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Particular interaction between pyrimethamine derivatives and quadruple mutant type dihydrofolate reductase of Plasmodium falciparum: CoMFA and quantum chemical calculations studies

Maitarad, Phornphimon and Saparpakorn, Patchreenart and Hannongbua, Supa and Kamchonwongpaisan, Sumalee and Tarnchompoo, Bongkoch and Yuthavong, Yongyuth (2008) Particular interaction between pyrimethamine derivatives and quadruple mutant type dihydrofolate reductase of Plasmodium falciparum: CoMFA and quantum chemical calculations studies. Journal of Enzyme Inhibition and Medicinal Chemistry . ISSN 1475-6366

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Abstract

Comparative molecular field analysis (CoMFA) was performed on twenty-three pyrimethamine (pyr) derivatives active against quadruple mutant type (Asn51Ile, Cys59Arg, Ser108Asn, Ile164Leu) dihydrofolate reductase of Plasmodium falcipaarum (PfDHFR). The represented CoMFA models were evaluated based on the various three different probe atoms, Csp3 (+1), Osp3 ( − 1) and H (+1), resulting in the best model with combined three types of probe atoms. The statistical results were = 0.702, Spress = 0.608, = 0.980, s = 0.156, and = 0.698 which can explain steric contribution of about 50%. In addition, an understanding of particular interaction energy between inhibitor and surrounding residues in the binding pocket was performed by using MP2/6-31G(d,p) quantum chemical calculations. The obtained results clearly demonstrate that Asn108 is the cause of pyr resistance with the highest repulsive interaction energy. Therefore, CoMFA and particular interaction energy analyses can be useful for identifying the structural features of potent pyr derivatives active against quadruple mutant type PfDHFR.Graphical Abstract CoMFA steric contour maps of Cyc derivatives against the quadruple mutant PfDHFR.

Item Type:Article
Subjects:Biomedical Science > Nanobiotechnology
ID Code:8749
Deposited By:CSMNT
Deposited On:27 Mar 2010 08:58
Last Modified:30 Mar 2010 13:08

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