3D-QSAR, molecular docking, and ONIOM studies on the structure-activity relationships and action mechanism of nitrogen-containing bisphosphonates

作者：Liu, Qing-Zhu; Wang, Shan-Shan; Li, Xi; Zhao, Xue-Yu; Li, Ke; Lv, Gao-Chao; Qiu, Ling^*; Lin, Jian-Guo^*

来源：Chemical Biology & Drug Design, 2018, 91(3): 735-746.

DOI：10.1111/cbdd.13134

• farnesyl pyrophosphate synthase
• molecular docking
• nitrogen-containing bisphosphonates
• ONIOM
• three-dimensional quantitative structure-activity relationship

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- 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.

• 出版日期2018-3
• 单位江南大学; 江苏省原子医学研究所