Docking Simulations Exhibit Bortezomib and other Boron-containing Peptidomimetics as Potential Inhibitors of SARS-CoV-2 Main Protease

Abstract

Background:: Treatment of the COVID19 pandemic requires drug development. Boron-containing compounds are attractive chemical agents, some of them act as proteases inhibitors. Objective:: The present study explores the role of boronic moieties in molecules interacting on the binding site of the SARS-CoV-2 main protease. Methods:: Conventional docking procedure was applied by assaying boron-free and boron-containing compounds on the recently reported crystal structure of SARS-CoV-2 main protease (PDB code: 6LU7). The set of 150 ligands includes bortezomib and inhibitors of coronavirus proteases. Results:: Most of the tested compounds share contact with key residues and poses on the cleavage pocket. Those compounds with a boron atom in its structure were often estimated with higher affinity than boron-free analogues. Conclusion:: Interactions and the affinity of boron-containing peptidomimetics strongly suggest boron-moieties increases affinity on the main protease, as it should be tested by in vitro assays. A Bis-boron-containing compound previously tested as active on SARS-virus protease and bortezomib were identified as potent ligands. These advances may be relevant for drug designing, in addition as to the suggestion of testing available boron-containing drugs in patients with COVID19 infection.

Exploring Covalent Docking Mechanisms of Boron-Based Inhibitors to Class A, C and D β-Lactamases Using Time-dependent Hybrid QM/MM Simulations

“…One should also mention recent work on the evaluation of Bortezomib and other boron-containing compounds, as inhibitors of SARS-CoV-2 main protease, e.g. Vega-Valdez et al, 2020 ). A very comprehensive overview of the mechanisms of β-lactamase inhibition by boron-based inhibitors, including cyclic boronates, and their applications in biomedicine is reported ( Brem et al, 2016 ; Cahill et al, 2017 ; Cahill et al, 2019 ; Tooke et al, 2019 ; Tooke et al, 2020 ; Song et al, 2021 ).…”

In Silico Drug Repositioning to Target the SARS-CoV-2 Main Protease as Covalent Inhibitors Employing a Combined Structure-Based Virtual Screening Strategy of Pharmacophore Models and Covalent Docking

“…For example, Vaborbactam and Ixazomib have a boron atom capable of forming the covalent interaction, and Cimetidine and Bicalutamide are sensitive to nucleophilic attack on the carbonitrile substituent, while Scopolamine undergoes epoxide opening, and Riociguat has its electrophilic warhead in a group hydrolyzable carbamate. It is important to note that, according to the scope of our search, the beta-lactamase inhibitor Vaborbactam has not been proposed as an inhibitor against SARS-CoV-2 M pro , whereas Ixazomib has been proposed as a non-covalent inhibitor in computational approaches [ 50 ] and an analysis of the transcriptional response of the host to SARS-CoV-2 infection and the drug-sensitive gene relationship, highlighting the potential use of Ixazomib and Carfilzomib for its proteasome inhibitory activity (Oprozomib was also identified in this study) [ 51 ].…”

Molecular Docking Studies of Boron‐Containing Compounds as Dual Inhibitors of SARS‐Cov‐2 Spike Receptor Binding Domain/ACE2 Complex and Main Protease and ADMET Investigations

“…Bortezomib and other boron-containing peptidomimetics, [33,34,35,36] boron nitride (BN) oxide nanosheets, [31] new generation of boron-doped or boron attached composite quantum dots (QDs), [30] combination of 2aminoethyl diphenyl borate with curcumin, [32] dioxaborole compounds, [29] boron-containing nanocages, [37] boron citrate and oleoylethanolamide, [38] biosensors (boron-doped), [39,40,41,42] boron nitride nanosheets (BNNS), [43] 10-vertex boron cage [44] and cobalt (III)-containing BÀ N cluster complexes. [45] The druggability properties of chemical compounds substantially depends on their ADMET properties where ADMET refers to adsorption, distribution, metabolism, extraction and toxicity of molecules.…”