Abstract
A novel coronavirus is the causative agent identified for the current COVID-19 outbreak. Globally, more than 43 million people have been infected by this virus. The total number of deaths has surpassed 1.6 million across 210 countries due to the current pandemic. Till date, there is no specific therapeutic agent available for its treatment. Mpro, a non-structural protein cleaves viral polyproteins into other non-structural proteins. Inhibition of Mpro could prevent the virus replication projecting it as a potential candidate for anti-COVID-19 drug development. The authors report herein 10 top-ranked curcumin derivatives as non-peptide covalent-binding Mpro inhibitors using systematic virtual screening approach. Detailed ligand-receptor interaction analysis conferred that the α,β-unsaturated carbonyl moiety of curcumin functions as a warhead to yield a Michael adduct with Cys145 of the catalytic dyad of Mpro. Collectively, these results have offered new high affinity molecules for the development of potential drugs for the treatment of COVID-19.
Highlights
Three major outbreaks of acute respiratory syndrome induced by coronaviruses (CoVs) have been witnessed in the last two decades
These compounds were screened in silico systematically using sequential conformational precision approaches which included HTVS, standard precision (SP), XP and CovDock protocols of Schrodinger Suite on the main protease (Mpro) protein and the molecules obtained in the final step were analyzed manually for their predicted binding modes and scores (Toledo Warshaviak et al, 2014; Al-Khafaji et al, 2020)
In Mpro-N3 enzyme-ligand complex, the distance between the sulfur atom of Cys145 and the covalent carbon atom of N3 ligand is 1.8 Å, whereas this distance is around 1.8 Å for all the reported curcumin derivatives
Summary
Three major outbreaks of acute respiratory syndrome induced by coronaviruses (CoVs) have been witnessed in the last two decades. The first outbreak was Severe Acute Respiratory Syndrome (SARS) in 2003 with Guangdong, China as epicenter (Peiris et al, 2004) followed by Middle East Respiratory Syndrome (MERS) in 2012 in Saudi Arabia (Zaki et al, 2012) and the novel coronavirus disease (COVID-19), first reported in Wuhan, China in late 2019(Wang et al, 2020). World Health Organization (WHO) declared COVID-19 outbreak as a global pandemic on 11th. As per the WHO report (28th October, 2020), COVID-19 is affecting more than 210 countries and territories with over 43,766,712 confirmed cases and over 1,663,459 total deaths around the world (World Health Organization, 2020). The global fatality rate is around 3.80% (calculated as deaths per confirmed cases). A large number of people are being identified as COVID positive every day in the USA followed by India, Brazil, Russia, South Africa and other countries
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