Identification of promising antiviral drug candidates against non-structural protein 15 (NSP15) from SARS-CoV-2: anin silicoassisted drug-repurposing study

Abstract

The recent COVID-19 pandemic caused by SARS-CoV-2 has recorded a high number of infected people across the globe. The virulent nature of the virus makes it necessary for us to identify promising therapeutic agents in a time-sensitive manner. The current study utilises an in silico based drug repurposing approach to identify potential anti-viral drug candidates targeting non-structural protein 15 (NSP15), i.e. a uridylate specific endoribonuclease of SARS-CoV-2 which plays an indispensable role in RNA processing and viral immune evasion from the host immune system. The NSP15 protein was screened against an in-house library of 123 antiviral drugs obtained from the DrugBank database from which three promising drug candidates were identified based on their estimated binding affinities (DG), estimated inhibition constants (Ki), the orientation of drug molecules in the active site and the key interacting residues of NSP15. Molecular dynamics (MD) simulations were performed for the screened drug candidates in complex with NSP15 as well as the apo form of NSP15 to mimic their physiological states. Based on the stable MD simulation trajectories, the binding free energies of the screened NSP15-drug complexes were calculated using the MM/PBSA approach. Two candidate drugs, Simeprevir and Paritaprevir, achieved the lowest binding free energies for NSP15, with a value of À259.522 ± 17.579 and À154.051 ± 33.628 kJ/mol, respectively. In addition, their complexes with NSP15 also exhibited the strongest structural stabilities. Taken together, we propose that Simeprevir and Paritaprevir are promising drug candidates to inhibit NSP15 and may act as potential therapeutic agents against SARS-CoV-2.

An in-silico evaluation of different bioactive molecules of tea for their inhibition potency against non structural protein-15 of SARS-CoV-2

“…Currently, there are no treatment measures or vaccination against SARS-CoV2, and the requirement of a prophylactic and therapeutic intervention technique is critical ( Shannon et al, 2020 , Sinha et al, 2020 , Walls et al, 2020 ). Targeting the conserved Nsp15 active site via potent inhibitor molecules will not only hinder its involvement in virus replication activity but also prohibit the protein from interfering with the host’s innate immune response, enabling it to fight the viral invasion ( Chandra et al, 2020 , Khan et al, 2020 , Surti et al, 2020 ). The current investigation was performed with the aim of finding potent inhibitor molecules that could strongly bind to the active site of Nsp15.…”

In silico identification of available drugs targeting cell surface BiP to disrupt SARS-CoV-2 binding and replication: Drug repurposing approach

“…Similar to velpatasvir, paritaprevir is an antiviral agent against the HCV protease complex that gained a considerable amount of attention in the studies of COVID-19. Through tools like artificial intelligence (AI) deep learning, molecular docking, and, in some studies, molecular dynamics simulation, these investigations unanimously suggested the potential of paritaprevir in inhibiting viral RdRp, S protein, and proteases ( Manikyam and Joshi, 2020 , Shah et al, 2020 , Alamri et al, 2020 , Khan et al, 2020 , Choi et al, 2020 ). Our results expand the current paradigm and suggest that paritaprevir may also be used to target the NBD of csBiP, thereby sabotaging viral activities.…”

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

“…The MD simulation observations were quite similar to the current study in regards to stability, convergence and energetics. Khan et al [ 50 ] was performed an in-silico drug repurposing approach to find promising therapeutics targeting the Nsp15. From starting with more than a hundred known drugs, the authors reported three promising drug molecules effective against Nsp15.…”