ABSTRACT
Originating in the city of Wuhan in China in December 2019, COVID-19 has emerged now as a global health emergency with a high number of deaths worldwide. COVID-19 is caused by a novel coronavirus, referred to as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), resulting in pandemic conditions around the globe. We are in the battleground to fight against the virus by rapidly developing therapeutic strategies in tackling SARS-CoV-2 and saving human lives from COVID-19. Scientists are evaluating several known drugs either for the pathogen or the host; however, many of them are reported to be associated with side effects. In the present study, we report the molecular binding mechanisms of the natural alkaloid, noscapine, for repurposing against the main protease of SARS-CoV-2, a key enzyme involved in its reproduction. We performed the molecular dynamics (MD) simulation in an explicit solvent to investigate the molecular mechanisms of noscapine for stable binding and conformational changes to the main protease (Mpro) of SARS-CoV-2. The drug repurposing study revealed the high potential of noscapine and proximal binding to the Mpro enzyme in a comparative binding pattern analyzed with chloroquine, ribavirin, and favipiravir. Noscapine binds closely to binding pocket-3 of the Mpro enzyme and depicted stable binding with RMSD 0.1-1.9 Å and RMSF profile peak conformational fluctuations at 202-306 residues, and a Rg score ranging from 21.9 to 22.4 Å. The MM/PB (GB) SA calculation landscape revealed the most significant contribution in terms of binding energy with ΔPB -19.08 and ΔGB -27.17 kcal/mol. The electrostatic energy distribution in MM energy was obtained to be -71.16 kcal/mol and depicted high free energy decomposition (electrostatic energy) at 155-306 residues (binding pocket-3) of Mpro by a MM force field. Moreover, the dynamical residue cross-correlation map also stated that the high pairwise correlation occurred at binding residues 200-306 of the Mpro enzyme (binding pocket-3) with noscapine. Principal component analysis depicted the enhanced movement of protein atoms with a high number of static hydrogen bonds. The obtained binding results of noscapine were also well correlated with the pharmacokinetic parameters of antiviral drugs.