Synthesis, Bioactivity, Docking and Molecular Dynamics Studies of Furan‐Based Peptides as 20S Proteasome Inhibitors

Abstract

Proteasome inhibitors are promising compounds for a number of therapies, including cardiovascular and eye diseases, diabetes, and cancers. We previously reported a series of furan-based peptidic inhibitors with moderate potencies against the proteasome β5 subunit, hypothesizing that the C-terminal furyl ketone motif could form a covalent bond with the catalytic residue, threonine 1. In this context, we describe further optimizations of the furan-based peptides, and a series of dipeptidic and tripeptidic inhibitors were designed and synthesized, aiming at improved potency and better solubility. Most of the tripeptidic inhibitors demonstrated improved potency and selectivity as β5 subunit inhibitors in both enzymatic and cellular assays, and good antineoplastic activities in various tumor cell lines were also observed. However, no inhibitory effects were observed for the dipeptidic compounds, which led us to presume that a noncovalent binding mode is adopted. Docking studies and molecular dynamics simulations were carried out to verify this presumption, with results showing that the distance between the furyl ketone motif and Thr1 is slightly too long to form covalent bond.

Computational Approaches for the Discovery of Human Proteasome Inhibitors: An Overview

“…Sun et al [160] performed the optimization of furan-based peptides through the design and synthesis of a series of dipeptidic and tripeptidic inhibitors with the aim of improving their potency and solubility. In vitro and in silico studies were also performed.…”

“…AutoDock 4.2 was the software selected to perform docking calculations of the ligands, the default parameters being used, except for those changes mentioned. The energy-scoring grid was prepared as a 40 × 40 × 40 Å box with a spacing of 0.375, centered on the ligand value (11.667, −137.254, 19.568) [160]. To obtain a more integrated and precise view of the binding process, molecular dynamics simulations were carried out with AMBER 11 software by starting from the docking pose of the most potent tripeptide derivative in complex with the CT-L active site of the 20S proteasome [160].…”

“…The energy-scoring grid was prepared as a 40 × 40 × 40 Å box with a spacing of 0.375, centered on the ligand value (11.667, −137.254, 19.568) [160]. To obtain a more integrated and precise view of the binding process, molecular dynamics simulations were carried out with AMBER 11 software by starting from the docking pose of the most potent tripeptide derivative in complex with the CT-L active site of the 20S proteasome [160]. Calculation of RMSDs with respect to the starting structure confirmed the stability of the trajectory.…”

“…Calculation of RMSDs with respect to the starting structure confirmed the stability of the trajectory. A more stable and reasonable binding mode for the most potent tripeptide derivative with the protein was obtained and seven hydrogen bonds with Arg19, Thr21 (2), Ala49, Ser130, Glu132, and Arg137 were established [160]. In conclusion, computational studies suggested a noncovalent binding mode which can be very useful for future structural modifications and synthesis of more potent and selective proteasome inhibitors [160].…”

Argyrin B, a non‐competitive inhibitor of the human immunoproteasome exhibiting preference for β1i

“…Inhibitors of the proteasome act in one or more of the active sites and have shown broad therapeutic applications, particularly for multiple myeloma and mantle cell lymphoma. However, as the proteasome is required for normal cell function, its inhibition becomes associated with severe toxicity (Crawford, Walker, & Irvine, ; Genin, Reboud‐Ravaux, & Vidal, ; Goldberg, ; Kisselev, van der Linden, & Overkleeft, ; Kuhn et al., ; Moore, Eustáquio, & McGlinchey, ; Parlati et al., ; Pellom & Shanker, ; Shah, Biran, & Vesole, ; Shivakumar & Jagganath, ; Sun et al., ; Teicher & Tomaszewski, ; Wu et al., ; Zhang et al., , ). Cells in disease states, where the demand for protein degradation is higher, are capable of producing immunoproteasomes in which the catalytic β1c, β2c and β5c subunits of the constitutive proteasome are replaced by the homologous β1i, β2i and β5i whilst all other subunits remain unchanged (Kniepert & Groettrup, ; Yewdell, ).…”