Prediction of the binding sites of huperzine A in acetylcholinesterase by docking studies

SummaryWe have performed docking studies with the SYSDOC program on acetylcholinesterase (AChE) to predict the binding sites in AChE of huperzine A (HA), which is a potent and selective, reversible inhibitor of AChE. The unique aspects of our docking studies include the following: (i) Molecular flexibility of the guest and the host is taken into account, which permits both to change their conformations upon binding. (ii) The binding energy is evaluated by a sum of energies of steric, electrostatic and hydrogen bonding interactions. In the energy calculation no grid approximation is used, and all hydrogen atoms of the system are treated explicitly. (iii) The energy of cation-π interactions between the guest and the host, which is important in the binding of AChE, is included in the calculated binding energy. (iv) Docking is performed in all regions of the host's binding cavity. Based on our docking studies and the pharmacological results reported for HA and its analogs, we predict that HA binds to the bottom of the binding cavity of AChE (the gorge) with its ammonium group interacting with Trp84, Phe330, Glu199 and Asp72 (catalytic site). At the the opening of the gorge with its ammonium group partially interacting with Trp279 (peripheral site). At the catalytic site, three partially overlapping subsites of HA were identified which might provide a dynamic view of binding of HA to the catalytic site.

[1]  I. Kuntz,et al.  Structure-based discovery of inhibitors of thymidylate synthase. , 1993, Science.

[2]  W. L. Jorgensen.  Quantum and statistical mechanical studies of liquids. 10. Transferable intermolecular potential functions for water, alcohols, and ethers. Application to liquid water , 2002 .

[3]  J M Blaney,et al.  A geometric approach to macromolecule-ligand interactions. , 1982, Journal of molecular biology.

[4]  H. Berendsen,et al.  COMPUTER-SIMULATION OF MOLECULAR-DYNAMICS - METHODOLOGY, APPLICATIONS, AND PERSPECTIVES IN CHEMISTRY , 1990 .

[5]  G A Petsko,et al.  Aromatic-aromatic interaction: a mechanism of protein structure stabilization. , 1985, Science.

[6]  J H Miller,et al.  Delineating the pharmacophoric elements of huperzine A: importance of the unsaturated three-carbon bridge to its AChE inhibitory activity. , 1991, Journal of medicinal chemistry.

[7]  A. Goldman,et al.  Atomic structure of acetylcholinesterase from Torpedo californica: a prototypic acetylcholine-binding protein , 1991, Science.

[8]  A. Itai,et al.  DEVELOPMENT OF AN EFFICIENT AUTOMATED DOCKING METHOD , 1993 .

[9]  P. Goodford.  A computational procedure for determining energetically favorable binding sites on biologically important macromolecules. , 1985, Journal of medicinal chemistry.

[10]  J. Janin,et al.  Computer analysis of protein-protein interaction. , 1978, Journal of molecular biology.

[11]  Jan Kroon,et al.  Stereochemistry of charged nitrogen-aromatic interactions and its involvement in ligand-receptor binding , 1993, J. Comput. Aided Mol. Des..

[12]  U. Singh,et al.  A NEW FORCE FIELD FOR MOLECULAR MECHANICAL SIMULATION OF NUCLEIC ACIDS AND PROTEINS , 1984 .

[13]  Christopher A. Hunter,et al.  The nature of .pi.-.pi. interactions , 1990 .

[14]  S. Lifson,et al.  Energy functions for peptides and proteins. I. Derivation of a consistent force field including the hydrogen bond from amide crystals. , 1974, Journal of the American Chemical Society.

[15]  D A Dougherty,et al.  Acetylcholine binding by a synthetic receptor: implications for biological recognition , 1990, Science.

[16]  C. Holden.  Animal rights activism threatens dissection. , 1990, Science.

[17]  J. Kuriyan,et al.  Binding of a high affinity phosphotyrosyl peptide to the Src SH2 domain: Crystal structures of the complexed and peptide-free forms , 1993, Cell.

[18]  M. Karplus,et al.  Dynamics of folded proteins , 1977, Nature.

[19]  G J Williams,et al.  The Protein Data Bank: a computer-based archival file for macromolecular structures. , 1977, Journal of molecular biology.

[20]  X. Tang,et al.  [Anti-cholinesterase activity of huperzine A]. , 1986, Zhongguo yao li xue bao = Acta pharmacologica Sinica.

[21]  Yuan-Ping Pang,et al.  Prediction of the binding site of 1-benzyl-4-[(5,6-dimethoxy-1-indanon-2-yl)methyl]piperidine in acetylcholinesterase by docking studies with the SYSDOC program , 1994, J. Comput. Aided Mol. Des..

[22]  P. Taylor,et al.  Role of the peripheral anionic site on acetylcholinesterase: inhibition by substrates and coumarin derivatives. , 1991, Molecular pharmacology.

[23]  C. Deakyne,et al.  Unconventional ionic hydrogen bonds. 2. NH+.cntdot..cntdot..cntdot..pi.. Complexes of onium ions with olefins and benzene derivatives , 1985 .

[24]  G A Petsko,et al.  Amino‐aromatic interactions in proteins , 1986, FEBS letters.

[25]  Odd Gropen,et al.  Gaussian basis sets for the fifth row elements, Mo‐Cd, and the sixth row elements W‐RN , 1987 .

[26]  C. D. Gelatt,et al.  Optimization by Simulated Annealing , 1983, Science.

[27]  S. Lifson,et al.  Consistent force field studies of intermolecular forces in hydrogen-bonded crystals. 1. Carboxylic acids, amides, and the C:O.cntdot..cntdot..cntdot.H- hydrogen bonds , 1979 .

[28]  M. Levitt,et al.  Aromatic Rings Act as Hydrogen Bond Acceptors , 2022 .

[29]  D. Goodsell,et al.  Automated docking of substrates to proteins by simulated annealing , 1990, Proteins.

[30]  M. Karplus,et al.  CHARMM: A program for macromolecular energy, minimization, and dynamics calculations , 1983 .

[31]  S. Yue.  Distance-constrained molecular docking by simulated annealing. , 1990, Protein Engineering.

[32]  J. Janin,et al.  Protein‐protein recognition analyzed by docking simulation , 1991, Proteins.

[33]  I. Kuntz.  Structure-Based Strategies for Drug Design and Discovery , 1992, Science.

[34]  Yuan-Ping Pang,et al.  Synthesis, molecular modeling, 2-D NMR, and biological evaluation of ILV mimics as potential modulators of protein kinase C , 1993 .

[35]  R. Cramer,et al.  Validation of the general purpose tripos 5.2 force field , 1989 .

[36]  Yan Xia,et al.  Synthesis of Huperzine A and Its Analogues and Their Anticholinesterase Activity , 1991 .

[37]  A. Kozikowski,et al.  Potencies and stereoselectivities of enantiomers of huperzine A for inhibition of rat cortical acetylcholinesterase. , 1991, European journal of pharmacology.

[38]  Y. Ashani,et al.  Mechanism of inhibition of cholinesterases by huperzine A. , 1992, Biochemical and biophysical research communications.

[39]  F R Salemme,et al.  An hypothetical structure for an intermolecular electron transfer complex of cytochromes c and b5. , 1976, Journal of molecular biology.

[40]  J Moult,et al.  Docking by least-squares fitting of molecular surface patterns. , 1992, Journal of molecular biology.

[41]  D E Koshland,et al.  Molecular recognition analyzed by docking simulations: the aspartate receptor and isocitrate dehydrogenase from Escherichia coli. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[42]  J. Sussman,et al.  Quaternary ligand binding to aromatic residues in the active-site gorge of acetylcholinesterase. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[43]  J. Warwicker,et al.  Investigating protein-protein interaction surfaces using a reduced stereochemical and electrostatic model. , 1989, Journal of molecular biology.

[44]  D. Koshland,et al.  Prediction of the structure of a receptor–protein complex using a binary docking method , 1992, Nature.