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.

Automated summary

This study identifies risedronate and zoledronate as potential therapeutic molecules for targeting the PSM beta 5 gene in multiple myeloma. Molecular docking and simulation analysis demonstrate their high binding affinities and stable interactions with PSM beta 5. Furthermore, zoledronate shows enhanced anti-proliferative activity when combined with bortezomib in MM cell lines.