3D-QSAR, Molecular Docking and ONIOM Studies on the Structure-Activity Relationships and Action Mechanism of Nitrogen-Containing Bisphosphonates

Abstract

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 development of novel potent inhibitors. Here, a series of N-BPs inhibitors of human FPPS (hFPPS) were investigated by 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.

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A 3D-QSAR model was constructed for 53 N-BPs with the inhibition activities on hFPPS.

A series of novel N-BPs inhibitors were designed and six novel N-BPs inhibitors with better biological activities and higher lipophilicity were screened out.

Molecular docking and ONIOM (B3LYP/6-31+G*:PM6:Amber) calculations showed that the inhibitors bound to the active site of hFPPS via hydrogen bonding interactions, hydrophobic interactions and cation-π interactions.

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