Combined3D-QSAR, Molecular Docking And Molecular Dynamics Study On Derivatives Of Peptide Epoxyketone And Tyropeptin-Boronic Acid As Inhibitors Against The β5Subunit Of Human20S Proteasome

Ubiquitin-proteasome system (UPS) is the major proteolytic enzyme system in eukaryotic cells, which has emerged as a central player in the regulation of several diverse cellular processes, such as cell proliferation, differentiation, signal transduction and apoptosis. The abnormal ubiquitin-proteasome is closely involved in the occurrence and development of cancer. As a promising cancer-targeted therapeutic drug, proteasome inhibitors (PIs) have received extensive attention in recent years.In this work, several in silico models have been built with two classes of PIs by using3D-QSAR, homology modeling, molecular docking and molecular dynamics (MD) simulations. The study has resulted in two types of satisfactory3D-QSAR models, i.e., the CoMFA model (Q2=0.462, R2pred=0.820) for epoxyketone inhibitors (EPK) and the CoMSIA model (Q2=0.622, R2pred=0.821) for tyropeptin-boronic acid derivatives (TBA). From the contour maps, some key structural factors responsible for the activity of these two series of PIs are revealed. As to EPK inhibitors, the N-cap part-should have higher electropositivity; large substituent such as benzene ring is favored at C6-position; molecular descriptors EEig04r and Mor24e are vital for the CoMFA model. In terms of TBA inhibitors, hydrophobic substituents with larger size of anisole group are preferential at C8-position; higher electropositive substituent like naphthalene group at C3-position can enhance the activity of the drug by providing hydrogen bond interaction with the protein target; molecular descriptors RDF050M and AlogP2greatly affect the activities of inhibitors. Molecular docking disclosed that residues Thr60, Thr80, Gly106and Ser189play a pivotal role in maintaining the drug-target interactions, which are consistent with the contour maps. MD simulations further indicated that the binding modes of each conformation derived from docking is stable and in accord with the corresponding structure extracted from MD simulation overall.From our study, the binding modes of β5subunit and EPK as well as β5subunit and TBA are clarified, providing helpful information for understanding the interaction mechanism of receptor and ligands. Meanwhile, these results can guide future structural modifications and offer useful theoretical references for designing more potent PIs.