Potential anti-viral activity of approved repurposed drug against main protease of SARS-CoV-2: anin silicobased approach

Abstract

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) which was first reported in Wuhan province of China, has become a deadly pandemic causing alarmingly high morbidity and mortality. In the absence of new targeted drugs and vaccines against SARS-CoV-2 at present, the choices for effective treatments are limited. Therefore, considering the exigency of the situation, we focused on identifying the available approved drugs as potential inhibitor against the promising Coronavirus drug target, the Main Protease, using computer-aided methods. We created a library of U. S. Food and Drug Administration approved anti-microbial drugs and virtually screened it against the available crystal structures of Main Protease of the virus. The study revealed that Viomycin showed the highest-CDocker energy after docking at the active site of SARS-CoV-2 Main Protease. It is noteworthy that Viomycin showed higher-CDocker energy as compared to the drugs currently under clinical trial for SARS-CoV-2 treatment viz. Ritonavir and Lopinavir. Additionally, Viomycin formed higher number of H-bonds with SARS-CoV-2 Main Protease than its co-crystallised inhibitor compound N3. Molecular dynamics simulation further showed that Viomycin embedded deeply inside the binding pocket and formed robust binding with SARS-CoV-2 Main Protease. Therefore, we propose that Viomycin may act as a potential inhibitor of the Main Protease of SARS-CoV-2. Further optimisations with the drug may support the much-needed rapid response to mitigate the pandemic.

Drug Repurposing for Candidate SARS-CoV-2 Main Protease Inhibitors by a Novel In Silico Method

“…A number of drugs selected in our study as repositioning candidates that potentially bind to the catalytic site were also identified in other in silico studies that analyzed the same target. In the molecular docking study, bacampicillin was among the best repurposed drugs against the main protease of SARS-CoV-2 [ 32 ]. Carbinoxamine showed in another docking study potential activity against SARS-CoV-2 M pro [ 33 ].…”

Molecular Basis of SARS-CoV-2 Infection and Rational Design of Potential Antiviral Agents: Modeling and Simulation Approaches

“… 184 Apart from natural products, other research groups have focused on FDA-approved antimicrobial drugs (such as viomycin) or other already known drugs (such as carfilzomib, eravacycline, valrubicin, lopinavir, elbasvir, streptomycin, and oftasceine, among others) to showcase, thanks to MD simulations, those with the highest potential. 188 …”

“…Most of the published studies making use of MD simulations evaluate the stability of the initial binding poses through the analysis of: (i) the RMSD of both the 3CLpro and the drug, (ii) the root-mean-square fluctuation (RMSF), and (iii) the radius of gyration ( R g ). These three descriptors are essential in evaluating the pose stability, as the RMSD determines the structural stability, the RMSF reveals the drug effect on the system flexibility and fluctuations, and R g is indicative of the compactness of the global structure (refs ( 143 , 173 , 175 , 184 , 185 , 187 , 188 , 190 , and 200 )). In addition, more specific criteria, such as the development of particular hydrogen bonds and hydrophobic interactions, are crucial to discriminate between potential or not efficient drugs because they ultimately determine the position of the drug with respect to the 3CLpro.…”

“…Indeed, to show inhibitory activity, the ligand should be firmly placed inside the binding pocket, lay close to the catalytic dyad, and possibly interact with the S1, S2, and S4 units, as shown in Figure 12 . 183 , 184 , 186 − 188 …”

Anin-silicoanalysis of ivermectin interaction with potential SARS-CoV-2 targets and host nuclear importin α

“…Globally, the data of infected people is alarming and as of September 13, 2020, approximately 28 637 952 confirmed cases have been registered with surpassing 917,417 deaths spanning over 216 countries, areas or territories (WHO, 2020 ). The pandemic caused by SARS-CoV-2 fueled considerable research efforts towards repurposing or repositioning of existing drugs as possible therapeutic agents (Borkotoky & Banerjee, 2020 ; de Oliveira et al, 2020 ; Khan et al, 2020 ; Mahanta et al, 2020 ; Sk et al, 2020 ).…”