Structure-based drug designing towards the identification of potential anti-viral for COVID-19 by targeting endoribonuclease NSP15

Abstract

The world is facing health and economic havoc due to the Corona Virus Disease-2019 (COVID-19) pandemic. Given the number of affected people and the mortality rate, the virus is undoubtedly a serious threat to humanity. By analogy with earlier reports about Severe Acute Respiratory Syndrome (SARS-CoV) and Middle East Respiratory Syndrome (MERS-CoV) - viruses, the novel Coronavirus’ replication mechanism is likely well understood. The structure of an endoribonuclease (NSP15) of SARS-CoV-2 was reported recently. This enzyme is expected to play a crucial role in replication. In this work, attempts were made to identify inhibitors of this enzyme. To achieve the goal, high throughput in silico screening and molecular docking procedures were performed. From an Enamine database of a billion compounds, 3978 compounds with potential antiviral activity were selected for screening and induced fit docking that funneled down to eight compounds with good docking score and docking energy. Detailed analysis of non-covalent interactions at the active site and the apparent match of the molecule with the shape of the binding pocket were assessed. All the compounds show significant interactions for tight binding. Since all the compounds are synthetic with favorable drug-like properties, these may be considered for immediate optimization and downstream applications.

Predicted therapeutic targets for COVID-19 disease by inhibiting SARS-CoV-2 and its related receptors

“…If the lung cell is infected with the SARS-CoV-2, preventing the virus from replicating is another treatment option [ 38 ]. Many studies have shown that miRNAs play an important role in inhibiting viruses' replication by preventing the translation of the viral genome [ 7 ].…”

Pharmacoinformatics approach based identification of potential Nsp15 endoribonuclease modulators for SARS-CoV-2 inhibition

“…A few recent studies on the screening of Nsp15 modulators for inhibition of SARS-CoV-2 were published. Krishnan et al [ 47 ] were explored the enamine for screening against the Nsp15. They have reported promising eight molecules for the inhibition of SARS-CoV-2.…”

A systems-based method to repurpose marketed therapeutics for antiviral use: a SARS-CoV-2 case study

“…The SARS-CoV-2 protein with the top-ranked drug repurposing opportunities was Nsp15. Nsp15 is of particular interest as a drug target because it is an endoribonuclease common to all coronaviruses, is necessary for SARS-CoV-2 replication and interferes with host immune responses ( 51 , 52 , 53 , 54 , 55 , 56 , 57 ).…”