Molecular Docking of Cathepsin L Inhibitors in the Binding Site of Papain

Abstract

The papain/CLIK-148 coordinate system was employed as a model to study the interactions of a non-peptide thiocarbazate inhibitor of cathepsin L (1). This small molecule inhibitor, a thiol ester containing a diacyl hydrazine functionality and one stereogenic center, was most active as the Senantiomer, with an IC 50 of 56 nM; the R-enantiomer (2) displayed only weak activity (33 μM). Correspondingly, molecular docking studies with Extra Precision Glide revealed a correlation between score and biological activity for the two thiocarbazate enantiomers when a structural water was preserved. The molecular interactions between 1 and papain were very similar to the interactions observed for CLIK-148 (3a and 3b) with papain, especially with regard to the hydrogen bonding and lipophilic interactions of the ligands with conserved residues in the catalytic binding site. Subsequent docking of virtual compounds in the binding site led to the identification of a more potent inhibitor (5), with an IC 50 of 7.0 nM. These docking studies revealed that favorable energy scores and correspondingly favorable biological activities could be realized when the virtual compound design included occupation of the S2, S3 and S1′ subsites by hydrophobic and aromatic functionalities of the ligand, and at least three hydrogen bonding contacts between the ligand and the conserved binding site residues of the protein.

SARS-CoV-2 Entry Inhibitors: Small Molecules and Peptides Targeting Virus or Host Cells

“…It is noteworthy that the oxocarbazate inhibitors are likely to act as covalent reversible inhibitors, because there is clear time-dependent inhibition and replacement of this moiety resulting in loss of activity; the mechanism of inhibition involves a tetrahedral intermediate by attack of the catalytic Cys25 on the oxocarbazate carbonyl [111]. The small-molecule oxocarbazate binding mode has been investigated by molecular modelling studies, suggesting that the tetrahydroquinoline fills the S1' subsite, the tert-butoxycarbonyl group establishing hydrophobic interactions on the S3 subsite, while the indole group in S configuration binds to the S2 subsite, likely directing the specificity of the substrate [112]. Interestingly, derivative CID 23631927 was able to potently inhibit SARS-CoV entry in cellular (human embryonic kidney 293T) pseudotype model of infection (EC 50 = 0.27 µM) and no toxicity up to 100 µM was observed in another cell type (human aortic endothelial cells).…”

Multi-conformation 3D QSAR study of benzenesulfonyl-pyrazol-ester compounds and their analogs as cathepsin B inhibitors

“…The inhibitor forms a covalent sulfur bond with protein amino acid Cys30. [22,23] In addition to experimental studies, computational methods have been used to study the binding structures of active inhibitors with the protein with the purpose to characterize interaction features and to interpret inhibition mechanism of small molecules for several members of the cathepsin class [25][26][27] including cathepsin L [28,29] and cathepsin S. [29] The authors also performed a computational study to establish the interaction and activity mode between these inhibitors and cathepsin B. [30,31].…”

QSAR models for predicting cathepsin B inhibition by small molecules—Continuous and binary QSAR models to classify cathepsin B inhibition activities of small molecules

“…Meanwhile, computational studies, such as docking and virtual screening, were also used to explore the binding and inhibition mechanism of these inhibitors [24][25][26]. These computational approaches have proved efficient and essential for optimizing and designing chemical agents with improved biological activities [27][28][29].…”