3D-QSAR, molecular docking, and molecular dynamics analysis of dihydrodiazaindolone derivatives as PARP-1 inhibitors.

Context: PARP-1 plays an important role in DNA repair and apoptosis, and PARP-1 inhibitors have shown to be effective in the treatment of several malignancies. To evaluate the function of new PARP-1 inhibitors as anticancer adjuvant medicines, 3D-QSAR, molecular docking, and molecular dynamics (MD) simulations of a sequence of dihydrodiazepinoindolone derivatives PARP-1 inhibitors were undertaken in this study.

Methods: In this paper, 43 PARP-1 inhibitors were studied in a three-dimensional quantitative structure-activity relationship (3D-QSAR) using comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA). CoMFA with q2 of 0.675 and r2 of 0.981 was achieved, as was CoMSIA with q2 of 0.755 and r2 of 0.992. The changed areas of these compounds are shown by steric, electrostatic, hydrophobic, and hydrogen-bonded acceptor field contour maps. Subsequently, molecular docking, and molecular dynamics simulations further confirmed that key residues Gly863 and Ser904 of PARP-1 are vital residues for protein interactions and their binding affinity. The effects of 3D-QSAR, molecular docking and molecular dynamics simulations supply a new route for the search of new PARP-1 inhibitors. Finally, we designed eight new compounds with exact activity and ADME/T properties.