Antitussive noscapine and antiviral drug conjugates as arsenal against COVID-19: a comprehensive chemoinformatics analysis

Abstract

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.

Structural Basis of Potential Inhibitors Targeting SARS-CoV-2 Main Protease

“…Fifteen drugs (chloroquine, hydroxychloroquine, lopinavir, ritonavir, nafamostat, camostat, famotidine, umifenovir, nitazoxanide, ivermectin, corticosteroids, tocilizumab, sarilumab, bevacizumab, and fluvoxamine) are under clinical trial but conducting solid clinical trials is reportedly more difficult with increased public inquiry over readily available drugs ( Shaffer, 2020 ). A combination of drugs could be more effective; for example, a combination of antitussive noscapine and hydroxychloroquine showed a strong binding affinity to SARS-CoV-2 M pro ( Kumar et al, 2020b ). A tremendous number of studies are underway to determine the therapeutic use of antivirals (bemcentinib, chloroquine & hydroxychloroquine, lopinavir boosted with ritonavir and remdesivir) and immune modulators (anakinra and canakinumab, azithromycin, brensocatib, convalescent plasma, corticosteroids, interferon beta, ruxolitinib, mesenchymal stromal cells and sarilumab and tocilizumab) to treat COVID-19 ( Connelly, 2020 ).…”

Molecular insights of hyaluronic acid-hydroxychloroquine conjugate as a promising drug in targeting SARS-CoV-2 viral proteins

“…Recently, Kumar et al, 2020 [70] reported the MD simulation results of Noscapine-Hydroxychloroquine (Nos-HCQ) conjugates. The authors showed strong binding affinity for the main protease (Mpro) of SARS-CoV-2, which performs key biological function in virus infection and progression.…”

Click triazole as a linker for drug repurposing against SARs-CoV-2: A greener approach in race to find COVID-19 therapeutic

“…Molecular dynamics simulation, a tool to analyze the physical movement of atoms and molecules, elucidate the free energy change of the drug upon binding with the target protein through the root mean square deviation (RMSD), the heat-map of decomposing, and other relevant parameters[ 21 , 22 ]. In addition, molecular docking lends a hand in recognizing the mechanistic interaction of the drug with the target receptor [ 23 , 24 ]. Mechanistically, molecular modeling studies are widely employed and proved to be very efficient to understand the background and preliminary efficacy of drugs out of large datasets [ [25] , [26] , [27] ].…”