Pharmacophore modeling, atom-based 3D-QSAR and molecular docking studies on N -benzylpyrimidin-4-amine derivatives as VCP/p97 inhibitors

In this study, the atom-based three-dimensional quantitative structure –activity relationship (3D-QSAR) and docking models were developed using PHASE and GLIDE modules of Schrödinger software, respectively. The theoretical models were generated from 38N-benzylpyrimidin-4-amine inhibitors of p97. An AADRRR model consisting of two hydrogen bond acceptors (A), one hydrogen bond donor (D), and three aromatic rings (R) was obtained. Thirty eight derivatives were divided into a training set with 27 molecules to generate 3D-QSAR models and a test set with 11 molecules to validate 3D-QSAR model. A robust QSAR model with good prediction in internal and external verification was constructed, whereR2,Q2, and Pearson-R were 0.924, 0.701, and 0.8783, respectively. QSAR model showed the hydrogen bond donor, electron-withdrawing group, and hydrophobic characteristics affecting the p97 activity. Molecular docking studies indicated that the H-bond and hydrophobic interactions existed between the inhibitors and p97, which was consistent with the results of 3D-QSAR. These results provided some useful information for designing new and effective p97 inhibitors.
Source: Medicinal Chemistry Research - Category: Chemistry Source Type: research