Virtual screening-driven drug discovery of SARS-CoV2 enzyme inhibitors targeting viral attachment, replication, post-translational modification and host immunity evasion infection mechanisms

Abstract

The novel coronavirus SARS-CoV2, the causative agent of the pandemic disease COVID-19, emerged in December 2019 forcing lockdown of communities in many countries. The absence of specific drugs and vaccines, the rapid transmission of the virus, and the increasing number of deaths worldwide necessitated the discovery of new substances for anti-COVID-19 drug development. With the aid of bioinformatics and computational modelling, ninety seven antiviral secondary metabolites from fungi were docked onto five SARS-CoV2 enzymes involved in viral attachment, replication, post-translational modification, and host immunity evasion infection mechanisms followed by molecular dynamics simulation and in silico ADMET prediction (absorption, distribution, metabolism, excretion and toxicity) of the hit compounds. Thus, three fumiquinazoline alkaloids scedapin C (15), quinadoline B (19) and norquinadoline A (20), the polyketide isochaetochromin D1 (8), and the terpenoid 11a-dehydroxyisoterreulactone A (11) exhibited high binding affinities on the target proteins, papain-like protease (PLpro), chymotrypsin-like protease (3CLpro), RNA-directed RNA polymerase (RdRp), non-structural protein 15 (nsp15), and the spike binding domain to GRP78. Molecular dynamics simulation was performed to optimize the interaction and investigate the stability of the top-scoring ligands in complex with the five target proteins. All tested complexes were found to have dynamic stability. Of the five top-scoring metabolites, quinadoline B (19) was predicted to confer favorable ADMET values, high gastrointestinal absorptive probability and poor blood-brain barrier crossing capacities.

Computational search for potential COVID-19 drugs from FDA-approved drugs and small molecules of natural origin identifies several anti-virals and plant products

“…COVID-19 outbreak has turned into a pandemic, which makes the identification of new target molecules, repurposing of drugs and designing vaccine an imminent necessity. Since the outbreak, many studies have been conducted along these lines (Chakraborti et al 2020;Gordon et al 2020;Narayanan and Nair 2020;Wu et al 2020a) (Manfredonia et al 2020;Quimque et al 2020). We used NSP1 protein as our target protein.…”

Targeting Host Defense System and Rescuing Compromised Mitochondria to Increase Tolerance against Pathogens by Melatonin May Impact Outcome of Deadly Virus Infection Pertinent to COVID-19

“…Currently, the majority of efforts are focused on curtailing virus spreading, e.g., by blocking its entry into cells, inhibiting its replication, reducing its assembly. Notably, all these approaches are depending on synthetic compounds [ 12 , 13 ]. On the other hand, the blood from convalescent COVID-19 patients which contains naturally occurring antibodies against SARS-CoV-2 has also been used to stop virus invasion and development [ 14 , 15 ].…”

Papain-Like Proteases as Coronaviral Drug Targets: Current Inhibitors, Opportunities, and Limitations

“…The molecular docking and molecular dynamics of 97 antiviral secondary metabolites from fungi identified norquinadoline A and scedapin C as the most potent inhibitors for SARS-CoV-2 PLpro. Norquinadoline A conferred high gastrointestinal absorption, poor blood–brain barrier penetrability, and high drug-likeness as per Lipinski’s rule of five and did not demonstrate any toxicity [ 93 ].…”