Computational insights of phytochemical-driven disruption of RNA-dependent RNA polymerase-mediated replication of coronavirus: a strategic treatment plan against coronavirus disease 2019.

ABSTRACT

The current pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has raised global health concerns. RNA-dependent RNA polymerase (RdRp) is the prime component of viral replication/proliferation machinery and is considered to be a potential drug target against SARS-CoV-2. The present study investigated the anti-RdRp activity of phytochemicals against SARS-CoV-2 infection. Virtual ligand screening was carried out to determine the potent compounds against RdRp. Molecular docking and an MD Simulation study were employed to evaluate the spatial affinity of selected phytochemicals for the active sites of RdRp. Structural stability of target compounds was determined using root mean square deviation computational analysis and drug-like abilities were investigated using ADMET. Bond distances between ligand and receptor were marked to predict the strength of interaction. Aloe, azadirachtin, columbin, cirsilineol, nimbiol, nimbocinol and sage exhibited the highest binding affinities and interacted with active sites of RdRp, surpassing the ability of chloroquine, lamivudine, favipiravir and remdesivir to target the same. All the natural metabolites exhibited stable conformation during MD Simulation of 101 ns at 310 K. Kinetic, potential and electrostatic energy were observed to be least in the case of natural metabolites in comparison with synthetic analogues. Deviations and fluctuations were observed to be structurally least in target phytochemicals. Physiochemical and biological properties of these compounds further validated their drug-like properties. Non-bonded distance was found to be short enough to form hydrogen bonding or hydrophobic interactions, which revealed that these target compounds can strongly bind with RdRp. The study found potential phytochemicals to disrupt the replication domain of SARS-CoV-2 by hindering RdRp. We therefore anticipate that the current findings could be considered as valuable for the development of an efficient preventive/therapeutic expedient against COVID-19.