Identification of Cyanobacteria-Based Natural Inhibitors Against SARS-CoV-2 Druggable Target ACE2 Using Molecular Docking Study, ADME and Toxicity Analysis.

In 2019-2020, the novel "severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)" had emerged as the biggest challenge for humanity, causing "coronavirus disease 19 (COVID-19)". Scientists around the world have been putting continuous efforts to unfold potential inhibitors of SARS-CoV-2. We have performed computational studies that help us to identify cyanobacterial photoprotective compounds as potential inhibitors against SARS-CoV-2 druggable target human angiotensin-converting enzyme (ACE2), which plays a vital role in the attachment and entry of the virus into the cell. Blocking the receptor-binding domain of ACE2 can prevent the access of the virus into the compartment. A molecular docking study was performed between photoprotective compounds mycosporine-like amino acids, scytonemins and ACE2 protein using AutoDock tools. Among sixteen molecularly docked metabolites, seven compounds were selected with binding energy < 6.8 kcal/mol. Afterwards, drug-likeness and toxicity of the top candidate were predicted using Swiss ADME and Pro Tox-II online servers. All top hits show desirable drug-likeness properties, but toxicity pattern analysis discloses the toxic effect of scytonemin and its derivatives, resulting in the elimination from the screening pipeline. Further molecular interaction study of the rest two ligands, mycosporine-glycine-valine and shinorine with ACE2 was performed using PyMol, Biovia Discovery studio and LigPlot+. Lastly biological activity of both the ligands was predicted by using the PASS online server. Combining the docking score and other studied properties, we believe that mycosporine-glycine-valine and shinorine have potential to be potent inhibitors of ACE2 and can be explored further to use against COVID-19.

Evolutionary aspects of mutation in functional motif and post-translational modifications in SARS-CoV-2 3CLpro (Mpro): an in-silico study

SARS CoV-2 is the virus that caused the COVID-19 pandemic. The main protease is one of the most prominent pharmacological targets for developing anti-COVID-19 therapeutic drugs (Mpro);SARS-CoV-2 replication is dependent on this component. SARS CoV-2's Mpro/cysteine protease is quite identical to SARS CoV-1's Mpro/cysteine protease. However, there is limited information on its structural and conformational properties. The present study aims to perform a complete in silico evaluation of Mpro protein's physicochemical properties. The motif prediction, post-translational modifications, effect of point mutation, and phylogenetic links were studied with other homologs to understand the molecular and evolutionary mechanisms of these proteins. The Mpro protein sequence was obtained in FASTA format from the RCSB Protein Data Bank. The structure of this protein was further characterized and analyzed using standard bioinformatics methods. According to Mpro's in-silico characterization, the protein is a basic, non-polar, and thermally stable globular protein. The outcomes of the phylogenetic and synteny study showed that the protein's functional domain amino acid sequence is substantially conserved. Furthermore, it has undergone many changes at the motif level over time from porcine epidemic diarrhoea virus to SARS-CoV 2, possibly to achieve various functions. Several post-translational modifications (PTMs) were also observed, and the possibilities of changes in Mpro protein exhibit additional orders of peptidase function regulation. During heatmap development, the effect of a point mutation on the Mpro protein was seen. This protein's structural characterization will aid in a better understanding of its function and mechanism of action. Supplementary Information The online version contains supplementary material available at 10.1007/s42485-023-00105-9.

Exploration of Novel Lichen Compounds as Inhibitors of SARS-CoV-2 Mpro: Ligand-Based Design, Molecular Dynamics, and ADMET Analyses.

In the year 2019-2020, the whole world witnessed the spread of a disease called COVID-19 caused by SARS-CoV-2. A number of effective drugs and vaccine has been formulated to combat this outbreak. For the development of anti-COVID-19 drugs, the main protease (Mpro) is considered a key target as it has rare mutations and plays a crucial role in the replication of the SARS CoV-2. In this study, a library of selected lichen compounds was prepared and used for virtual screening against SARS-CoV-2 Mpro using molecular docking, and several hits as potential inhibitors were identified. Remdesivir was used as a standard inhibitor of Mpro for its comparison with the identified hits. Twenty-six compounds were identified as potential hits against Mpro, and these were subjected to in silico ADMET property prediction, and the compounds having favorable properties were selected for further analysis. After manual inspection of their interaction with the binding pocket of Mpro and binding affinity score, four compounds, namely, variolaric acid, cryptostictinolide, gyrophoric acid, and usnic acid, were selected for molecular dynamics study to evaluate the stability of complex. The molecular dynamics results indicated that except cryptostictinolide, all the three compounds made a stable complex with Mpro throughout a 100-ns simulation time period. Among all, usnic acid seems to be more stable and effective against SARS-CoV-2 Mpro. In summary, our findings suggest that usnic acid, variolaric acid, and gyrophoric acid have potential to inhibit SARS-Cov-2 Mpro and act as a lead compounds for the development of antiviral drug candidates against SARS-CoV-2.