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Recent progress in protein drug design and discovery with a focus on novel approaches to the development of anticocaine medications

    Fang Zheng

    Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 725 Rose Street, Lexington, KY 40536, USA.

    &
    Chang-Guo Zhan

    † Author for correspondence

    Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 725 Rose Street, Lexington, KY 40536, USA.

    Published Online:https://doi.org/10.4155/fmc.09.20

    Cocaine is highly addictive and no anticocaine medication is currently available. Accelerating cocaine metabolism, producing biologically inactive metabolites, is recognized as an ideal anticocaine medication strategy, especially for the treatment of acute cocaine toxicity. However, currently known wild-type enzymes have either too low a catalytic efficiency against the abused cocaine, in other words (-)-cocaine, or the in vivo half-life is too short. Novel computational strategies and design approaches have been developed recently to design and discover thermostable or high-activity mutants of enzymes based on detailed structures and catalytic/inactivation mechanisms. The structure- and mechanism-based computational design efforts have led to the discovery of high-activity mutants of butyrylcholinesterase and thermostable mutants of cocaine esterase as promising anticocaine therapeutics. The structure- and mechanism-based computational strategies and design approaches may be used to design high-activity and/or thermostable mutants of many other proteins that have clear therapeutic potentials and to design completely new therapeutic enzymes.

    Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

    Bibliography

    • Zhan CG. Modeling reaction mechanism of cocaine hydrolysis and rational drug design for therapeutic treatment of cocaine abuse. In: Topics in Heterocyclic Drugs (Volume 4). Gupta SP (Ed.). Springer-Verlag, Heidelberg, Germany, 107–159 (2006).
    • Landry DW, Yang GX. Anticocaine catalytic antibodies: a novel approach to the problem of addiction. J. Addict. Dis.16,1–17 (1997).
    • Treadwell SD, Robinson TG. Cocaine use and stroke. Postgrad. Med. J.83,389–394 (2007).
    • Gorelick DA. Enhancing cocaine metabolism with butyrylcholinesterase as a treatment strategy. Drug Alcohol Depend.48,159–165 (1997).
    • Redish AD. Addiction as a computational process gone awry. Science306,1944–1947 (2004).
    • Huang X, Zhan CG. How dopamine transporter interacts with dopamine: insights from molecular modeling and simulation. Biophys. J.93,3627–3639 (2007).
    • Beuming T, Kniazeff J, Bergmann ML et al. The binding sites for cocaine and dopamine in the dopamine transporter overlap. Nat. Neurosci.11,780–789 (2008).
    • Gorelick DA, Gardner EL, Xi ZX. Agents in development for the management of cocaine abuse. Drugs64,1547–1573 (2004).
    • Landry DW, Zhao K, Yang GXQ, Glickman M, Georgiadis TM. Antibody catalyzed degradation of cocaine. Science259,1899–1901 (1993).
    • 10  Zhan CG, Deng SX, Skiba JG et al. First-principle studies of intermolecular and intramolecular catalysis of protonated cocaine. J. Comput. Chem.26,980–986 (2005).
    • 11  Zheng F, Zhan CG. Structure-and-mechanism-based design and discovery of therapeutics for cocaine overdose. Org. Biomol. Chem.6,836–843 (2008).
    • 12  Larsen NA, Turner JM, Stevens J et al. Crystal structure of a bacterial cocaine esterase. Nat. Struct. Biol.9,17–21 (2002).
    • 13  Cooper ZD, Narasimhan D, Sunahara RK et al. Rapid and robust protection against cocaine-induced lethality in rats by the bacterial cocaine esterase. Mol. Pharmacol.70,1885–1891 (2006).
    • 14  Ko MC, Bowen LD, Narasimhan D et al. Cocaine esterase: interactions with cocaine and immune responses in mice. J. Pharmacol. Exp. Ther.320,926–933 (2007).
    • 15  Zheng F, Zhan CG. Rational design of an enzyme mutant for anticocaine therapeutics. J. Comput. Aided Mol. Des.22,661–671 (2008).
    • 16  Lehmann M, Wyss M. Engineering proteins for thermostability: the use of sequence alignments versus rational design and directed evolution. Curr. Opin. Biotechnol.12,371–375 (2001).
    • 17  Korkegian A, Black ME, Baker D, Stoddard BL. Computational thermostabilization of an enzyme. Science308,857–860 (2005).
    • 18  Dantas G, Kuhlman B, Callender D, Wong M, Baker D. A large scale test of computational protein design: folding and stability of nine completely redesigned globular proteins. J. Mol. Biol.332,449–460 (2003).
    • 19  Looger LL, Dwyer MA, Smith JJ, Hellinga HW. Computational design of receptor and sensor proteins with novel functions. Nature423,185–190 (2003).
    • 20  Kuhlman B, Dantas G, Ireton GC, Varani G, Stoddard BL, Baker D. Design of a novel globular protein fold with atomic-level accuracy. Science302,1364–1368 (2003).
    • 21  Kuhlman B, Baker D. Native protein sequences are close to optimal for their structures. Proc. Natl Acad. Sci. USA97,10383–10388 (2000).
    • 22  Gao D, Narasimhan DL, Macdonald J et al. Thermostable variants of cocaine esterase for long-time protection against cocaine toxicity. Mol. Pharmacol.75,318–323 (2009).▪▪ Novel computational strategy based on molecular dynamics simulation at a high temperature was proposed and tested to uncover the inactivation pathway of an enzyme and to design thermostable mutants of the enzyme.
    • 23  Corchado JC, Coitino EL, Chuang YY, Fast PL, Truhlar DG. Interpolated vibrational transition-state theory by mapping. J. Phys. Chem. A 102,2424–2438 (1998).
    • 24  Gao D, Zhan CG. Modeling evolution of hydrogen bonding and stabilization of transition states in the process of cocaine hydrolysis catalyzed by human butyrylcholinesterase. Proteins62,99–110 (2006).
    • 25  Gao D, Zhan CG. Modeling effects of oxyanion hole on the ester hydrolyses catalyzed by human cholinesterases. J. Phys. Chem. B109,23070–23076 (2005).
    • 26  Gao D, Cho H, Yang W et al. Computational design of a human butyrylcholinesterase mutant for accelerating cocaine hydrolysis based on the transition-state simulation. Angew. Chem. Int. Ed. Engl.45,653–657 (2006).
    • 27  Zhan CG, Zheng F, Landry DW. Fundamental reaction mechanism for cocaine hydrolysis in human butyrylcholinesterase. J. Am. Chem. Soc.125,2462–2474 (2003).▪ First computational study on the fundamental reaction pathway for cocaine hydrolysis in human butyrylcholinesterase.
    • 28  Zhan CG, Gao D. Catalytic mechanism and energy barriers for butyrylcholinesterase-catalyzed hydrolysis of cocaine. Biophys. J.89,3863–3872 (2005).▪ First quantum mechanics/molecular mechanics reaction coordinate calculations on the reaction pathway for cocaine hydrolysis in human butyrylcholinesterase.
    • 29  Hamza A, Cho H, Tai HH, Zhan CG. Molecular dynamics simulation of cocaine binding with human butyrylcholinesterase and its mutants. J. Phys. Chem. B109,4776–4782 (2005).
    • 30  Sun H, Yazal JE, Lockridge O, Schopfer LM, Brimijoin S, Pang YP. Predicted Michaelis–Menten complexes of cocaine–butyrylcholinesterase: engineering effective butyrylcholinesterase mutants for cocaine detoxication. J. Biol. Chem.276,9330–9336 (2005).
    • 31  Gao Y, Atanasova E, Sui N, Pancook JD, Watkins JD, Brimijoin S. Gene transfer of cocaine hydrolase suppresses cardiovascular responses to cocaine in rats. Mol. Pharmacol.67,204–211 (2001).
    • 32  Sun H, Pang YP, Lockridge O, Brimijoin S. Re-engineering butyrylcholinesterase as a cocaine hydrolase. Mol. Pharmacol.62,220–224 (2002).
    • 33  Pan Y, Gao D, Yang W et al. Computational redesign of human butyrylcholinesterase for anticocaine medication. Proc. Natl. Acad. Sci. USA102,16656–16661 (2005).▪▪ First version of the novel virtual screening approach based on transition state simulations, leading to the discovery of a mutant of human butyrylcholinesterase with considerably improved catalytic efficiency against (-)-cocaine.
    • 34  Pan Y, Gao D, Yang W, Cho H, Zhan CG. Free energy perturbation (FEP) simulation on the transition-states of cocaine hydrolysis catalyzed by human butyrylcholinesterase and its mutants. J. Am. Chem. Soc.129,13537–13543 (2007).▪▪ First study that proposed performing free energy perturbation simulations on the mutations of the transition states for the purpose of designing high-activity mutants of an enzyme.
    • 35  Zheng F, Yang W, Ko MC et al. Most efficient cocaine hydrolase designed by virtual screening of transition States. J. Am. Chem. Soc.130,12148–12155 (2008).▪▪ Novel, generalized and systematic computational design approach for the virtual screening of transition states, leading to the discovery of the most efficient cocaine hydrolase.
    • 36  Pan Y, Gao D, Zhan CG. Modeling the catalysis of anticocaine catalytic antibody: competing reaction pathways and free energy barriers. J. Am. Chem. Soc.130,5140–5149 (2008).▪▪ Novel computational strategy and protocol that can be used to predict the free energy barriers for chemical reactions catalyzed by a catalytic antibody.
    • 37  Yang W, Pan Y, Zheng F, Cho H, Tai HH, Zhan CG. Free energy perturbation (FEP) simulation on transition states and design of high-activity mutants of human butyrylcholinesterase for accelerating cocaine metabolism. Biophys. J.96,1931–1993 (2009).
    • 38  Brimijoin S, Gao Y, Anker JJ et al. A cocaine hydrolase engineered from human butyrylcholinesterase selectively blocks cocaine toxicity and reinstatement of drug seeking in rats. Neuropsychopharmacology33,2715–2725 (2008).▪ Extensive studies in vitro and in vivo confirmed the high-activity mutant designed by Zhan et al. and demonstrated that the mutant can selectively block cocaine toxicity and reinstatement of drug seeking in rats.
    • 39  Pancook JD, Pecht G, Ader M, Mosko M, Lockridge O, Watkins JD. Application of directed evolution technology to optimize the cocaine hydrolase activity of human butyrylcholinesterase. FASEB J.17,A565 (2003).
    • 40  Poole AM, Ranganathan R. Knowledge-based potentials in protein design. Curr. Opin. Struct. Biol.16,508–513 (2006).
    • 41  Russ WP, Lowery DM, Mishra P, Yaffe MB, Ranganathan R. Natural-like function in artificial WW domains. Nature437,579–583 (2005).
    • 42  Alvizo O, Mayo SL. Evaluating and optimizing computational protein design force fields using fixed composition-based negative design. Proc. Natl Acad. Sci. USA105,12242–12247 (2008).
    • 43  Alvizo O, Allen BD, Mayo SL. Computational protein design promises to revolutionize protein engineering. BioTechniques42,31–39 (2007).
    • 44  Benson DE, Wisz MS, Liu W, Hellinga HW. Construction of a novel redox protein by rational design: conversion of a disulfide bridge into a mononuclear iron–sulfur center. Biochemistry37,7070–7076 (1998).
    • 45  Benson DE, Conrad DW, de Lorimier RM, Trammell SA, Hellinga HW. Design of bioelectronic interfaces by exploiting hinge-bending motions in proteins. Science293,1641–1644 (2001).
    • 46  Looger LL, Dwyer MA, Smith JJ, Hellinga HW. Computational design of receptor and sensor proteins with novel functions. Nature423,185–190 (2003).
    • 47  Allert M, Rizk SS, Looger LL, Hellinga HW. Computational design of receptors for an organophosphate surrogate of the nerve agent soman. Proc. Natl Acad. Sci. USA101,7907–7912 (2004).
    • 48  Huang YJ, Huang Y, Baldassarre H et al. Recombinant human butyrylcholinesterase from milk of transgenic animals to protect against organophosphate poisoning. Proc. Natl Acad. Sci. USA104,13603–13608 (2007).
    • 49  Huang YJ, Lundy PM, Lazaris A et al. Substantially improved pharmacokinetics of recombinant human butyrylcholinesterase by fusion to human serum albumin. BMC Biotechnol.8,50 (2008).
    • 50  Barr AM, Markou A. Psychostimulant withdrawal as an inducing condition in animal models of depression. Neurosci. Biobehav. Rev.29. 675–706 (2005).
    • 51  Keating GM, Simpson D. Agalsidase β: a review of its use in the management of Fabry disease. Drugs67,435–455 (2007).
    • 52  Clarke JTR. A Clinical Guide to Inherited Metabolic Diseases (2nd Edition). Cambridge University Press, Cambridge, UK (2007).
    • 53  Jiang L, Althoff EA, Clemente FR et al.De novo computational design of retro-aldol enzymes. Science319,1387–1391 (2008).▪▪ Successful computational design of a new type of enzyme, retro-aldol enzymes, with the desired catalytic activity.
    • 54  Röthlisberger D, Khersonsky O, Wollacott AM et al. Kemp elimination catalysts by computational enzyme design. Nature453,190–195 (2008).▪▪ Successful computational design of a new type of enzyme with the desired catalytic activity for Kemp elimination.