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Conrad Pitts1·3, Donnell Bowen2'3 and William M. Southerland1'3* 'Department of Biochemistry and Molecular Biology, 2Department of Pharmacology and 3The Howard University Drug Discovery Unit, Howard University College of Medicine, Washington, D.C. 20059, USA SUMMARY The three-dimensional structure of the human dihydrofolate reductase (DHFR), methotrexate tetrazole, and NADPH ternary complex was used to model the corresponding ternary complexes with methotrexate tetrazole replaced by methotrexate, methotrexatepolyglutamate with three glutamyl residues, and 5,10-deazaaminopterin, respectively. Each complex was solvated in a 60-angstrom cube of explicit water and subjected to structural minimization followed by interaction energy analyses. Interaction energy calculations were performed for the antifolate interaction with water, NADPH, the DHFR binding site residues, the entire DHFR protein, and the solvated NADPH:DHFR complex. These studies revealed that methotrexate-polyglutamate exhibited the most stable and that approximately one half of antifolate:DHFR stability could be accounted for by the interaction of the antifolate with the binding site residues. The antifolate structures were also subdivided into hetero* Author for correspondence: Dr. William M. Sc itherland Department of Bio :hemistry and Molecular Biology Howard University College of Medicine 520 "W" Street N W Washington, D.C. 20059, USA e-mail: wsoutherland@howard.edu ©Freund Publishing House Ltd., 2 0 0 0 Vol.
Drug Metabolism and Drug Interactions – de Gruyter
Published: Mar 1, 2000
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