Computational Screening of Phenylamino-Phenoxy-Quinoline Derivatives against the Main Protease of SARS-CoV-2 Using Molecular Docking and the ONIOM Method

Abstract

In the search for new anti-HIV-1 agents, two forms of phenylamino-phenoxy-quinoline derivatives have been synthesized, namely, 2-phenylamino-4-phenoxy-quinoline and 6-phenylamino-4-phenoxy-quinoline. In this study, the binding interactions of phenylamino-phenoxy-quinoline derivatives and six commercially available drugs (hydroxychloroquine, ritonavir, remdesivir, S-217622, N3, and PF-07321332) with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) were investigated using molecular docking and the ONIOM method. The molecular docking showed the hydrogen bonding and hydrophobic interactions of all the compounds in the pocket of SARS-CoV-2 main protease (Mpro), which plays an important role for the division and proliferation of the virus into the cell. The binding free energy values between the ligands and Mpro ranged from −7.06 to −10.61 kcal/mol. The molecular docking and ONIOM results suggested that 4-(2′,6′-dimethyl-4′-cyanophenoxy)-2-(4″-cyanophenyl)-aminoquinoline and 4-(4′-cyanophenoxy)-2-(4″-cyanophenyl)-aminoquinoline have low binding energy values and appropriate molecular properties; moreover, both compounds could bind to Mpro via hydrogen bonding and Pi-Pi stacking interactions with amino acid residues, namely, HIS41, GLU166, and GLN192. These amino acids are related to the proteolytic cleavage process of the catalytic triad mechanisms. Therefore, this study provides important information for further studies on synthetic quinoline derivatives as antiviral candidates in the treatment of SARS-CoV-2.

Virtual screening of substances used in the treatment of SARS-CoV-2 infection and analysis of compounds with known action on structurally similar proteins from other viruses

“… Target Molecular docking software Binding affinity Kcal/mol Hydrogen bond with Ref 6M71 Autodock Vina -9 ASN781, HIS133, SER709, TYR129 LYS A47, ASP711 [156] 6M71 Autodock Vina − 8 LYS47, TYR129, SER709, ASP711, ASN781 [146] 6M71 Autodock Vina − 7.1 Lys621, Cys622, Asp761, Lys798, Glu811. [157] 7VH8 AutoDock 4.2 -8.56 GLY143 CYS145 LEU167 TYR54 CYS145 GLU166 [158] 6M71 AutoDock Vina -7.8 Gly143, Ser144 (2), Cys145, Glu166, Asn142 [159] 7BV2 AutoDockVina -7.2 ILE23, LEU126, GLY48 [160] 7BTF DOCK 6 -8.8 ALA 550, LYS 55, ARG 55, CYS 813, SER814, GLN 815 [161] Legend: ASN, asparagine; HIS, histidine; SER, serine; TYR, tyrosine; LYS, lysine; ASP, aspartic acid; ALA, alanine; ARG, arginine; CYS, cysteine; GLN, glutamine; GLY, glycine; LEU, leucine; GLU, glutamic acid; ILE, isoleucine. …”

Docking covalent targets for drug discovery: stimulating the computer-aided drug design community of possible pitfalls and erroneous practices

“…Therefore, docking research that considers N3 as a standard for validating their docking protocols prior to a virtual-screening campaign should make use of one of the two approaches to docking covalent systems. Unfortunately, this has not been the case for several retrospective computational studies where noncovalent interactions of N3 with the Mpro target (6LU7) have been reported [ 107 – 116 ].

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2‐Oxoquinoline‐based‐thiosemicarbazones as multitargeting neurotherapeutics against Alzheimer's disease: In vitro and in silico studies of MAO and ChE inhibitors

“…Quinoline, a fused structure of benzene and pyridine at adjacent carbon atoms, is a major pharmacophore system among nitrogencontaining heterocycles that have received renewed attention in the drug discovery field due to its intriguing pharmacological profile and fascinating biological properties. Both naturally occurring and synthetic derivatives of quinoline are critical in achieving important tasks and serving as an active ingredient in various medicines, including anticancer, [1] antimalarial, [2] antitubercular, [3] antiviral, [4] antibacterial, [5] antifungal, [6] anticonvulsant, [7] and anti-inflammatory. [8] Quinoline has been recognized as a promising starting point for developing drugs to combat Alzheimer's disease (AD) with several hybrid compounds, including 1,2-dihydroquinoline-3-carboxamides linked benzylpiperidines (3a, 3b), [9] quinoline-thiosemicarbazone (1a, 1b), [10] hydroxyquinoline analogs containing piperidine ring (2a) [11] have demonstrated strong anti-Alzheimer's activity.…”