3D-QSAR, molecular docking and molecular dynamics simulations study of 3-pyrimidin-4-yl-oxazolidin-2-one derivatives to explore the structure requirements of mutant IDH1 inhibitors

Gain-of-function mutation in isocitrate dehydrogenase 1 (IDH1) is closely related to certain human cancers and is emerging as an attractive antitumor target. However, developing safe and effective inhibitors of mutant IDH1 (mIDH1) are facing many challenges. In this study, an integrated computational approach was applied to a series of 3-pyrimidin-4-yl-oxazolidin-2-one derivatives to explore the critical factors contributing to their inhibitory activity against mIDH1. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques were used to generate 3D-QSAR models. Good predictability was obtained for our best CoMFA model (q2 = 0.584; r2 = 0.952; r2pred = 0.915) and CoMSIA model (q2 = 0.759; r2 = 0.927; r2pred = 0.793). 3D contour maps generated from CoMFA and CoMSIA illustrated that the hydrophobic and H-bond donor/acceptor fields played key roles for the inhibitory activity. Molecular docking and molecular dynamics (MD) simulation were carried out to further understand the binding modes and the interactions between the protein and these inhibitors. The docking scores and the binding free energies calculated for these inhibitors agreed well with the experimental bioactivity and demonstrated that hydrophobic interaction was the main driving force for their binds. Based on these results, seven new potent molecules with better predicted activity than the drug candidates in the literature have been designed.