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3D‐QSAR, molecular docking, and ONIOM studies on the structure–activity relationships and action mechanism of nitrogen‐containing bisphosphonates
Author(s) -
Liu QingZhu,
Wang ShanShan,
Li Xi,
Zhao XueYu,
Li Ke,
Lv GaoChao,
Qiu Ling,
Lin JianGuo
Publication year - 2018
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13134
Subject(s) - oniom , quantitative structure–activity relationship , farnesyl pyrophosphate , chemistry , docking (animal) , stereochemistry , lipophilicity , molecular model , active site , mevalonate pathway , hydrogen bond , enzyme , molecule , biochemistry , atp synthase , organic chemistry , biosynthesis , medicine , nursing
Nitrogen‐containing bisphosphonates (N‐BPs) have been used widely to treat various bone diseases by inhibiting the key enzyme farnesyl pyrophosphate synthase (FPPS) in the mevalonate pathway. Understanding the structure–activity relationships and the action mechanisms of these bisphosphonates is instructive for the design and the development of novel potent inhibitors. Here, a series of N‐BPs inhibitors of human FPPS (hFPPS) were investigated using a combination of three‐dimensional quantitative structure–activity relationship (3D‐QSAR), molecular docking, and three‐layer ONIOM studies. The constructed 3D‐QSAR model yielded a good correlation between the predicted and experimental activities. Based on the analysis of comparative molecular field analysis (CoMFA) contour maps, a series of novel N‐BPs inhibitors were designed and ten novel potent N‐BPs inhibitor candidates were screened out. Molecular docking and ONIOM (B3LYP/6‐31 + G*:PM6:Amber) calculations revealed that the inhibitors bound to the active site of hFPPS via hydrogen‐bonding interactions, hydrophobic interactions, and cation‐π interactions. Six novel N‐BPs inhibitors with better biological activities and higher lipophilicity were further screened out from ten candidates based on the calculated interaction energy. This study will facilitate the discovery of novel N‐BPs inhibitors with higher activity and selectivity.