Cysteine focused covalent inhibitors against the main protease of SARS-CoV-2

Abstract

In viral replication and transcription, the main protease (Mpro) of SARS-CoV-2 plays an important role and appears to be a vital target for drug design. In Mpro, there is a Cys-His catalytic dyad, and ligands that interact with the Cys145 assumed to be an effective approach to inhibit the Mpro. In this study, approximately 1400 cysteine-focused ligands were screened to identify the best candidates that can act as potent inhibitors against Mpro. Our results show that the selected ligands strongly interact with the key Cys145 and His41 residues. Covalent docking was performed for the selected candidates containing the acrylonitrile group, which can form a covalent bond with Cys145. All atoms molecular dynamics (MD) simulation was performed on the selected four inhibitors including L1, L2, L3 and L4 to validate the docking interactions. Our results were also compared with a control ligand, a-ketoamide (11r). Principal component analysis on structural and energy data obtained from the MD trajectories shows that L1, L3, L4 and a-ketoamide (11r) have structural similarity with the apo-form of the Mpro. Quantitative structure-activity relationship method was employed for pattern recognition of the best ligands, which discloses that ligands containing acrylonitrile and amide warheads can show better performance. ADMET analysis displays that our selected candidates appear to be safer inhibitors. Our combined studies suggest that the best cysteine focused ligands can help to design an effective lead drug for COVID-19 treatment.

Identification of a dual acting SARS-CoV-2 proteases inhibitor through in silico design and step-by-step biological characterization

“…The first comprises peptidomimetics designed to covalently interact with Cys145 in the catalytic site that share four features: a) moderate size; b) a group mimicking a glutamine side chain; c) a branched lipophilic group; d) a reactive electrophilic ‘warhead’, such as aldehydes, Michael acceptors, and epoxy ketones responsible for the covalent bond [ 25 , 26 ]. However, the possibility of non-specific biological interactions due to their huge reactivity, must be considered for the subsequent in vivo evaluation of this type of inhibitors [ 27 , 28 ]. Accordingly, the less reactive non-covalent inhibitors may represent safer antiviral agents.…”

Docking-based virtual screening studies aiming at the covalent inhibition of SARS-CoV-2 MPro by targeting the cysteine 145

“…(Pillaiyar, et al, 2020) While classical docking studies are widely reported in the literature,( Kitchen et al, 2004 ) docking studies for covalent protein inhibition are less common,( Kumalo et al, 2015 ; Sotriffer, 2018 ) in particular with SARS-CoV-2 main protease. ( Liu et al, 2020 ; Paul et al, 2020 ) Despite covalent inhibition approaches are less studied because the requirement of a nucleophilic residue is a structural limitation and they can be considered as harmful, the resurgence of covalent drugs encourage to also consider covalent inhibition. ( Dalton and Campos, 2020 ; Ghosh et al, 2019 ; Singh et al, 2011 ) Irreversible specific protein inhibitors are now reported, such as in the case of the Ras protein possessing a G12C mutation, a promising example of potential anticancer strategy.…”

Drug targets, mechanisms of drug action, and therapeutics against SARS-CoV-2

“…However, in vivo studies of these ligands can only yield their true efficacy against M pro . Similarly, several covalent inhibitors, such as ketone-based covalent inhibitors [69] , cysteine focussed covalent inhibitors [70] , etc. were proposed for the inhibition of M pro .…”