Targeting the RBD of Omicron Variant (B.1.1.529) with Medicinal Phytocompounds to Abrogate the Binding of Spike Glycoprotein with the hACE2 Using Computational Molecular Search and Simulation Approach.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus continues to inflict chaos globally. The emergence of a novel Omicron variant (B.1.1.529) in South Africa harbors 30 mutations in the spike protein. The variant is distinguished from other variants of concern (VOCs) with an increased (15) number of mutations in the receptor-binding domain (RBD) and suggests higher chances of causing reinfections. Initial reports also claimed that this variant escapes all the neutralizing antibodies, thus demanding a novel strategy against it. Thus, in this study, we performed a computational molecular screening against the RBD of the Omicron (B.1.1.529) variant and assessed the binding affinity of potent drugs against the RBD. The multi-steps screening of the South African Natural Compounds Database (SANCDB) revealed four medicinal compounds as excellent (potential) anti-viral agents against the Omicron variant, namely SANC00944, SANC01032, SANC00992, and SANC00317. The simulation analysis of these compounds in complex with the RBD demonstrated stable dynamics and structural compactness. Moreover, the residual flexibility analysis revealed that the flexibility of three loops required for interaction with hACE2 has been reduced by the binding of these drugs. The post-simulation validation of these compounds such as binding free energy, in silico bioactivity, and dissociation constant prediction validated the anti-viral potency of these compounds. The total binding free energy (TBFE) for the SANC01032-RBD complex was reported to be -46.54 kcal/mol; for the SANC01032-RBD complex, the TBFE was -41.88 kcal/mol; for the SANC00992-RBD complex the TBFE was -29.05 kcal/mol, while for the SANC00317-RBD complex the TBFE was -31.03 kcal/mol. The results showed the inhibition potential of these compounds by targeting the RBD. In conclusion, this study will help in the design and discovery of novel drug therapeutics, which may be used against the emerging Omicron variant of SARS-CoV-2.

Selection of SARS-CoV-2 main protease inhibitor using structure-based virtual screening.

Background: Conserved domains within SARS-CoV-2 nonstructural proteins represent key targets for the design of novel inhibitors. Methods: The authors aimed to identify potential SARS-CoV-2 NSP5 inhibitors using the ZINC database along with structure-based virtual screening and molecular dynamics simulation. Results: Of 13,840 compounds, 353 with robust docking scores were initially chosen, of which ten hit compounds were selected as candidates for detailed analyses. Three compounds were selected as coronavirus NSP5 inhibitors after passing absorption, distribution, metabolism, excretion and toxicity study; root and mean square deviation; and radius of gyration calculations. Conclusion: ZINC000049899562, ZINC000169336666 and ZINC000095542577 are potential NSP5 protease inhibitors that warrant further experimental studies.

Studying the effect of particulate matter as SARS-CoV-2 transmitters.

BACKGROUND: Studies of risk factors are especially valuable at this difficult time in the midst of a pandemic. High levels of particulate matter (PM) represent a serious risk factor on health. While this is a direct impact on health, indirect effects are worth considering, too. DESIGN AND METHODS: The aim of this study was to investigate the role of PM in the transmission of viruses, especially SARS-CoV-2. Also, we sought to understand dynamics of PM in still air at high and low altitudes. Historic AQI and physical PM measurements were collected between August and September 2020 using air quality detector. Potential correlations between the number of total confirmed COVID-19 cases and average air quality index (AQI) from varied geographic locations were also assessed. RESULTS: Airborne PM levels were weakly associated with COVID-19 cases after analysing 77 territories. PM remained longer in the air at high altitudes compared to measurements made at sea level. This suggests that the link between PM and COVID-19 transmission could be aggravated in areas of high altitude. CONCLUSIONS: This article highlights that particulate matter can be involved in SARS-CoV-2 transmission. However, confounding factors may have impacted the association between the two variables. These findings can serve as a foundation for future studies on the effect of air pollutants and fine particulate matter on viral transmission.

Blue Biotechnology: Computational Screening of Sarcophyton Cembranoid Diterpenes for SARS-CoV-2 Main Protease Inhibition.

The coronavirus pandemic has affected more than 150 million people, while over 3.25 million people have died from the coronavirus disease 2019 (COVID-19). As there are no established therapies for COVID-19 treatment, drugs that inhibit viral replication are a promising target; specifically, the main protease (Mpro) that process CoV-encoded polyproteins serves as an Achilles heel for assembly of replication-transcription machinery as well as down-stream viral replication. In the search for potential antiviral drugs that target Mpro, a series of cembranoid diterpenes from the biologically active soft-coral genus Sarcophyton have been examined as SARS-CoV-2 Mpro inhibitors. Over 360 metabolites from the genus were screened using molecular docking calculations. Promising diterpenes were further characterized by molecular dynamics (MD) simulations based on molecular mechanics-generalized Born surface area (MM-GBSA) binding energy calculations. According to in silico calculations, five cembranoid diterpenes manifested adequate binding affinities as Mpro inhibitors with ΔGbinding < -33.0 kcal/mol. Binding energy and structural analyses of the most potent Sarcophyton inhibitor, bislatumlide A (340), was compared to darunavir, an HIV protease inhibitor that has been recently subjected to clinical-trial as an anti-COVID-19 drug. In silico analysis indicates that 340 has a higher binding affinity against Mpro than darunavir with ΔGbinding values of -43.8 and -34.8 kcal/mol, respectively throughout 100 ns MD simulations. Drug-likeness calculations revealed robust bioavailability and protein-protein interactions were identified for 340; biochemical signaling genes included ACE, MAPK14 and ESR1 as identified based on a STRING database. Pathway enrichment analysis combined with reactome mining revealed that 340 has the capability to re-modulate the p38 MAPK pathway hijacked by SARS-CoV-2 and antagonize injurious effects. These findings justify further in vivo and in vitro testing of 340 as an antiviral agent against SARS-CoV-2.

Virtual Screening and Molecular Docking Studies for Discovery of Potential RNA-Dependent RNA Polymerase Inhibitors

The current COVID-19 pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Globally, this pandemic has affected over 111 million individuals and posed many health and economic challenges. Much research effort is dedicated to discovering new treatments to address the associated challenges and restrict the spread of SARS-CoV-2. Since SARS-CoV-2 is a positive-strand RNA virus, its replication requires the viral RNA-dependent RNA polymerase (RdRp) enzyme. In this study, we report the discovery of new potential RdRp enzyme inhibitors based on computer modeling and simulation methodologies. The antiviral ZINC database was utilized for covalent docking virtual screening followed by molecular interaction analyses based on reported hot spots within the RdRp binding pocket (PDB: 7BV2). Eleven molecules, ZINC000014944915, ZINC000027556215, ZINC000013556344, ZINC000003589958, ZINC000003833965, ZINC000001642252, ZINC000028525778, ZINC000027557701, ZINC000013781295, ZINC000001651128 and ZINC000013473324, were shown to have the highest binding interactions. These molecules were further assessed by molecular dynamics (MD) simulations and absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies. The results showed that all 11 molecules except ZINC000027557701 formed stable complexes with the viral RdRp and fell within the accepted ADMET parameters. The identified molecules can be used to design future potential RdRp inhibitors.