Coronavirus pandemic has caused a vast number of deaths worldwide. Thus creating an urgent need to develop effective counteragents against novel coronavirus disease (COVID-19). Many antiviral drugs have been repurposed for treatment but implicated minimal recovery, which further advanced the need for clearer insights and innovation to derive effective therapeutics. Strategically, Noscapine, an approved antitussive drug with positive effects on lung linings may show favorable outcomes synergistically with antiviral drugs in trials. Hence, we have theoretically examined the combinatorial drug therapy by culminating the existing experimental results with in silico analyses. We employed the antitussive noscapine in conjugation with antiviral drugs (Chloroquine, Umifenovir, Hydroxychloroquine, Favlplravir and Galidesivir). We found that Noscapine-Hydroxychloroquine (Nos-Hcq) conjugate has strong binding affinity for the main protease (Mpro) of SARS-CoV-2, which performs key biological function in virus infection and progression. Nos-Hcq was analyzed through molecular dynamics simulation. The MD simulation for 100 ns affirmed the stable binding of conjugation unprecedentedly through RMSD and radius of gyration plots along with critical reaction coordinate binding free energy profile. Also, dynamical residue cross-correlation map with principal component analysis depicted the stable binding of Nos-Hcq conjugate to Mpro domains with optimal secondary structure statistics of complex dynamics. Also, we reveal the drugs with stable binding to major domains of Mpro can significantly improve the work profile of reaction coordinates, drug accession and inhibitory regulation of Mpro. The designed combinatorial therapy paves way for further prioritized in vitro and in vivo investigations for drug with robust binding against Mpro of SARS-CoV-2.

Mycobacterium tuberculosis (Mtb) resistance toward anti-tuberculosis drugs is a widespread problem. Pyrazinamide (PZA) is a first line antitubercular drug that kills semi-dormant bacilli when converted into its activated form, that is, pyrazinoic acid (POA) by Pyrazinamidase (PZase) enzyme coded by pncA gene. In this study, we conducted several analyses on native and mutant structures (W68R, W68G) of PZase before and after docking with the PZA drug to explore the molecular mechanism behind PZA resistance caused due to pncA mutations. Structural changes caused by mutations were studied with respect to their effects on functionality of protein. Docking was performed to analyze the protein-drug binding and comparative analysis was done to observe how the mutations affect drug binding affinity and binding site on protein. Native PZase protein was observed to have the maximum binding affinity in terms of docking score as well as shape complementarity in comparison to the mutant forms. Molecular dynamics simulation analyses showed that mutation in the 68th residue of protein results in a structural change at its active site which further affects the biological function of protein, that is, conversion of PZA to POA. Mutations in the protein thereby led to PZA resistance in the bacterium due to the inefficient binding.

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