QSAR and molecular docking approaches on a wide range of natural and synthetic antivirals against MERS-CoV and SARS-CoV-2


Daniel I. Hadaruga


Volume 27, Issue 2;

Pages: 236-242; 2021

ISSN: 2069-0053 (print) (former ISSN: 1453-1399), Agroprint;

ISSN (online): 2068-9551


Various natural and synthetic compounds were evaluated in the last decades for their inhibitory activity against coronaviruses. They belong to many chemical classes such as terpenoids, alkaloids, peptides, phenothiazines, or steroids. Twenty one compounds from these classes were evaluated as antivirals (50 % effective concentration for virus binding inhibition, EC50) against Middle East respiratory syndrome coronavirus (MERS-CoV). The goal of the study was to evaluate the main structural characteristics of these antivirals that influence the anti-MERS-CoV activity through the quantitative structure-activity relationships (QSARs) and to use them for prediction of the inhibitory activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by molecular docking experiments. Valuable QSARs were obtained with the logarithm of the octanol/water partition coefficient, logP, for a parabolic equation with r = 0.905 for the non-peptide related set of anti-MERS-CoV compounds, acting by inhibiting the virus binding to the human cell. On the other hand, better results were obtained for the second set, mainly of peptide-related anti-MERS-CoV, which inhibit virus replication. The most important parameters were the centered Broto-Moreau autocorrelation - lag 0 / weighted by I-state (ATSC0s, with r = 0.965), the largest absolute eigenvalue of Burden modified matrix - n 4 / weighted by relative I-state (SpMax4_Bhs, r = 0.965), and count of E-states for (strong) hydrogen bond donors (nHBd, r = 0.937). The most active antivirals were subjected to molecular docking into the MERS-CoV and SARS-CoV-2 receptor sites corresponding to S1 protein:dihydrofolic acid and protease:2-chlorocyclohexylmethyl-2-hydroxymethyl-6-nitrocyclohexanol complexes, respectively. In both cases, the best interaction energies were obtained for bufalin, a steroid derivative with two H-donor and four H-acceptor groups, suggesting that the inhibition mechanism can be similar and can be further studied as starting structural architecture for new compounds with possible effects against SARS-CoV-2.

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