Combined In Silico Approaches for Virtual Screening of Noncovalent Immunoproteasome Inhibitors for Multiple Myeloma Treatment.

Selective inhibition of the immunoproteasome offers a therapeutic avenue for diseases where dysregulated proteasomal activity plays a role such as multiple myeloma. The development of noncovalent inhibitors avoids the off-target toxicity issues often associated with covalent inhibitors. This study provides a comprehensive investigation into the binding mechanisms and inhibitory activities of noncovalent inhibitors for the β1i and β5i subunits of the immunoproteasome. The computational methods (MD simulations, Binding Pose Metadynamics, Induced fit docking, pharmacophore modeling, and virtual screening) and experimental assays have provided valuable insights into inhibitor binding, which could be further exploited to optimize inhibitor potency and selectivity.