Evaluation of therapeutic potentials of selected phytochemicals against Nipah virus, a multi-dimensional in silico study.

The current study attempted to evaluate the potential of fifty-three (53) natural compounds as Nipah virus attachment glycoprotein (NiV G) inhibitors through in silico molecular docking study. Pharmacophore alignment of the four (4) selected compounds (Naringin, Mulberrofuran B, Rutin and Quercetin 3-galactoside) through Principal Component Analysis (PCA) revealed that common pharmacophores, namely four H bond acceptors, one H bond donor and two aromatic groups were responsible for the residual interaction with the target protein. Out of these four compounds, Naringin was found to have the highest inhibitory potential ( - 9.19 kcal mol-1) against the target protein NiV G, when compared to the control drug, Ribavirin ( - 6.95 kcal mol-1). The molecular dynamic simulation revealed that Naringin could make a stable complex with the target protein in the near-native physiological condition. Finally, MM-PBSA (Molecular Mechanics-Poisson-Boltzmann Solvent-Accessible Surface Area) analysis in agreement with our molecular docking result, showed that Naringin ( - 218.664 kJ mol-1) could strongly bind with the target protein NiV G than the control drug Ribavirin ( - 83.812 kJ mol-1). Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03595-y.

An in-silico pharmacophore-based molecular docking study to evaluate the inhibitory potentials of novel fungal triterpenoid Astrakurkurone analogues against a hypothetical mutated main protease of SARS-CoV-2 virus.

BACKGROUND: The main protease is an important structural protein of SARS-CoV-2, essential for its survivability inside a human host. Considering current vaccines' limitations and the absence of approved therapeutic targets, Mpro may be regarded as the potential candidate drug target. Novel fungal phytocompound Astrakurkurone may be studied as the potential Mpro inhibitor, considering its medicinal properties reported elsewhere. METHODS: In silico molecular docking was performed with Astrakurkurone and its twenty pharmacophore-based analogues against the native Mpro protein. A hypothetical Mpro was also constructed with seven mutations and targeted by Astrakurkurone and its analogues. Furthermore, multiple parameters such as statistical analysis (Principal Component Analysis), pharmacophore alignment, and drug likeness evaluation were performed to understand the mechanism of protein-ligand molecular interaction. Finally, molecular dynamic simulation was done for the top-ranking ligands to validate the result. RESULT: We identified twenty Astrakurkurone analogues through pharmacophore screening methodology. Among these twenty compounds, two analogues namely, ZINC89341287 and ZINC12128321 showed the highest inhibitory potentials against native and our hypothetical mutant Mpro, respectively (-7.7 and -7.3 kcal mol-1) when compared with the control drug Telaprevir (-5.9 and -6.0 kcal mol-1). Finally, we observed that functional groups of ligands namely two aromatic and one acceptor groups were responsible for the residual interaction with the target proteins. The molecular dynamic simulation further revealed that these compounds could make a stable complex with their respective protein targets in the near-native physiological condition. CONCLUSION: To conclude, Astrakurkurone analogues ZINC89341287 and ZINC12128321 can be potential therapeutic agents against the highly infectious SARS-CoV-2 virus.

Curcumin inhibits spike protein of new SARS-CoV-2 variant of concern (VOC) Omicron, an in silico study.

BACKGROUND: Omicron (B.1.1.529), a variant of SARS-CoV-2 is currently spreading globally as a dominant strain. Due to multiple mutations at its Spike protein, including 15 amino acid substitutions at the receptor binding domain (RBD), Omicron is a variant of concern (VOC) and capable of escaping vaccine generated immunity. So far, no specific treatment regime is suggested for this VOC. METHODS: The three-dimensional structure of the Spike RBD domain of Omicron variant was constructed by incorporating 15 amino acid substitutions to the Native Spike (S) structure and structural changes were compared that of the Native S. Seven phytochemicals namely Allicin, Capsaicin, Cinnamaldehyde, Curcumin, Gingerol, Piperine, and Zingeberene were docked with Omicron S protein and Omicron S-hACE2 complex. Further, molecular dynamic simulation was performed between Crcumin and Omicron S protein to evaluate the structural stability of the complex in the physiological environment and compared with that of the control drug Chloroquine. RESULTS: Curcumin, among seven phytochemicals, was found to have the most substantial inhibitory potential with Omicron S protein. Further, it was found that curcumin could disrupt the Omicron S-hACE2 complex. The molecular dynamic simulation demonstrated that Curcumin could form a stable structure with Omicron S in the physiological environment. CONCLUSION: To conclude, Curcumin can be considered as a potential therapeutic agent against the highly infectious Omicron variant of SARS-CoV-2.

In silico study of some selective phytochemicals against a hypothetical SARS-CoV-2 spike RBD using molecular docking tools.

BACKGROUND: This world is currently witnessing a pandemic outbreak of 'COVID-19' caused by a positive-strand RNA virus 'SARS-CoV-2'. Millions have succumbed globally to the disease, and the numbers are increasing day by day. The viral genome enters into the human host through interaction between the spike protein (S) and host angiotensin-converting enzyme-2 (ACE2) proteins. S is the common target for most recently rolled-out vaccines across regions. A recent surge in single/multiple mutations in S region is of great concern as it may escape vaccine induced immunity. So far, the treatment regime with repurposed drugs has not been too successful. HYPOTHESIS: Natural compounds are capable of targeting mutated spike protein by binding to its active site and destabilizing the spike-host ACE2 interaction. MATERIALS AND METHODS: A hypothetical mutated spike protein was constructed by incorporating twelve different mutations from twelve geographical locations simultaneously into the receptor-binding domain (RBD) and docked with ACE2 and seven phytochemicals namely allicin, capsaicin, cinnamaldehyde, curcumin, gingerol, piperine and zingeberene. Molecular Dynamic (MD) simulation and Principal Component Analysis (PCA) were finally used for validation of the docking results. RESULT: The docking results showed that curcumin and piperine were most potent to bind ACE2, mutated spike, and mutated spike-ACE2 complex, thereby restricting viral entry. ADME analysis also proved their drug candidature. The docking complexes were found to be stable by MD simulation. CONCLUSION: This result provides a significant insight about the phytochemicals' role, namely curcumin and piperine, as the potential therapeutic entities against mutated spike protein of SARS-CoV-2.

Phytochemicals as potential drug candidates for targeting SARS CoV 2 proteins, an in silico study.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a member of the family Coronaviridae, and the world is currently witnessing a global pandemic outbreak of this viral disease called COVID-19. With no specific treatment regime, this disease is now a serious threat to humanity and claiming several lives daily. In this work, we selected 24 phytochemicals for an in silico docking study as candidate drugs, targeting four essential proteins of SARS-CoV-2 namely Spike glycoprotein (PDB id 5WRG), Nsp9 RNA binding protein (PDB id 6W4B), Main Protease (PDB id 6Y84), and RNA dependent RNA Polymerase (PDB id 6M71). After statistical validation, the results indicated that a total of 11 phytochemicals divided into two clusters might be used as potential drug candidates against SARS-CoV-2. Supplementary Information: The online version contains supplementary material available at 10.1007/s13337-021-00654-x.