In silico discovery of multi-targeting inhibitors for the COVID-19 treatment by molecular docking, molecular dynamics simulation studies, and ADMET predictions

Coronavirus disease-2019 (COVID-19), a global pandemic, has currently infected more than 247 million people around the world. Nowadays, several receptors of COVID-19 have been reported, and few of them are explored for drug discovery. New mutant strains of COVID-19 are emerging since the first outbreak of disease and causing significant morbidity and mortality across the world. Although, few drugs were approved for emergency uses, however, promising drug with well-proven clinical efficacy is yet to be discovered. Hence, researchers are continuously attempting to search for potential drug candidates targeting the well-established enzymatic targets of the virus. The present study aims to discover the antiviral compounds as potential inhibitors against the five targets in various stages of the SARS-CoV-2 life cycle, i.e., virus attachments (ACE2 and TMPRSS2), viral replication, and transcription (M-pro, PLpro and RdRp), using the most reliable molecular docking and molecular dynamics method. The ADMET study was then carried out to determine the pharmacokinetics and toxicity of several compounds with the best docking results. To provide a more effective mechanism for demonstrating protein-ligand interactions, molecular docking data were subjected to a molecular dynamic (MD) simulation at 300 K for 100 ns. In terms of structural stability, structure compactness, solvent accessible surface area, residue flexibility, and hydrogen bond interactions, the dynamic features of complexes have been compared.

Bioactive compounds from mangosteen (Garcinia mangostana L.) as an antiviral agent via dual inhibitor mechanism against SARSCoV- 2: an in silico approach

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus that causes COVID-19 which is responsible for respiratory illness infection in humans. The virus was first identified in China in 2019 and later spread to other countries worldwide. This study aims to identify the bioactive compounds from mangosteen (Garcinia mangostana L.) as an antiviral agent via dual inhibitor mechanisms against two SARS-CoV-2 proteases through the in silico approach. The three-dimensional structure of various bioactive compounds of mangosteen from the database was examined. Furthermore, all the target compounds were analyzed for drug, antiviral activity prediction, virtual screening, molecular interactions, and threedimensional structure visualization. It aimed to determine the potential of the bioactive compounds from mangosteen that can serve as antiviral agents to fight SARS-CoV-2. Results showed that the bioactive compounds from mangosteen have the prospective to provide antiviral agents that contradict the virus via dual inhibitory mechanisms. In summary, the binding of the various bioactive compounds from mangosteen results in low binding energy and is expected to have the ability to induce any activity of the target protein binding reaction. Therefore, it allows various bioactive compounds from mangosteen to act as dual inhibitory mechanisms for COVID-19 infection.

Molecular Docking of Novel 5-O-benzoylpinostrobin Derivatives as SARS-CoV-2 Main Protease Inhibitors

Background: COVID-19, a global pandemic caused by SARS-CoV-2 infection, has led researchers around the world to search for therapeutic agents for treatment of the disease. The main protease (M-Pro) of SARS-CoV-2 is one of the potential targets in the development of new drug compounds for the disease. Some known drugs such as chloroquine and remdesivir have been repurposed for treatment of COVID-19, although the the mechanism of action of these compounds is still unknown. In addition to these known drugs, new drug compounds such as 5-O-benzoylpinostrobin derivatives are also potentially used as SARS-CoV-2 M-Pro inhibitors. This study aims to determine the potential of 5-O-benzoylpinostrobin derivatives as SARS-CoV-2 M-Pro inhibitors, compared with several other compounds used in COVID-19 therapy. Methods: In silica study was carried out by molecular docking of 5-O-benzoylpinostrobin derivatives using Autodock Vina on two SARS-CoV-2 M-Pro receptors with PDB IDs of 5R84 and 6LU7. The free energy of binding was calculated and the the interactions of each ligand were analyzed and compared with reference ligand. Results: Three 5-O-benzoylpinostrobin derivatives each with fluoro, tertiary butyl, and trifluoromethyl substituents at 4-position of benzoyl group showed the lowest free energy of binding value and the highest similarity of ligand-receptor interactions with co-crystalized ligands. These three compounds even exhibited promising results in comparison with other reference ligands such as remdesivir and indinavir. Conclusion: The results of this investigation anticipate that some 5-O-benzoylpinostrobin derivatives have the potential as SARS-CoV-2 M-Pro inhibitors.