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 Noxide 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 Q 2 ¼ 0.54 and r 2 ext ¼ 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 Noxyde 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.

Mechanisms of Proteolytic Enzymes and Their Inhibition in QM/MM Studies

“…A semiempirical QM/MM DFT calculation of the hydrolytic reaction of M Pro dimer with the fluorogenic substrate Ac-Val-Lys-Leu-Gln-ACC exhibited four transition states, with excellent agreement of computed and experimental ∆G ‡ values [114]. DFT based approaches were applied to a large set of pyridine N-oxide compounds as potential inhibitors of SARS-CoV-2 M Pro , peptidic Michael acceptor compounds, as well as to small molecule Schiff bases [115][116][117]. Moreover, SARS-2 M Pro was virtually screened for inhibition by several hundred natural compounds [118].…”

Novel and versatile artificial intelligence algorithms for investigating possible GHSR1α and DRD1 agonists for Alzheimer's disease

“…ADMET descriptors module in DS include absorption, distribution, metabolism, excretion, toxicity, and other information, which were used to describe and comprehensively analyze the solubility, blood–brain barrier (BBB) penetration, hepatotoxicity, and cytochrome P450 2D6 (CYP2D6) of small molecules in the TCM database. 36,37 In addition, SwissADME 38 was used to judge whether the candidate compounds are the substrates of P-glycoprotein. According to the dock scores, ADMET descriptors results, and the predict results, we selected three possible candidates as the multi-target drugs for AD to perform the subsequent experiments.…”

Pyridine Compounds with Antimicrobial and Antiviral Activities

“…Continuing their research, the Ghaleb group [ 100 ] found the structural conditions that N-oxides must meet in order to have an increased antiviral activity, which is shown in Figure 23 . In this study, pyridine N-oxide 223 with SARS-CoV inhibitory activity was selected for a further 3 D-QSAR studies.…”