In silico molecular investigations of pyridine N-Oxide compounds as potential inhibitors of SARS-CoV-2: 3D QSAR, molecular docking modeling, and ADMET screening

Abstract

The new coronavirus SARS-CoV-2 virus is causing a severe pneumonia in human, provoking the serious outbreak epidemic CoV-2. Since its appearance in Wuhan, China on December 2019, CoV-2 becomes the biggest challenge the world is facing today, including the discovery of antiviral drug for SARS-CoV-2. In this study, the potential inhibitory of a class of human SARS inhibitors, namely pyridine N-oxide derivatives, against CoV-2 was addressed by quantitative structure-activity relationship 3 D-QSAR. The reliable CoMSIA developed model of 110 pyridine N-oxide based-antiviral compounds, showed Q²= 0.54 and$r_{\mathrm{ext}}^2=0.71.$ The molecular surflex-docking was applied to identify the crystal structure of CoV-2 main protease 3CLpro (PDB: 6LU7) and two potentially and largely used antiviral molecules, namely chloroquine, hydroxychloroquine. The obtained free energy affinity and ADMET properties indicate that among the series of model antiviral compounds examined, the new antiviral compound A5 could be an excellent antiviral drug inhibitor against COVID-19. The inhibition activity of pyridine N-oxyde compounds against CoV-2 was compared with the activity of two common antiviral drug, namely chloroquine (CQ) and hydroxychloroquine (HCQ). DFT method was also used to define the sites of reactivity of pyridine N-oxyde derivatives as well as CQ and HCQ.Communicated by Ramaswamy H. Sarma.

Keywords: 3D-QSAR; COVID-19; drug discovery; molecular docking; pyridine N-oxide.