Comparison of X-ray Crystallographic Structures and Docking Models of Dihydrofolate Reductase-Inhibitor Complexes

Dihydrofolate Reductase-저해제 복합체에 대한 X-선 결정체 구조와 docking model의 구조 비교

  • 안미현 (이화여자대학교 약학대학) ;
  • 최인희 (이화여자대학교 약학대학) ;
  • 김춘미 (이화여자대학교 약학대학)
  • Published : 2002.12.01

Abstract

A comparative study to validate the reliability of a fully automated docking program, FlexiDock, was carried out to predict the binding modes of DHFR-inhibitor complex. The inhibitors were extracted from the crystallographically determined DHFR-NADP$^{+}$(H)-inhibitor ternary complexes of human, Escherichia coli and Candida albicans and then docked back into the remaining DHFR-NADP$^{+}$(H) binary complexes using FlexiDock. The resulting conformations and orientations were compared to the original crystal complex structures for reproducibility. Then, folate, the substrate, and known inhibitors such as methotrexate, piritrexim and trimethoprim were docked into the wild-type human DHFR and their binding modes were compared with X-ray crystallographic or other modeling data. The root mean square deviations (RMSDs) for ligands ranged from 1.14 to 1.57$\AA$, and the protein backbone RMSDs from 0.94 to 1.26$\AA$. FlexiDock reproduced the orientations and binding modes of all seven ligands in good agreement with the crystal structures. It proved to be a reliable and efficient program in studying binding modes of DHFR-inhibitor complexes of different species, and the information obtained from this work may provide additional insight into the design of new agents with improved activity.ity.

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