Background: In December 2019, SARS-Cov-2 epidemic was reported in Wuhan, China and then it spreads widely affects millions of people around the world. Nsp15 is one of the key members of EndoU family which perform several biological functions like RNA endonuclease activity which generate 2’-3’ cyclic phosphodiester termini. In viruses, Nsp15 is conserved among nidoviruses and absent in other RNAviruses which makes it potential target for recent coronavirus outbreak.
Methods: In this study, we have used earlier studied Benzopurpurin B which has inhibition property against Nsp15 protein of SARS virus (0.2 μM). Next, we have developed structure-based pharmacophore model with the help of Benzopurpurin B and crystal structure of Nsp15 endoribonuclease NendoU from SARS-CoV-2 (6vww). For pharmacophore development, we have employed two different software, viz., Discovery Studio 4.0 and Ligandscout. The selected pharmacophore was used to screen FDA approved drugs from DrugBank Database. The hits retrieved were next subjected to molecular docking analysis followed by molecular dynamics studies.
Results: The best pharmacophore model A with 6 features (2 hydrogen bond acceptor, 2 hydrogen bond donor and 2 hydrophobic group, AADDHH) was selected based on highest selectivity score of 11.155. the validated hypo model 1 able to screen out 136 drugs out of 2454 FDA approved drugs from DrugBank Database. These drugs were further filtered out using molecular docking to remove any false-positive hits. Finally, 3 top hits were selected for MD simulation to confirm their binding stability.
Conclusion: Daclatasvir (DB09102), an antiviral approved drug was identified as possible candidate for designing the potent inhibitor against Nsp15 of SARS-CoV-2 virus, although further evaluation via wet lab is required to measure its efficacy.