In silico identification of 20S proteasome-β5 subunit inhibitors using structure-based virtual screening

Proteasome inhibitors have effective anti-tumor activity in cell culture and can induce apoptosis by interfering with the degradation of cell cycle proteins. 20S Proteasome is acknowledged to be a satisfactory target that has persistent properties against the human immune defense and is obligatory for the degradation of some vital proteins. This study aimed to identify potential inhibitors against 20S proteasome, specifically the β5 subunit, using structure-based virtual screening and molecular docking to reduce the number of ligands that should be eligible for experimental assays. A total of 4961 molecules with anticancer activity were screened from the ASINEX database. The filtered compounds that showed higher docking affinity were then used in more sophisticated molecular docking simulations with AutoDock Vina for validation. Finally, six drug molecules (BDE 28974746, BDE 25657353, BDE 29746159, BDD 27844484, BDE 29746109, and BDE 29746162) exhibited highly significant interactions compared to the positive controls were retained. Among these six molecules, three molecules (BDE 28974746, BDE 25657353, and BDD 27844484) showed high binding affinity and binding energy compared with Carfilzomib and Bortezomib. Molecular simulation and dynamics studies of the top three drug molecules in each case allowed us to draw further conclusions about their stability with the β5 subunit. Computed absorption, distribution, metabolism, excretion and toxicity studies on these derivatives showed encouraging results with very low toxicity, distribution, and absorption. These compounds may serve as potential hits for further biological evaluation in the development of new proteasome inhibitors.Communicated by Ramaswamy H. Sarma