XVIth International Workshop on
Quantum Systems in
Chemistry and Physics
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Enzyme-inhibitor interaction : Key Structural and Energetic Properties for Inhibitor Design
Supa Hannongbua
Department of Chemistry, Faculty of Science, and Center of Nanotechnology, Kasetsart University, Bangkok 10903, Thailand.
Quantum chemical calculations and ONIOM methods have been used to investigate enzyme-inhibitor interaction. The pairwise analyses between efavirenz and individual residue in the binding pocket of both WT and K103N HIV-1 RT were calculated and the ONIOM2 methods was used to evaluate the binding energies. The results show that the K103N RT is more repulsive interactions between efavirenz and residues surrounding the binding pocket than of the WT structure. The results from pairwise energies perfectly demonstrate that the K103N RT slightly affect on the loss of interaction energy. The main influences are due to residues around the binding pocket (Lys101, Lys102, Ser105, Val179, Trp229, Pro236 and Glu138). Baesd on ONIOM2 calculations, these evidently show that the K103N decreases the stabilization energy of efavirenz bound to its binding pocket. Furthermore, the analyses of the energy components in terms of interaction energy and deformation energy also shows a significant structural rearrangement upon efavirenz binding, and more energy is needed for conformational adaptation in the binding pocket. The potent inhibitor accommodates the K103N RT by the formation of an additional interaction to the asparagine side chain and minor rearrangement of the inhibitor position in the binding pocket. It is worth to note that the K101 and S105 residues are important as strong interaction for further novel inhibitor development. Taken into account, the K101 residue shows the key main interaction of the binding due to the presence of hydrogen bonding between efavirenz and the backbone of K101. Advantages and disadvantages of the studies, applied on different enzyme targets will be also given.

1. Srivab, P. and Hannongbua, S.*, A study of the binding energies of efavirenz to wild-type and K103N/Y181C HIV-1 reverse transcriptase based on the ONIOM method, Chem. Med. Chem., 3(5), 803-811 ( 2008)
2. Maitarad, P., Kamchonwongpaisan, S., Vanichtanankul, J., Vilaivan, T., Yuthavong, Y., Hannongbua, S.*, Interactions between Cycloguanil Derivatives and Wild-Type and Resistance-Associated Mutant P. falciparum Dihydrofolate Reductases, J.Comput-Aided Drug Des., 23(4), 241-252 ( 2009)
3. Sae-Tang, D., Kittakoop, P., and Hannongbua, S., Role of Key Residue Specific to Cyclooxygenase II : An ONIOM Study, Monatsh. Chemie, 140, 1533-1541 ( 2009).
4. Vailikhit, V, Holzschuh, W.J. and Hannongbua, S., 1H-NMR chemical shifts of some DMSO-solvated amines using MDONIOM2, J. Mol.Struct. ( THEOCHEM), 944, 173-176 ( 2010).
5. Kittisripanya, N., Wolschann, P., and Hannongbua, S., Binding of Huperzine A and Galanthamine to Acetylcholinesterase, Based on ONIOM Method, Nanomedicine: Nanotechnology, Biology, and Medicine 7, 60–68 ( 2011).
6. Saparpakorn, P., Wolschann, P., Karpfen, A., Pungpo, P., Hannongbua, S., Systematic investigation on the methodology in the binding of GW420867X as NNRTI by using quantum chemical calculations, Monatsch Chemie, ( 2011) in press.
7. Treesuwan, W., H., Hajime, Morokuma, K., and Hannongbua, S.*, Characteristic vibration patterns and protein binding of odor compounds from bread baking volatiles: Density functional, ONIOM study and principle component analysis (PCA), J. Theor.Biol., ( 2011), accepted.
8. Boonsri, P., Kuno, M. and Hannongbua, S.* Key interactions of the mutant HIV-1 Reverse Transcriptase/Efavirenz: An evidence obtained from ONIOM method” to you. The response to reviewers has been done according to the reviewers ( 2011) submitted.

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