Determination of potential inhibitors based on isatin derivatives against SARS-CoV-2 main protease (m^pro): a molecular docking, molecular dynamics and structure-activity relationship studies

Abstract

SARS-COV-2, the novel coronavirus and root of global pandemic COVID-19 caused a severe health threat throughout the world. Lack of specific treatments raised an effort to find potential inhibitors for the viral proteins. The recently invented crystal structure of SARS-CoV-2 main protease (M pro) and its key role in viral replication; non-resemblance to any human protease makes it a perfect target for inhibitor research. This article reports a computer-aided drug design (CADD) approach for the screening of 118 compounds with 16 distinct heterocyclic moieties in comparison with 5 natural products and 7 repurposed drugs. Molecular docking analysis against M pro protein were performed finding isatin linked with a oxidiazoles (A2 and A4) derivatives to have the best docking scores of À11.22 kcal/ mol and À11.15 kcal/mol respectively. Structure-activity relationship studies showed a good comparison with a known active M pro inhibitor and repurposed drug ebselen with an IC 50 value of À0.67 lM. Molecular Dynamics (MD) simulations for 50 ns were performed for A2 and A4 supporting the stability of the two compounds within the binding pocket, largely at the S1, S2 and S4 domains with high binding energy suggesting their suitability as potential inhibitors of M pro for SARS-CoV-2.

Isatin derivatives as broad-spectrum antiviral agents: the current landscape

“…Badavath and his coworkers performed a molecular docking analysis on a series of heterocyclic derivatives in the binding site of the SARS-COV-2 main protease [ 65 ]. Among them, two isatin derivatives, 26 and 27 (Fig.…”

Natural and Nature-Derived Products Targeting Human Coronaviruses

“…Regarding 3CL pro , recent efforts, have identified potential inhibitors among: alkaloids [ 133 , 134 , 135 , 136 , 137 , 138 ], and especially indole alkaloids [ 139 , 140 , 141 , 142 , 143 , 144 ]; terpenoids [ 138 ], and especially diterpenes [ 133 , 145 ]; sesquiterpenes [ 134 , 146 , 147 ], sesquiterpene lactones [ 148 ], and triterpenes [ 133 , 136 , 140 , 149 ]; anthocyanins [ 150 , 151 ] and proanthocyanidins [ 152 , 153 ]; ellagitannins [ 153 , 154 ]; flavonoids [ 133 , 137 , 140 , 144 , 147 , 148 , 152 , 155 , 156 , 157 , 158 , 159 , 160 , 161 ], biflavonoids [ 162 ], and macrocyclic flavonoids [ 148 ]; isoflavones [ 144 , 148 ]; chalcones […”

Metal-Promoted Heterocyclization: A Heterosynthetic Approach to Face a Pandemic Crisis

“…Substitution of the carboxamide group with an ester or carboxylic acid coincides with a loss of activity due to hydrogen bonds breaking within the protein active site. Rigid aromatic cycles at the N-1 position favor hydrophobic interactions, which results in better fitting in the pocket and subsequently higher inhibition activity [ 16 , 116 ].…”