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.

Garcia & Koelling (1966) showed that if rats are poisoned after ingesting a flavored solution in the presence of audiovisual cues, they will subsequently avoid only the taste stimulus, whereas if they are shocked, they learn to avoid only the audiovisual cues. The present experiments replicated these findings with one major change in experimental conditions: both taste and nongustatory CSs were presented in the absence of approach and ingestive behaviors to minimize involvement of ingestion in the associative process. (The taste CS was presented by flushing the oral cavity with a saccharin solution under conditions in which the rat would not drink.) Despite these changes, Garcia and Koelling’s results were confirmed.