Coronavirus belongs to the family of Coronaviridae, comprising single-stranded, positive-sense RNA genome (+ ssRNA) of around 26 to 32 kilobases, and has been known to cause infection to a myriad of mammalian hosts, such as humans, cats, bats, civets, dogs, and camels with varied consequences in terms of death and debilitation. Strikingly, novel coronavirus (2019-nCoV), later renamed as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), and found to be the causative agent of coronavirus disease-19 (COVID-19), shows 88% of sequence identity with bat-SL-CoVZC45 and bat-SL-CoVZXC21, 79% with SARS-CoV and 50% with MERS-CoV, respectively. Despite key amino acid residual variability, there is an incredible structural similarity between the receptor binding domain (RBD) of spike protein (S) of SARS-CoV-2 and SARS-CoV. During infection, spike protein of SARS-CoV-2 compared to SARS-CoV displays 10–20 times greater affinity for its cognate host cell receptor, angiotensin-converting enzyme 2 (ACE2), leading proteolytic cleavage of S protein by transmembrane protease serine 2 (TMPRSS2). Following cellular entry, the ORF-1a and ORF-1ab, located downstream to 5′ end of + ssRNA genome, undergo translation, thereby forming two large polyproteins, pp1a and pp1ab. These polyproteins, following protease-induced cleavage and molecular assembly, form functional viral RNA polymerase, also referred to as replicase. Thereafter, uninterrupted orchestrated replication-transcription molecular events lead to the synthesis of multiple nested sets of subgenomic mRNAs (sgRNAs), which are finally translated to several structural and accessory proteins participating in structure formation and various molecular functions of virus, respectively. These multiple structural proteins assemble and encapsulate genomic RNA (gRNA), resulting in numerous viral progenies, which eventually exit the host cell, and spread infection to rest of the body. In this review, we primarily focus on genomic organization, structural and non-structural protein components, and potential prospective molecular targets for development of therapeutic drugs, convalescent plasm therapy, and a myriad of potential vaccines to tackle SARS-CoV-2 infection.

Currently, there is no specific treatment to cure COVID-19. Many medicinal plants have antiviral, antioxidant, antibacterial, antifungal, anticancer, wound healing etc. Therefore, the aim of the current study was to screen for potent inhibitors of N-terminal domain (NTD) of nucleocapsid phosphoprotein of SARS-CoV-2. The structure of NTD of RNA binding domain of nucleocapsid phosphoprotein of SARS coronavirus 2 was retrieved from the Protein Data Bank (PDB 6VYO) and the structures of 100 different phytocompounds were retrieved from Pubchem. The receptor protein and ligands were prepared using Schrodinger’s Protein Preparation Wizard. Molecular docking was done by using the Schrodinger’s maestro 12.0 software. Drug likeness and toxicity of active phytocompounds was predicted by using Swiss adme, admetSAR and protox II online servers. Molecular dynamic simulation of the best three protein- ligand complexes (alizarin, aloe-emodin and anthrarufin) was performed to study the interaction stability. We have identified three potential active sites (named as A, B, C) on receptor protein for efficient binding of the phytocompounds. We found that, among 100 phytocompounds, emodin, aloe-emodin, anthrarufin, alizarine, and dantron of Rheum emodi showed good binding affinity at all the three active sites of RNA binding domain of nucleocapsid phosphoprotein of COVID-19.The binding energies of emodin, aloe-emodin, anthrarufin, alizarine, and dantron were −8.299, −8.508, −8.456, −8.441, and −8.322 Kcal mol⁻¹ respectively (site A), −7.714, −6.433, −6.354, −6.598, and −6.99 Kcal mol⁻¹ respectively (site B), and −8.299, 8.508, 8.538, 8.841, and 8.322 Kcal mol⁻¹ respectively (site C). All the active phytocompounds follows the drug likeness properties, non-carcinogenic, and non-toxic. Theses phytocompounds (alone or in combination) could be developed into effective therapy against COVID-19. From MD simulation data, we found that all three complexes of 6VYO with alizarin, aloe-emodin and anthrarufin were stable up to 50 ns. These phytocompounds can be tested further for in vitro or in vivo and used as a potential drug to cure SARS-CoV-2 infection. Communicated by Ramaswamy H. Sarma

The coronavirus disease-2019 caused by a novel SARS CoV-2 virus has emerged as a global threat. Still, no drugs are available for its treatment. The main protease is the most conserved structure responsible for the posttranslational processing of non-structural polyproteins of this virus. Therefore, it can be the potential target for drug discovery against SARS CoV-2. Twenty-one thousand two hundred and seven chemical compounds used for sequential virtual screening studies including coronavirus screening compounds (Life Chemical database) and antiviral compounds (Asinex database). The Schrodinger suite 2019 employed for high throughput screening, molecular docking and MM-GBSA through the Glide module. Subsequently, 23 compounds were selected in the phase first selection criteria for re-docking with AutoDock and iDock followed by ADMET prediction. The drug-likeness predicted through Lipinski’s rule of five, Veber’s rule and Muegge’s rule. Finally, three ligands were selected for molecular dynamics simulation studies over 150 ns against the main protease of the SARS CoV-2. They showed promising docking scores on Glide, iDock and AutoDock Vina algorithms (ligand F2679-0163: −10.75, −10.29 and −9.2; ligand F6355-0442: −9.38, −8.61 and −7.6; ligand 8250: −9.795, −7.94 and −7.5), respectively. The RMSD parameter remained stable at 2.5 Å for all the three ligands for 150 ns. The high RMSF fluctuations, RoG of around 22 Å and the binding free energy were favorable in each case. The hydrogen bond interactions of 8250, F6355-0442 and F2679-0163 were six, five and three, respectively. These compounds can be further explored for in vitro experimental validation against SARS-CoV-2. Communicated by Ramaswamy H. Sarma

Since the beginning of the coronavirus 19 (COVID-19) pandemic in late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been evolving through the acquisition of genomic mutations, leading to the emergence of multiple variants of concern (VOCs) and variants of interest (VOIs). Currently, four VOCs (Alpha, Beta, Delta, and Gamma) and seven VOIs (Epsilon, Zeta, Eta, Theta, Iota, Kappa, and Lambda) of SARS-CoV-2 have been identified in worldwide circulation. Here, we investigated the interactions of the receptor-binding domain (RBD) of five SARS-CoV-2 variants with the human angiotensin-converting enzyme 2 (hACE2) receptor in host cells, to determine the extent of molecular divergence and the impact of mutation, using protein-protein docking and dynamics simulation approaches. Along with the wild-type (WT) SARS-CoV-2, this study included the Brazilian (BR/lineage P.1/Gamma), Indian (IN/lineage B.1.617/Delta), South African (SA/lineage B.1.351/Beta), United Kingdom (UK/lineage B.1.1.7/Alpha), and United States (US/lineage B.1.429/Epsilon) variants. The protein-protein docking and dynamics simulation studies revealed that these point mutations considerably affected the structural behavior of the spike (S) protein compared to the WT, which also affected the binding of RBD with hACE2 at the respective sites. Additional experimental studies are required to determine whether these effects have an influence on drug–S protein binding and its potential therapeutic effect.

Zika virus (ZIKV), belongs to the flavivirus genus and Flaviviridae family that associated with serious diseased conditions like microcephaly and other neurological disorders (Guillan–Barré syndrome). As there is no vaccine or therapies available against ZIKV to date. Hence, it is an unmet need to find potential drug candidates and target sites against Zika virus infection. NS2B-NS3 protease making an attractive target for therapeutic intervention in ZIKV infections because of its critical role in hydrolysis of a single polyprotein encoded by Zika virus. Recently, there are some experimental evidence about the flavonoids as Zika virus NS2B-NS3 protease inhibitors. However, molecular interaction between protease complex and inhibitors at atomic levels has not been explored. Here, we have taken the experimentally validated thirty-eight flavonoids inhibitors against NS2B-NS3 protease to examine the molecular interaction using molecular docking and molecular dynamics simulations. We found out few flavonoids such as EGCG and its two derivatives, isoquercetin, rutin and sanggenon O showing interaction with catalytic triad (His51, Asp75, and Ser135) of the active site of NS2B-NS3 protease and found to be stable throughout the simulation. Therefore it is evident that interaction with the catalytic triad playing a vital role in the inhibition of the enzyme activity as a result inhibition of the virus propagation. However these compounds can be explored further for understanding the mechanism of action of these compounds targeting NS2B-NS3 protease for inhibition of Zika virus. Investigating into the Molecular Interactions of Flavonoids targeting NS2B-NS3 protease from ZIKA virus through in-silico approaches ZIKA virus protease (NS2B-NS3pro) is essential for ZIKA virus replication and maturation. Therefore targeting this protein complex with potential inhibitors will block the viral replication. Here we revealed the interaction of the flavonoids, a successful ZIKA NS2B-NS3pro inhibitors through Molecular modeling and Simulation studies. Communicated by Ramaswamy H. Sarma