Antimalarial phytochemicals as potential inhibitors of SARS-CoV-2 guanine N7-methyltransferase (nsp 14): an integrated computational approach.

The inhibition of capping enzymes such as guanine-N7-methyltransferase (GMT) is an attractive target for regulating viral replication, transcription, virulence, and pathogenesis. Thus, compounds that target the Severe Acute Respiratory Syndrome Corona Virus 2 GMT (S2GMT) will enhance drug development against COVID-19. In this study, an in-house library of 249 phytochemicals from African medicinal plants was screened using computational approaches including homology modeling, molecular docking, molecular dynamic simulations, binding free energy calculations based on molecular mechanics/Poisson-Boltzmann surface area (MMPBSA) and Absorption-Distribution-Metabolism-Excretion-Toxicity (ADMET) analysis for inhibitors of S2GMT. The top-ten ranked phytochemicals (TTRP) obtained from the docking analysis to S2GMT were further docked to SARS-COV N7-MTase. Among the TTRP, the top-four ranked phytocompounds (TFRP) viz: 3 alkaloids (Isocryptolepine, 10'-Hydroxyusambarensine and Isostrychnopentamine) and a flavonoid (Mulberrofuran F) interacted strongly with critical catalytic residues whose interference either reduce or completely abolish N7-MTase activity, indicating their potential as capping machinery disruptors. The interactions of TFRP with the catalytic residues of S2GMT were preserved in a 100 ns simulated dynamic environment, thereby, demonstrating high degree of structural stability. The MMPBSA binding free energy calculations corroborated the docking scores with biscryptolepine having the highest binding free energy to S2GMT. The TFRP showed favourable drug-likeness and ADMET properties over a wide range of molecular descriptors. Therefore, the TFRP can be further explored as potential S2GMT inhibitors in in vitro and in vivo experiments.Communicated by Ramaswamy H. Sarma.

African derived phytocompounds may interfere with SARS-CoV-2 RNA capping machinery via inhibition of 2'-O-ribose methyltransferase: An in silico perspective.

Despite the ongoing vaccination against the life-threatening COVID-19, there is need for viable therapeutic interventions. The S-adenosyl-l-Methionine (SAM) dependent 2-O'-ribose methyltransferase (2'-O-MTase) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents a therapeutic target against COVID-19 infection. In a bid to profile bioactive principles from natural sources, a custom-made library of 226 phytochemicals from African medicinal plants with especially anti-malarial activity was screened for direct interactions with SARS-CoV-2 2'-O-MTase (S2RMT) using molecular docking and molecular dynamics (MD) simulations as well as binding free energies methods. Based on minimal binding energy lower than sinefungin (a reference methyl-transferase inhibitor) and binding mode analysis at the catalytic site of S2RMT, a list of 26 hit phytocompounds was defined. The interaction of these phytocompounds was compared with the 2'-O-MTase of SARS-CoV and MERS-CoV. Among these compounds, the lead phytocompounds (LPs) viz: mulberrofuran F, 24-methylene cycloartenol, ferulate, 3-benzoylhosloppone and 10-hydroxyusambarensine interacted strongly with the conserved KDKE tetrad within the substrate binding pocket of the 2'-O-MTase of the coronavirus strains which is critical for substrate binding. The thermodynamic parameters analyzed from the MD simulation trajectories of the LPs-S2RMT complexes presented an eminent structural stability and compactness. These LPs demonstrated favorable druggability and in silico ADMET properties over a diverse array of molecular computing descriptors. The LPs show promising prospects in the disruption of S2RMT capping machinery in silico. However, these LPs should be validated via in vitro and in vivo experimental models.