Abstract
An abnormal ubiquitin-proteasome is found in many human diseases, especially in cancer, and has received extensive attention as a promising therapeutic target in recent years. In this work, several in silico models have been built with two classes of proteasome inhibitors (PIs) by using 3D-QSAR, homology modeling, molecular docking and molecular dynamics (MD) simulations. The study resulted in two types of satisfactory 3D-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. For EPK inhibitors, the N-cap part should have higher electropositivity; a large substituent such as a benzene ring is favored at the C6-position. In terms of TBA inhibitors, hydrophobic substituents with a larger size anisole group are preferential at the C8-position; higher electropositive substituents like a naphthalene group at the C3-position can enhance the activity of the drug by providing hydrogen bond interaction with the protein target. Molecular docking disclosed that residues Thr60, Thr80, Gly106 and Ser189 play 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. These results can offer useful theoretical references for designing more potent PIs.
Highlights
Ubiquitin-proteasome system (UPS), as a major factor in regulated intracellular proteolysis in eukaryotic cells, is essential to maintain intracellular protein homeostasis and control important signaling pathways [1,2]
The CoMFA models are constructed from steric and electrostatic descriptor fields, and the CoMSIA models are built by varying the steric, electrostatic, hydrophobic, and hydrogen-bond donor and acceptor descriptor fields
For epoxyketone inhibitors (EPK), the study of its optimal model reveals that both steric and electrostatic fields and molecular descriptors EEig04r, Mor24e are critical to its inhibitory activities, and tyropeptin-boronic acid derivatives (TBA)
Summary
Ubiquitin-proteasome system (UPS), as a major factor in regulated intracellular proteolysis in eukaryotic cells, is essential to maintain intracellular protein homeostasis and control important signaling pathways [1,2]. X-ray crystallography studies [6,7,8,9] have demonstrated that 19S RP is built of a ring shaped base and a lid-structure, that regulates the entrance of substrate to the attached 20S proteasome [10], the 20S CP is a conserved hollow cylinder-shaped structure which is composed of four homologous rings, arranged in the sequence α7β7β7α7. Each β ring contains three distinct catalytic activities with three different subunits, namely chymotrypsin-like (β5), trypsin-like (β2) and the post-glutamyl peptide hydrolyzing, or caspase-like (β1) [11,12,13]. The importance of individual subunit activities for proteasomal function is as follows: β5 >> β2 ≥ β1 [16]
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