In-silico screening and molecular dynamics simulation of quinazolinone derivatives as PARP1 and STAT3 dual inhibitors: a novel DML approaches

Abstract

Modern cancer therapy now routinely employs the blocking of many oncoproteins or pathways. With two or more medicines, multiple inhibitions are often accomplished via DML techniques. In this study, we developed 30 quinazolinone derivatives as PARP1 and STAT3 dual inhibitors using DML methods and these compounds were tested for their dual inhibitory effect on PARP1 and STAT3 using docking, MM-GBSA, and molecular dynamics simulation investigations. The docking studies of ligands against PARP1 and STAT3 were performed using the Glide module, in silico ADMET screening was performed using the quickprob module, binding energy calculation was performed using the Prime MM-GBSA module, MD simulation was performed using the Desmond module, and atomic charges were calculated using the Jaguar module of Schrodinger suite 2019-4. Of the substances studied, the derivative 1f has a considerable gliding score. The in silico ADMET characteristics are within the approved range. PRIME MM-GB/SA was used to compute the binding free energy, and the results are substantial. To investigate the dynamic behavior of the protein-ligand complex, compound 1f was subjected to MD simulation at 100 ns. The tested chemical 1f produced the greatest results in MD simulations and MM-GBSA calculations, indicating that this ligand can inhibit more effectively. Communicated by Ramaswamy H. Sarma