Identification and in-vitro analysis of potential proteasome inhibitors targeting PSMβ5 for multiple myeloma

The proteasome subunit beta 5 (PSM beta 5) is a chief target of proteasome inhibitors (PIs) for treatment of multiple myeloma (MM). The relevance of PSM beta 5 mutations and their functional impact on the development of resistance to PIs have been demonstrated recently. Therefore, this present study deals with an in-depth E-pharmacophore based screening and repurposing of FDA-approved drugs that could target PSM beta 5 for MM. Our molecular docking-based investigation revealed risedronate and zoledronate as potential alternative therapeutic molecules for targeting the PSM beta 5 gene. Risedronate and zoledronate displayed high binding affinity (-9.51 and-8.56 kcal/mol respectively) to PSM beta 5. Moreover, 100 ns molecular dynamics simulation analysis of docking com-plexes revealed risedronate and zoledronate with a superior binding free energies and stable interactions with PSM beta 5. The RMSD plot shows that the risedronate-PSM beta 5 (mean: 0.24 nm) and zoledronate-PSM beta 5 (mean: 0.25 nm) complexes are identical and stays stable until 100 ns. We further validated the activity of zoledronate in MM cell lines RPMI8226 and U266 where zoledronate showed significant anti-proliferative and apoptotic activity. Importantly, zoledronate showed an enhanced anti-proliferative activity when combined with bortezomib in MM cell lines. Thus, this study demonstrates that combining bortezomib with zoledronate could have a significant impact on reducing MM cell growth and can be an alternative strategy for treating MM.