (1997)

    CAS  Google Scholar 

  16. Johanson, C.E., Fischman, M.W.: The pharmacology of cocaine related to its abuse. Pharmacol. Rev. 41, 3–52 (1989)

    CAS  Google Scholar 

  17. Ritz, M.C., Lamb, R.J., Goldberg, S.R., Kuhar, M.J.: Cocaine receptors on dopamine transporters are related to self-administration of cocaine. Science 237, 1219–1223 (1987)

    Article  CAS  Google Scholar 

  18. Kuhar, M.J., Ritz, M.C., Boja, J.W.: The dopamine hypothesis of the reinforcing properties of cocaine. Trends Neurosci. 14, 299–302 (1991)

    Article  CAS  Google Scholar 

  19. Garrido, J.M.P., Marques, M.P.M., Silva, A.M.S., Macedo, T.R.A., Oliveira-Brett, A.M., Borges, F.: Spectroscopic and electrochemical studies of cocaine–opioid interactions. Anal. Bioanal. Chem. 388, 1799–1808 (2007)

    Article  CAS  Google Scholar 

  20. Bader, R.F.W.: Atoms in Molecules: A Quantum Theory. Oxford University Press, New York (1990)

    Google Scholar 

  21. Jorgensen, W.L., Tirado-Rives, J.: The OPLS [optimized potentials for liquid simulations] potential functions for proteins, energy minimizations for crystals of cyclic peptides and crambin. J. Am. Chem. Soc. 110, 1657–1666 (1988)

    Article  CAS  Google Scholar 

  22. Hermans, J., Berendsen, H.J.C., Van Gunsteren, W.F., Postma, J.P.M.: A consistent empirical potential for water–protein interactions. Biopolymers 23, 1513–1518 (1984)

    Article  CAS  Google Scholar 

  23. Bader, R.F.W.: A quantum theory of molecular structure and its applications. Chem. Rev. 91, 893–928 (1991)

    Article  CAS  Google Scholar 

  24. Deng, S., Bharat, N., de Prada, P., Landry, D.W.: Substrate-assisted antibody catalysis. Org. Biomol. Chem. 2, 288–290 (2004)

    Article  CAS  Google Scholar 

  25. Zhu, N., Klein, C.L.: Electrostatic properties of (–)-norcocaine by X-ray diffraction. J. Phys. Chem. 98, 10699–10705 (1994)

    Article  CAS  Google Scholar 

  26. Carey, R.J., DePalma, G.: A simple, rapid HPLC method for the concurrent measurement of cocaine and catecholamines in brain tissue samples. J. Neurosci. Methods 58, 25–28 (1995)

    Article  CAS  Google Scholar 

  27. Rincón, D.A., Cordeiro, M.N.D.S., Mosquera, R.A., Borges, F.: Theoretical study of cocaine and ecgonine methyl ester in gas phase and in aqueous solution. Chem. Phys. Lett. 467, 249–254 (2009)

    Article  Google Scholar 

  28. Becke, A.D.: Density-functional exchange-energy approximation with correct asymptotic behavior. Phys. Rev. A 38, 3098–3100 (1988)

    Article  CAS  Google Scholar 

  29. Lee, C., Yang, W., Parr, R.G.: Development of the Colle–Salvetti correlation-energy formula into a functional of the electron density. Phys. Rev. B 37, 785–789 (1988)

    Article  CAS  Google Scholar 

  30. Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Montgomery, J.A. Jr., Vreven, T., Kudin, K.N., Burant, J.C., Millam, J.M., Iyengar, S.S., Tomasi, J., Barone, V., Mennucci, B., Cossi, M., Scalmani, G., Rega, N., Petersson, G.A., Nakatsuji, H., Hada, M., Ehara, M., Toyota, K., Fukuda, R., Hasegawa, J., Ishida, M., Nakajima, T., Honda, Y., Kitao, O., Nakai, H., Klene, M., Li, X., Knox, J.E., Hratchian, H.P., Cross, J.B., Adamo, C., Jaramillo, J., Gomperts, R., Stratmann, R.E., Yazyev, O., Austin, A.J., Cammi, R., Pomelli, C., Ochterski, J.W., Ayala, P.Y., Morokuma, K., Voth, G.A., Salvador, P., Dannenberg, J.J., Zakrzewski, V.G., Dapprich, S., Daniels, A.D., Strain, M.C., Farkas, O., Malick, D.K., Rabuck, A.D., Raghavachari, K., Foresman, J.B., Ortiz, J.V., Cui, Q., Baboul, A.G., Clifford, S., Cioslowski, J., Stefanov, B.B., Liu, G., Liashenko, A., Piskorz, P., Komaromi, I., Martin, R.L., Fox, D.J., Keith, T., Al-Laham, M.A., Peng, C.Y., Nanayakkara, A., Challacombe, M., Gill, P.M.W., Johnson, B., Chen, W., Wong, M.W., Gonzalez, C., Pople, J.A.: Gaussian 03, Revision C.02, Gaussian Inc., Wallingford, CT (2004)

  31. Cancès, M.T., Mennucci, B., Tomasi, J.: A new integral equation formalism for the polarizable continuum model: theoretical background and applications to isotropic and anisotropic dielectrics. J. Chem. Phys. 107, 3032–3042 (1997)

    Article  Google Scholar 

  32. Cossi, M., Barone, V., Mennucci, B., Tomasi, J.: Ab initio study of ionic solutions by a polarizable continuum dielectric model. Chem. Phys. Lett. 286, 253–260 (1998)

    Article  CAS  Google Scholar 

  33. Mennucci, B., Tomasi, J.: A new integral equation formalism for the polarizable continuum model: theoretical background and applications to isotropic and anisotropic dielectrics. J. Chem. Phys. 106, 5151–5159 (1997)

    Article  CAS  Google Scholar 

  34. Rincón, D.A., Cordeiro, M.N.D.S., Mosquera, R.A.: On the electronic structure of cocaine and its metabolites. J. Phys. Chem. A 113, 13937–13942 (2009)

    Google Scholar 

  35. Bader, R.F.W.: AIMPAC: A suite of programs for the AIM theory. Mc. Master, University Hamilton, Ont. L8S 4M1, Canada

  36. Berendsen, H.J.C., van der Spoel, D., van Drunen, R.: GROMACS: a message-passing parallel molecular dynamics implementation. Comput. Phys. Commun. 91, 43–56 (1995)

    Article  CAS  Google Scholar 

  37. Lindahl, E., Hess, B., van der Spoel, D.: GROMACS 3.0: a package for molecular simulation and trajectory analysis. J. Mol. Model. 7, 306–317 (2001)

    CAS  Google Scholar 

  38. Bekker, H., Berendsen, H.J.C., Dijkstra, E.J., Achterop, S., van Drunen, R., van der Spoel, D., Sijbers, A., Keegstra, H., Reitsma, B., Renardus, M.K.R.: Gromacs: a parallel computer for molecular dynamics simulations. In: de Groot, R.A., Nadrchal, J. (eds.) Physics Computing, vol. 92. World Scientific, Singapore (1993)

    Google Scholar 

  39. van der Spoel, D., Lindahl, E., Hess, B., Groenhof, G., Mark, A.E., Berendsen, H.J.C.: GROMACS: fast, flexible, and free. J. Comput. Chem. 26, 1701–1718 (2005)

    Article  Google Scholar 

  40. Verlet, L.: Computer “experiments” on classical fluids. I. Thermodynamical properties of Lennard–Jones molecules. Phys. Rev. 159, 98–103 (1967)

    Article  CAS  Google Scholar 

  41. Hess, B., Bekker, H., Berendsen, H.J.C., Fraaije, J.G.E.M.: LINCS: a linear constraint solver for molecular simulations. J. Comput. Chem. 18, 1463–1472 (1997)

    Article  CAS  Google Scholar 

  42. Nosé, S.: A molecular dynamics method for simulations in the canonical ensemble. Mol. Phys. 52, 255–268 (1984)

    Article  Google Scholar 

  43. Hoover, W.G.: Canonical dynamics: equilibrium phase-space distributions. Phys. Rev. A 31, 1695–1697 (1985)

    Article  Google Scholar 

  44. Parrinello, M. Rahman: A.: Polymorphic transitions in single crystals: a new molecular dynamics method. J. Appl. Phys. 52, 7182–7191 (1981)

    Article  CAS  Google Scholar 

  45. Darden, T., York, D., Pedersen, L.: Particle mesh Ewald: an n⋅log (n) method for Ewald sums in large systems. J. Chem. Phys. 98, 10089–10093 (1993)

    Article  CAS  Google Scholar 

  46. Essmann, U., Perera, L., Berkowitz, M.L., Darden, T., Lee, H., Pedersen, L.G.: A smooth particle mesh Ewald method. J. Chem. Phys. 103, 8577–8593 (1995)

    Article  CAS  Google Scholar 

  47. Berendsen, H.J.C., Grigera, J.R., Straatsma, T.P.: The missing term in effective pair potentials. J. Phys. Chem. 91, 6269–6271 (1997)

    Article  Google Scholar 

  48. Villa, A. Mark: A.E.: Calculation of the free energy of solvation for neutral analogs of amino acid side chains. J. Comput. Chem. 23, 548–553 (2002)

    Article  CAS  Google Scholar 

  49. Melissa, T., Martínez, J.A.: Toxicología postmortem de cocaína. implicaciones en la práctica forense. Cien. Forense Latinoam. 1, 16–23 (2007)

    Google Scholar 

  50. Clarke, E.G.C.: Clarke’s Isolation and Identification of Drugs in Pharmaceuticals, Body Fluids, and Post-Mortem Materials, 2nd edn. The Pharmaceutical Press, London (1986)

    Google Scholar 

  51. Sun, L., Lau, C.E.: Simultaneous pharmacokinetic modeling of cocaine and its metabolites, norcocaine and benzoylecgonine, after intravenous and oral administration in rats. Drug Metab. Dispos. 29, 1183–1189 (2001)

    CAS  Google Scholar 

  52. Luzar, A.: Resolving the hydrogen bond dynamics conundrum. J. Chem. Phys. 113, 10663–10676 (2000)

    Article  CAS  Google Scholar 

  53. Xu, H., Stern, H.A., Berne, B.J.: Can water polarizability be ignored in hydrogen bond kinetics? J. Phys. Chem. B 106, 2054–2060 (2002)

    Article  CAS  Google Scholar 

  54. Rapaport, D.C.: Hydrogen bonds in water. Mol. Phys. 50, 1151–1162 (1983)

    Article  CAS  Google Scholar 

  55. Starr, F.W., Nielsen, J.K., Stanley, H.E.: Fast and slow dynamics of hydrogen bonds in liquid water. Phys. Rev. Lett. 82, 2294–2297 (1999)

    Article  CAS  Google Scholar 

  56. Chandra, A.: Effects of ion atmosphere on hydrogen-bond dynamics in aqueous electrolyte solutions. Phys. Rev. Lett. 85, 768–771 (2000)

    Article  CAS  Google Scholar 

  57. Chandra, A.: Dynamical behavior of anion–water and water–water hydrogen bonds in aqueous electrolyte solutions: a molecular dynamics study. J. Phys. Chem. B 107, 3899–3906 (2003)

    Article  CAS  Google Scholar 

  58. Balasubramanian, S., Pal, S., Bagchi, B.: Hydrogen-bond dynamics near a micellar surface: origin of the universal slow relaxation at complex aqueous interfaces. Phys. Rev. Lett. 89, 115505 (2002)

    Article  Google Scholar 

  59. Bagchi, B.: Water solvation dynamics in the bulk and in the hydration layer of proteins and self-assemblies. Annu. Rep. Prog. Chem., Sect. C Phys. Chem. 99, 127–175 (2003)

    Article  CAS  Google Scholar 

  60. Tarek, M., Tobias, D.J.: Role of protein–water hydrogen bond dynamics in the protein dynamical transition. Phys. Rev. Lett. 88, 138101 (2002)

    Article  CAS  Google Scholar 

  61. Boese, A.D., Chandra, A., Martin, J.M.L., Marx, D.: From ab initio quantum chemistry to molecular dynamics: the delicate case of hydrogen bonding in ammonia. J. Chem. Phys. 119, 5965–5981 (2003)

    Article  CAS  Google Scholar 

  62. van der Spoel, D., van Maaren, P.J., Larsson, P., Tmneanu, N.: Thermodynamics of hydrogen bonding in hydrophilic and hydrophobic media. J. Phys. Chem. B 110, 4393–4398 (2006)

    Article  Google Scholar 

  63. Starr, F.W., Nielsen, J.K., Stanley, H.E.: Hydrogen-bond dynamics for the extended simple point-charge model of water. Phys. Rev. E 62, 579–587 (2000)

    Article  CAS  Google Scholar 

  64. Luzar, A., Chandler, D.: Hydrogen-bond kinetics in liquid water. Nature 379, 55–57 (1996)

    Article  CAS  Google Scholar 

  65. Luzar, A. Chandler: D.: Effect of environment on hydrogen bond dynamics in liquid water. Phys. Rev. Lett. 76, 928–931 (1996)

    Article  CAS  Google Scholar 

  66. Soper, A.K.: Tests of the empirical potential structure refinement method and a new method of application to neutron diffraction data on water. Mol. Phys. 99, 1503–1516 (2001)

    Article  CAS  Google Scholar 

  67. Soper, A.K.: The radial distribution functions of water and ice from 220 to 673 K and at pressures up to 400 MPa. Chem. Phys. 258, 121–137 (2000)

    Article  CAS  Google Scholar 

  68. Svishchev, I.M., Kusalik, P.G.: Structure in liquid water: a study of spatial distribution functions. J. Chem. Phys. 99, 3049–3059 (1993)

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Departamento de Química Física, Universidade de Vigo, Campus Universitario Lagoas-Marcosende, 36310, Vigo, Spain

    David A. Rincón, M. Natália D. S. Cordeiro & Ricardo A. Mosquera

  2. Laboratory of Separation and Reaction Engineering (LSRE), Faculdade de Engenharia, Universidade do Porto, Rua Dr. Roberto Frias, 4200-465, Porto, Portugal

    Miguel Jorge

  3. REQUIMTE, Departamento de Química, Universidade do Porto, Rua do Campo Alegre 687, 4169-007, Porto, Portugal

    David A. Rincón & M. Natália D. S. Cordeiro

  4. UQFM/Departamento de Química Orgânica, Faculdade de Farmácia, Universidade do Porto, 4050-047, Porto, Portugal

    Fernanda Borges

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  1. David A. Rincón
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  2. Miguel Jorge
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Rincón, D.A., Jorge, M., Cordeiro, M.N.D.S. et al. Hydration Structure of Cocaine and its Metabolites: A Molecular Dynamics Study. J Solution Chem 40, 656–679 (2011). https://doi.org/10.1007/s10953-011-9672-8

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