Dihydrofolate Reductase-저해제 복합체에 대한 X-선 결정체 구조와 docking model의 구조 비교 = Comparison of X-ray Crystallographic Structures and Docking Models of Dihydrofolate Reductase-Inhibitor Complexes

다국어 초록 (Multilingual Abstract)

A comparative study to validate the reliability of a fully automated docking program, FlexiDock, was carriedout to predict the binding modes of DHFR-inhibitor complex. The inhibitors were extracted from the crystallographicallydetermined DHFR-NADP^+(H)-inhibitor ternary complexes of human, Escherichia coli and Candida albicans and thendocked back into the remaining DHPR-NADP^+(H) binary complexes using FlexiDock. The resulting conformations and ori-entations were compared to the original crystal complex structures for reproducibility. Then, folate, the substrate, andknown inhibitors such as methotrexate, piritrexim and trimethoprim were docked into the wild-type human DHFR and theirbinding modes were compared with X-ray crystallographic or other modeling data. The root mean square deviations(RMSDs) for ligands ranged from 1.14 to 1.57A˙, and the protein backbone RMSDs from 0.94 to 1.26A. FlexiDock repro-duced the orientations and binding modes of all seven ligands in good agreement with the crystaㅣ structures. It proved tobe a reliable and efficient program in studying binding modes of DHFR-inhibitor complexes of different species, and theinformation obtained from this work may provide additional insight into the design of new agents with improved activity.