Identification of natural compounds as potent inhibitors of SARS-CoV-2 main protease using combined docking and molecular dynamics simulations

Coronavirus disease 2019 (COVID-19) has emerged from China and globally affected the entire population through the human-to-human transmission of a newly emerged virus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The genome of SARS-CoV-2 encodes several proteins that are essential for multiplication and pathogenesis. The main protease (M^pro or 3CL^pro) of SARS-CoV-2 plays a central role in its pathogenesis and thus is considered as an attractive drug target for the drug design and development of small-molecule inhibitors. We have employed an extensive structure-based high-throughput virtual screening to discover potential natural compounds from the ZINC database which could inhibit the M^pro of SARS-CoV-2. Initially, the hits were selected on the basis of their physicochemical and drug-like properties. Subsequently, the PAINS filter, estimation of binding affinities using molecular docking, and interaction analyses were performed to find safe and potential inhibitors of SARS-CoV-2 M^pro. We have identified ZINC02123811 (1-(3-(2,5,9-trimethyl-7-oxo-3-phenyl-7H-furo[3,2-g]chromen-6-yl)propanoyl)piperidine-4-carboxamide), a natural compound bearing appreciable affinity, efficiency, and specificity towards the binding pocket of SARS-CoV-2 M^pro. The identified compound showed a set of drug-like properties and preferentially binds to the active site of SARS-CoV-2 M^pro. All-atom molecular dynamics (MD) simulations were performed to evaluate the conformational dynamics, stability and interaction mechanism of M^pro with ZINC02123811. MD simulation results indicated that M^pro with ZINC02123811 forms a stable complex throughout the trajectory of 100 ns. These findings suggest that ZINC02123811 may be further exploited as a promising scaffold for the development of potential inhibitors of SARS-CoV-2 M^pro to address COVID-19.     

Identification and analysis of novel small molecule inhibitors of RNase E: Implications for antibacterial targeting and regulation of RNase E

Increasing resistance of bacteria to antibiotics is a serious global challenge and there is a need to unlock the potential of novel antibacterial targets. One such target is the essential prokaryotic endoribonuclease RNase E. Using a combination of in silico high-throughput screening and in vitro validation we have identified three novel small molecule inhibitors of RNase E that are active against RNase E from Escherichia coli, Francisella tularensis and Acinetobacter baumannii. Two of the inhibitors are non-natural small molecules that could be suitable as lead compounds for the development of broad-spectrum antibiotics targeting RNase E. The third small molecule inhibitor is glucosamine-6-phosphate, a precursor of bacterial cell envelope peptidoglycans and lipopolysaccharides, hinting at a novel metabolite-mediated mechanism of regulation of RNase E.     

In silico identification of potential inhibitors against main protease of SARS-CoV-2 6LU7 from Andrographis panniculata via molecular docking,binding energy calculations and molecular dynamics simulation studies

BackgroundThe ongoing global outbreak of new corona virus (SARS-CoV-2) has been recognized as global public health concern since it causes high morbidity and mortality every day. Due to the rapid spreading and re-emerging, we need to find a potent drug against SARS-CoV-2. Synthetic drugs, such as hydroxychloroquine, remdisivir have paid more attention and the effects of these drugs are still under investigation, due to their severe side effects. Therefore, the aim of the present study was performed to identify the potential inhibitor against main protease SARS-CoV-2 6LU7.ObjectiveIn this study, RO5, ADME properties, molecular dynamic simulations and free binding energy prediction were mainly investigated.ResultsThe molecular docking study findings revealed that andrographolide had higher binding affinity among the selected natural diterpenoids compared to co-crystal native ligand inhibitor N3. The persistent inhibition of Ki for diterpenoids was analogous. Furthermore, the simulations of molecular dynamics and free binding energy findings have shown that andrographolide possesses a large amount of dynamic properties such as stability, flexibility and binding energy.ConclusionIn conclusion, findings of the current study suggest that selected diterpenoids were predicted to be the significant phytonutrient-based inhibitor against SARS-CoV-2 6LU7 (M^pro). However, preclinical and clinical trials are needed for the further scientific validation before use.