Inhibition of acetylcholinesterase by two genistein derivatives: kinetic analysis, molecular docking and molecular dynamics simulation

In this study two genistein derivatives (G1 and G2) are reported as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), and differences in the inhibition of AChE are described. Although they differ in structure by a single methyl group, the inhibitory effect of G1 (IC50=264 nmol/L) on AChE was 80 times stronger than that of G2 (IC50=21,210 nmol/L). Enzyme-kinetic analysis, molecular docking and molecular dynamics (MD) simulations were conducted to better understand the molecular basis for this difference. The results obtained by kinetic analysis demonstrated that G1 can interact with both the catalytic active site and peripheral anionic site of AChE. The predicted binding free energies of two complexes calculated by the molecular mechanics/generalized born surface area (MM/GBSA) method were consistent with the experimental data. The analysis of the individual energy terms suggested that a difference between the net electrostatic contributions (ΔEele+ΔGGB) was responsible for the binding affinities of these two inhibitors. Additionally, analysis of the molecular mechanics and MM/GBSA free energy decomposition revealed that the difference between G1 and G2 originated from interactions with Tyr124, Glu292, Val294 and Phe338 of AChE. In conclusion, the results reveal significant differences at the molecular level in the mechanism of inhibition of AChE by these structurally related compounds.

[1]  T. Darden,et al.  Particle mesh Ewald: An N⋅log(N) method for Ewald sums in large systems , 1993 .

[2]  R F Woolson,et al.  A double-blind, placebo-controlled multicenter study of tacrine for Alzheimer's disease. The Tacrine Collaborative Study Group. , 1992, The New England journal of medicine.

[3]  Giulio Rastelli,et al.  Application of a post-docking procedure based on MM-PBSA and MM-GBSA on single and multiple protein conformations. , 2012, European journal of medicinal chemistry.

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

[5]  Wei Cui,et al.  The molecular mechanism studies of chirality effect of PHA-739358 on Aurora kinase A by molecular dynamics simulation and free energy calculations , 2011, J. Comput. Aided Mol. Des..

[6]  Junmei Wang,et al.  Development and testing of a general amber force field , 2004, J. Comput. Chem..

[7]  P. Carlier,et al.  Potent, easily synthesized huperzine A-tacrine hybrid acetylcholinesterase inhibitors. , 1999, Bioorganic & medicinal chemistry letters.

[8]  K. Courtney,et al.  A new and rapid colorimetric determination of acetylcholinesterase activity. , 1961, Biochemical pharmacology.

[9]  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.

[10]  Wei Huang,et al.  Synthesis, biological evaluation and molecular modeling of aloe-emodin derivatives as new acetylcholinesterase inhibitors. , 2013, Bioorganic & medicinal chemistry.

[11]  N. Greig,et al.  Inhibition of human acetyl- and butyrylcholinesterase by novel carbamates of (-)- and (+)-tetrahydrofurobenzofuran and methanobenzodioxepine. , 2006, Journal of Medicinal Chemistry.

[12]  P. Carlier,et al.  Evaluation of short-tether bis-THA AChE inhibitors. A further test of the dual binding site hypothesis. , 1999, Bioorganic & medicinal chemistry.

[13]  P. Kollman,et al.  A well-behaved electrostatic potential-based method using charge restraints for deriving atomic char , 1993 .

[14]  N. Ip,et al.  Design, synthesis and evaluation of novel heterodimers of donepezil and huperzine fragments as acetylcholinesterase inhibitors. , 2013, Bioorganic & medicinal chemistry.

[15]  Wei Cui,et al.  Studies of chirality effect of 4-(phenylamino)-pyrrolo[2,1-f][1,2,4]triazine on p38α by molecular dynamics simulations and free energy calculations , 2009, J. Comput. Aided Mol. Des..

[16]  Xiaopeng Hu,et al.  The molecular basis for the inhibition of phosphodiesterase-4D by three natural resveratrol analogs. Isolation, molecular docking, molecular dynamics simulations, binding free energy, and bioassay. , 2013, Biochimica et biophysica acta.

[17]  G. Ciccotti,et al.  Numerical Integration of the Cartesian Equations of Motion of a System with Constraints: Molecular Dynamics of n-Alkanes , 1977 .

[18]  H. Sugimoto,et al.  Synthesis and structure-activity relationships of acetylcholinesterase inhibitors: 1-benzyl-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine hydrochloride and related compounds. , 1995, Journal of medicinal chemistry.

[19]  Maurizio Recanatini,et al.  Computational investigation of the binding mode of bis(hydroxylphenyl)arenes in 17β-HSD1: molecular dynamics simulations, MM-PBSA free energy calculations, and molecular electrostatic potential maps , 2011, J. Comput. Aided Mol. Des..

[20]  Ming Liu,et al.  The molecular basis for the inhibition of human cytochrome P450 1A2 by oroxylin and wogonin , 2012, European Biophysics Journal.

[21]  Li Tang,et al.  Searching for the Multi-Target-Directed Ligands against Alzheimer's disease: discovery of quinoxaline-based hybrid compounds with AChE, H₃R and BACE 1 inhibitory activities. , 2011, Bioorganic & medicinal chemistry.

[22]  P. Carlier,et al.  Heterodimeric tacrine-based acetylcholinesterase inhibitors: investigating ligand-peripheral site interactions. , 1999, Journal of medicinal chemistry.

[23]  Zhe Li,et al.  The Molecular Basis for the Selectivity of Tadalafil toward Phosphodiesterase 5 and 6: A Modeling Study , 2013, J. Chem. Inf. Model..

[24]  Christian Kramer,et al.  MM/GBSA Binding Energy Prediction on the PDBbind Data Set: Successes, Failures, and Directions for Further Improvement , 2013, J. Chem. Inf. Model..

[25]  F. J. Luque,et al.  Pyrano[3,2-c]quinoline-6-chlorotacrine hybrids as a novel family of acetylcholinesterase- and beta-amyloid-directed anti-Alzheimer compounds. , 2009, Journal of medicinal chemistry.

[26]  Z. Xi,et al.  Insight into herbicide resistance of W574L mutant Arabidopsis thaliana acetohydroxyacid synthase: molecular dynamics simulations and binding free energy calculations , 2010 .

[27]  Guang-Fu Yang,et al.  Design, synthesis, and bioevaluation of benzamides: novel acetylcholinesterase inhibitors with multi-functions on butylcholinesterase, Aβ aggregation, and β-secretase. , 2012, Bioorganic & medicinal chemistry.

[28]  F. J. Luque,et al.  Novel donepezil-based inhibitors of acetyl- and butyrylcholinesterase and acetylcholinesterase-induced beta-amyloid aggregation. , 2008, Journal of medicinal chemistry.

[29]  I. Melnikova.  Therapies for Alzheimer's disease , 2007, Nature Reviews Drug Discovery.

[30]  J. Rubio-Martínez,et al.  Structural analysis of the inhibition of APRIL by TACI and BCMA through molecular dynamics simulations. , 2013, Journal of molecular graphics & modelling.

[31]  Chia-Ning Yang,et al.  Molecular Modeling of p38α Mitogen-Activated Protein Kinase Inhibitors through 3D-QSAR and Molecular Dynamics Simulations , 2013, J. Chem. Inf. Model..

[32]  M. Citron,et al.  Alzheimer's disease: strategies for disease modification , 2010, Nature Reviews Drug Discovery.

[33]  Holger Gohlke,et al.  The Amber biomolecular simulation programs , 2005, J. Comput. Chem..

[34]  X. Chai,et al.  Efficacy of tablet huperzine-A on memory, cognition, and behavior in Alzheimer's disease. , 1995, Zhongguo yao li xue bao = Acta pharmacologica Sinica.

[35]  Keun Woo Lee,et al.  Molecular dynamics simulation study of PTP1B with allosteric inhibitor and its application in receptor based pharmacophore modeling , 2008, J. Comput. Aided Mol. Des..

[36]  P. Kollman,et al.  New-generation amber united-atom force field. , 2006, The journal of physical chemistry. B.

[37]  Hai-Bin Luo,et al.  Binding of curcumin with glyoxalase I: Molecular docking, molecular dynamics simulations, and kinetics analysis. , 2010, Biophysical chemistry.

[38]  G. Campiani,et al.  Novel and potent tacrine-related hetero- and homobivalent ligands for acetylcholinesterase and butyrylcholinesterase. , 2001, Bioorganic & medicinal chemistry letters.

[39]  D. Case,et al.  Exploring protein native states and large‐scale conformational changes with a modified generalized born model , 2004, Proteins.

[40]  N. Ariel,et al.  Structures of recombinant native and E202Q mutant human acetylcholinesterase complexed with the snake-venom toxin fasciculin-II. , 2000, Acta crystallographica. Section D, Biological crystallography.

[41]  K. Davis.  Cholinesterase Inhibitors in Alzheimer's Disease , 1994, Neuropsychopharmacology.

[42]  Jörg Weiser,et al.  Approximate atomic surfaces from linear combinations of pairwise overlaps (LCPO) , 1999, J. Comput. Chem..

[43]  Laura De Luca,et al.  Insight into the Fundamental Interactions between LEDGF Binding Site Inhibitors and Integrase Combining Docking and Molecular Dynamics Simulations , 2012, J. Chem. Inf. Model..

[44]  Xingshu Li,et al.  Synthesis, biological evaluation, and molecular modeling of berberine derivatives as potent acetylcholinesterase inhibitors. , 2010, Bioorganic & medicinal chemistry.

[45]  J. Grassi,et al.  Conformational Flexibility of the Acetylcholinesterase Tetramer Suggested by X-ray Crystallography* , 1999, The Journal of Biological Chemistry.

[46]  F. Leonetti,et al.  Design, synthesis and biological evaluation of coumarin alkylamines as potent and selective dual binding site inhibitors of acetylcholinesterase. , 2013, Bioorganic & medicinal chemistry.

[47]  M. Rudolph,et al.  Structures of human acetylcholinesterase in complex with pharmacologically important ligands. , 2012, Journal of medicinal chemistry.

[48]  J. Raftery,et al.  Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomised double-blind trial , 2004, The Lancet.

[49]  Youyong Li,et al.  Assessing the performance of MM/PBSA and MM/GBSA methods. 3. The impact of force fields and ligand charge models. , 2013, The journal of physical chemistry. B.

[50]  W. L. Jorgensen,et al.  Comparison of simple potential functions for simulating liquid water , 1983 .

[51]  T. Thomsen,et al.  Selective inhibition of human acetylcholinesterase by galanthamine in vitro and in vivo. , 1990, Life sciences.

[52]  F. J. Luque,et al.  Donepezil-tacrine hybrid related derivatives as new dual binding site inhibitors of AChE. , 2005, Bioorganic & medicinal chemistry.

[53]  S. Singh,et al.  Extra precision docking, free energy calculation and molecular dynamics simulation studies of CDK2 inhibitors. , 2013, Journal of theoretical biology.

[54]  M. Sabbagh.  Drug development for Alzheimer's disease: where are we now and where are we headed? , 2009, The American journal of geriatric pharmacotherapy.