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Molecular calculations on ligand-protein and protein-protein interactions by quantum chemical methods

Peter Wolschann, Institute of Theoretical Chemistry, University of Vienna, Währinger
Straße 17, 1090 Wien, Tel.: +43 (1) 4277 52772, Fax: +43 (1) 4277 9527, Project Progress Report: Quantum chemical calculations on the interaction of ligands with
proteins have been performed on several systems, in order to gain knowledge about the applicability of various methods on particular problems. Quantum chemical calculations based on ab initio and density functional theory (DFT) methods have been applied to analyze detailed local interactions in proteins or between protein and ligands. To describe these interactions, like hydrogen bonding or stacking of aromatic rings, or hydrophobic Van der Waals interactions accurately, more precise quantum chemical methods have to be applied. Various methods were tested for ligand protein (peptide) interactions: In one of these this studies, the subtle interaction between individual residues from the HIV-1 reverse transcriptase (RT) allosteric binding site and an inhibitor, S- 3-ethyl-7-fluoro-4-isopropoxy-carbonyl-3,4-dihydro-quinoxalin-2(1H)-one, was investigated by using high-level quantum chemical calculations (MP2, M06-2X and B3LYP) with the following basis sets: 6-31G(d), 6-31G(d,p), 6-311G(d), and 6-311G(d,p). The results obtained indicate that the interaction between the inhibitor and Lys101 is the most important for the binding. The interactions between ligands and the surrounding binding site depend on different contributions of individual amino acids. The determination of these particular interaction energies is sensitive to the model used, i.e. which part of the amino acids has been taken into account and which terminating procedure has been applied. The results show that even systems where the amide bond is cut and capped with hydrogen atoms can be used as reliable models for estimating the individual interaction energies. Furthermore, the interaction energies of GW420867X in wild-type and Lys101Glu mutant are also investigated in order to explain the loss of GW420867X’s activity in Lys101Glu mutant. The results have been In a study on the interaction of the enzyme enoyl-ACP reductase from Mycobacterium Tuberculosis with isoniazid derivatives the interaction energies in the binding pocket were calculated using quantum chemical calculations (MP2/6-31G(d)). Structure optimization and calculations of partial charges of series of ligands have been carried out for various systems of biological and medicinal relevance: Arylamides as novel inhibitors of the enoyl-ACP reductase from Mycobacterium tuberculosis, tryptamine derivatives at NMAD, 5HT1A and 5HT2A receptors, Huperzine A and Galanthamine binding to Acetylcholinesterase, and screening by a series of natural products to the Epidermal Growth Factor Receptor in a Tyrosine Kinase Domain. About all these investigations papers have been already published, or have been submitted, or are in preparation. Extensive preliminary calculations were performed on inhibitors for voltage-gated ion channels, in particular Ca2+ and K+ ion channels. These data are used for docking and MD studies on the open and the closed forms of these channels. For the quantum chemical calculations the program package GAUSSIAN09 was used throughout. In this software package several ab initio methods (HF, MP2) and density functionals (BLYP, B3LYP, M06-2X) with a large number of different basis sets are included. Also the ONIOM method is implemented in this program package. The Docking procedures as well as the Molecular Dynamics simulations were carried out on local clusters using AMBER and GROMACS. Up to now both Molecular Dynamics programs are not available at the VSC. Moreover, GAUSSVIEW as support program for the installation GAUSSIAN09 would be necessary. Publications A. Punkvang, P. Sarparpakorn, S. Hannongbua, P. Wolschann, P. Pungpo Elucidating Drug-Enzyme Interactions and Their Structural Basis for Improving the Affinity and Potency of Isoniazid and Its Derivatives Based on Computer Modeling Approaches Molecules 15, 2791-2813 (2010) A. Punkvang, P. Saparpakorn, S. Hannongbua, P. Wolschann, H. Berner, P. Pungpo Insight into Crucial Inhibitor-Enzyme Interaction of Arylamides as Novel Direct Inhibitors of the Enoyl ACP Reductase (InhA) from Mycobacterium Tuberculosis: computer-aided molecular design Mh.Chem. 141, 1029-1041 (2010) A. Punkvang, P. Sarparpakorn, S. Hannongbua, P. Wolschann, P. Pungpo Investigating the Structural Basis of Arylamides to Improve Potency against M. Tuberculosis Strain through Molecular Dynamics Simulations Europ. J. Med. Chem. 45, 5585-5593 (2010) Nareenart. , P. Wolschann, S. Hannongbua Binding of Huperzine A and Galanthamine to Acetylcholinesterase, Based on ONIOM Method Nanomedicine: Nanotechnology, Biology, and Medicine P. Saparpakorn, P. Wolschann, A. Karpfen, P. Pungpo, S. Hannongbua Systematic investigation on the methodology in the binding of GW420867X as NNRTI by using quantum chemical calculations M. L. Berger, R. Palangsuntikul, P. Rebernik, P. Wolschann, H. Berner Screening of 64 tryptamine derivatives at NMDA, 5HT2A and 5HT1A receptors: a comparative binding and modeling study R. Palangsuntikul, H. Berner., M. Berger, P. Rebernik, P. Wolschann Holographic Quantitative Structure-Activity Relationships of Tryptamine Derivatives at NMDA, 5HT1A and 5HT2A Receptors


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