In silico screening, ADMET analysis and MD simulations of phytochemicals of Onosma bracteata Wall. as SARS CoV-2 inhibitors.

Being attracted with their cardiotonic, antidiabetic, cough relieving activity, treatment of fever, absorbent, anti-asthmatic, etc. activities reported in ancient Ayurvedic literature, phytochemicals of Onosma bracteata wall should be evaluated for their activity against SARS-CoV-2 virus. The main objective of this study is to identify a hit molecule for the inhibition of entry, replication, and protein synthesis of SARS CoV-2 virus into the host. To achieve given objective, computational virtual screening of phytochemicals of Onosma bracteata wall has been performed against three main viral targets: spike, RdRp, and Mpro. Further, the analysis of Lipinski's Ro5 and their estimation of ADMET profiles were performed using computational tools. The MD simulations studies of top hits against each viral target have also been performed for 20 ns to ensure their stability. The analysis of results revealed that Pulmonarioside C (9) and other plant compounds showed better binding affinity towards targets than existing antiviral compounds, making them probable lead compounds against SARS-CoV-2. Structural modifications and studies through in silico analysis provided the founding stone for the establishment of SARS CoV-2 inhibitory potential of phytoconstitutents of Onosma bracteata wall.

DFT and MD investigations of the biomolecules of phenothiazine derivatives: interactions with gold and water molecules and investigations in search of effective drug for SARS-CoV-2.

Theoretical analyses of two phenothiazine derivatives, 10-[3-(dimethylamino)-2-methylpropyl]phenothiazine-2-carbonitrile (CYM) and 2-[4-[3-(2-chlorophenothiazin-10-yl)propyl]piperazin-1-yl]ethanol (PAZ) are reported using density functional theory (DFT) and molecular dynamics (MD) simulations. Spectroscopic studies, different electronic and chemical parameters are predicted. Red and yellow in electrostatic potential plot is in rings and oxygen atom in PAZ and C≡N and rings in CYM are sensitive to nucleophilic attacks. The blue in hydrogen atoms refer to electrophilic attack in both PAZ and CYM. Stability of the protein-ligand complex formed with these derivatives and angiotensin-converting enzyme 2 (ACE2) was investigated using MD simulation. Radius of gyration of C-alpha atom of 6VW1 displayed the conformational convergence toward a compact structure leading to stable 6VW1-ligand complex which are also in agreement with root mean square fluctuation (RMSF) values. Localized area predicts reactive sites for Au and H2O molecules interaction with these compounds for further practical applications. Charge density is localized on both molecules and also tries to move toward Au-Au dimer and water molecule and such they are expected to contribute to the sensing performance. Communicated by Ramaswamy H. Sarma.

Unbinding of hACE2 and inhibitors from the receptor binding domain of SARS-CoV-2 spike protein.

The first direful biomolecular event leading to COVID-19 disease is the SARS-CoV-2 virus surface spike (S) protein-mediated interaction with the human transmembrane protein, angiotensin-converting enzyme 2 (hACE2). Prevention of this interaction presents an attractive alternative to thwart SARS-CoV-2 replications. The development of monoclonal antibodies (mAbs) in the convalescent plasma treatment, nanobody, and designer peptides, which recognizes epitopes that overlap with hACE2 binding sites in the receptor-binding domain (RBD) of S protein (S/RBD) and thereby blocking the infection has been the center stage of therapeutic research. Here we report atomistic and reliable in silico structure-energetic features of the S/RBD interactions with hACE2 and its two inhibitors (convalescent mAb, B38, and an alpaca nanobody, Ty1). The discovered potential of mean forces exhibits free energy basin and barriers along the interaction pathways, providing sufficient molecular insights to design a B38 mutant and a Ty1-based peptide with higher binding capacity. While the mutated B38 forms a 60-fold deeper free energy minimum, the designer peptide (Ty1-based) constitutes 38 amino acids and is found to form a 100-fold deeper free energy minimum in the first binding basin than their wild-type variants in complex with S/RBD. Our strategy may help to design more efficacious biologics towards therapeutic intervention against the current raging pandemic.Communicated by Ramaswamy H. Sarma.

Synthesis and studies of new purines/pyrimidine derivatives as multi-targeted agents involving various receptor sites in the immune system.

Pro-inflammation, which is developed due to the increased production of cytokines, mainly interleukin-6 (IL-6), during the working of immune system pathways, becomes a major concern these days for many researchers. So, it is desired to design, screen, and synthesize new molecules with multi-parametric features showing their efficacy for Toll-like receptors (TLRs) and inhibiting the disease-causing receptor sites like viral infections, cancers, etc. along with controlling inflammation, fever, and other side effects during such pathways. Further, looking at the literature, curcumin a multi-targeted agent is showing its efficiency toward various receptor sites involved in many diseases as mentioned above. This fascinated us to build up new molecules which behave like curcumin with minimum side effects. In silico studies, involving ADMET studies, toxicological data, and docking analyses, of newly synthesized compounds (3-5) along with tautomers of curcumin i.e., (1-2), and some reported compounds like 9 and 10 have been studied in detail. Great emphasis has been made on analyzing binding energies, protein-ligand structural interactions, stabilization of newly synthesized molecules against various selected receptor sites using such computational tools. Compound 3 is the most efficient multifunctional agent, which has shown its potential toward most of the receptor sites in docking analysis. It has also responded well in Molecular dynamics (MD) simulation toward 5ZLN, 4RJ3, 4YO9, 4YOJ, and 1I1R sites. Finally, studies were extended to understand in vitro anti-inflammatory activity for particularly compound 3 in comparison to diclofenac and curcumin, which signifies the efficiency of compound 3.

Coating of favipiravir (FVP) on silver nanoparticles: First principle study

Silver nanoparticles, thanks to their antiviral and antibacterial properties, have great potential in a variety of applications, such as drug-delivery carriers. The coating properties of silver nanoparticles (size range of 1.6 nm) with a well-known drug, Favipirair, were investigated in this study using quantum mechanical and classical atomistic molecular dynamics simulation in order to use as the drug delivery to treat COVID-19 disease. The drug molecule's optimized structure, frequencies, charge distribution, and electrostatic potential maps were simulated using density functional theory (DFT) at the B3LYP/6–311++g(d,p) level of theory. The coating of AgNP with each of these drugs was then studied using molecular dynamics simulation. The interaction affinity obtained from MD results agrees with the DFT results on drug adsorption on the Ag(1 1 1) slab. © 2023

Many Roles of Carbohydrates: A Computational Spotlight on the Coronavirus S Protein Binding.

Glycosylation is one of the post-translational modifications with more than 50% of human proteins being glycosylated. The exact nature and chemical composition of glycans are inaccessible to X-ray or cryo-electron microscopy imaging techniques. Therefore, computational modeling studies and molecular dynamics must be used as a "computational microscope". The spike (S) protein of SARS-CoV-2 is heavily glycosylated, and a few glycans play a more functional role "beyond shielding". In this mini-review, we discuss computational investigations of the roles of specific S-protein and ACE2 glycans in the overall ACE2-S protein binding. We highlight different functions of specific glycans demonstrated in myriad computational models and simulations in the context of the SARS-CoV-2 virus binding to the receptor. We also discuss interactions between glycocalyx and the S protein, which may be utilized to design prophylactic polysaccharide-based therapeutics targeting the S protein. In addition, we underline the recent emergence of coronavirus variants and their impact on the S protein and its glycans.

Rutaretin1'-(6″-sinapoylglucoside): promising inhibitor of COVID 19 mpro catalytic dyad from the leaves of Pittosporum dasycaulon miq (Pittosporaceae).

SARS CoV2 is a novel strain of coronavirus, first reported in Wuhan of China, in 2019 and drugs specific to COVID-19 treatment are still lacking. The main protease (3CL) present in the new coronavirus strain is considered a potential drug target due to its role in viral replications. The plant Pittosporum dasycaulon Miq. is a medicinal plant reported to have prominent antimicrobial including antibacterial and antifungal activity. In this study, 12 natural compounds were selected on the basis of major peaks observed in the LC-HRMS analysis of P. dasycaulon aqueous leaves extract (AQLE). The pharmacological properties of the selected compounds against 3CLpro were investigated through in silico studies along with the standard antiviral drugs Lopinavir and Nelfinavir. The molecular docking study was done using Autodock 4.2 tool and visualized using Pymol (1.7.4.5 Edu). The docking analysis revealed that three compounds showed a better binding affinity than the standard drug Lopinavir. To validate the docking interactions, behaviour and stability of protein- ligand complex, molecular dynamics (100 ns) simulations were performed with the four best-ranked bioactive compounds identified through molecular docking analysis namely; Leptinidine, Rutaretin1'-(6″-sinapoylglucoside), Kalambroside A, and 5,7-dimethoxy', 4'methylenedioxyflavanone. The stability of the docking conformation was studied in depth by calculating the binding free energy using MM-PBSA method. Our findings on molecular docking, MD simulations and binding energy calculations suggest that Rutaretin1'-(6''-sinapoylglucoside) could be a potential inhibitor of COVID-19 3CLpro. However, considering the current pandemic situation of COVID-19, further research is required to experimentally validate their potential medicinal use against COVID-19 3CLpro both in vitro and in vivo along with clinical practices. Communicated by Ramaswamy H. Sarma.

Molecular dynamics simulation, 3D-pharmacophore and scaffold hopping analysis in the design of multi-target drugs to inhibit potential targets of COVID-19.

SARS-CoV-2 has posed serious threat to the health and has inflicted huge costs in the world. Discovering potent compounds is a critical step to inhibit coronavirus. 3CLpro and RdRp are the most conserved targets associated with COVID-19. In this study, three-dimensional pharmacophore modeling, scaffold hopping, molecular docking, structure-based virtual screening, QSAR-based ADMET predictions and molecular dynamics analysis were used to identify inhibitors for these targets. Binding free energies estimated by molecular docking for each ligand in different binding sites of RdRp were used to predict the active site. Previously reported active 3CLpro and RdRp inhibitors were used to build a pharmacophore model to develop different scaffolds. Structure-based simulations and pharmacophore modeling based on Hip Hop algorithm converged in a state that suggest hydrogen bond acceptor and donor features have a critical role in the two binding sites. Further validations indicated that the best pharmacophore model has fairly good correlation values compared with approved inhibitors. Structure-based simulation results approved that GLu166 and Gln189 in 3CLpro and Lys551 and Glu811 in RdRp, are critical residues for dual activities. Ten compounds were extracted from pharmacophore-based virtual screening in six databases. The results, gained by repurposing approach, suggest the effectiveness of these ten compounds with different scaffolds as possible inhibitors of the two targets. Some quinoline-based hybrid derivatives also were designed. QSAR descriptors plot predicted that the scaffolds have had accepted pharmacokinetic profiles. Multiple molecular dynamics simulations in 100 ns and MM/PBSA studies of some reference inhibitors and the novel compounds in complex with both targets demonstrated stable complexes and confirmed the interaction modes. Based on different computational methods, COVID-19 multi-target inhibitors are proposed.

Exploiting the co-crystal ligands shape, features and structure-based approaches for identification of SARS-CoV-2 Mpro inhibitors.

SARS-CoV-2 enters the host cell through the ACE2 receptor and replicates its genome using an RNA-Dependent RNA Polymerase (RDRP). The functional RDRP is released from pro-protein pp1ab by the proteolytic activity of Main protease (Mpro) which is encoded within the viral genome. Due to its vital role in proteolysis of viral polyprotein chains, it has become an attractive potential drug target. We employed a hierarchical virtual screening approach to identify small synthetic protease inhibitors. Statistically optimized molecular shape and color-based features (various functional groups) from co-crystal ligands were used to screen different databases through various scoring schemes. Then, the electrostatic complementarity of screened compounds was matched with the most active molecule to further reduce the hit molecules' size. Finally, five hundred eighty-seven molecules were docked in Mpro catalytic binding site, out of which 29 common best hits were selected based on Glide and FRED scores. Five best-fitting compounds in complex with Mpro were subjected to MD simulations to analyze their structural stability and binding affinities with Mpro using MM/GB(PB)SA models. Modeling results suggest that identified hits can act as the lead compounds for designing better active Mpro inhibitors to enhance the chemical space to combat COVID-19.Communicated by Ramaswamy H. Sarma.

Identifying Drug Candidates for COVID-19 with Large-Scale Drug Screening.

Papain-like protease (PLpro) is critical to COVID-19 infection. Therefore, it is a significant target protein for drug development. We virtually screened a 26,193 compound library against the PLpro of SARS-CoV-2 and identified several drug candidates with convincing binding affinities. The three best compounds all had better estimated binding energy than those of the drug candidates proposed in previous studies. By analyzing the docking results for the drug candidates identified in this and previous studies, we demonstrate that the critical interactions between the compounds and PLpro proposed by the computational approaches are consistent with those proposed by the biological experiments. In addition, the predicted binding energies of the compounds in the dataset showed a similar trend as their IC50 values. The predicted ADME and drug-likeness properties also suggested that these identified compounds can be used for COVID-19 treatment.

Accelerating the discovery of the beyond rule of five compounds that have high affinities toward SARS-CoV-2 spike RBD.

The battle against SARS-CoV-2 coronavirus is the focal point for the global pandemic that has affected millions of lives worldwide. The need for effective and selective therapeutics for the treatment of the disease caused by SARS-CoV-2 is critical. Herein, we performed a hierarchical computational approach incorporating molecular docking studies, molecular dynamics simulations, absolute binding energy calculations, and steered molecular dynamics simulations for the discovery of potential compounds with high affinity towards SARS-CoV-2 spike RBD. By leveraging ZINC15 database, a total of 1282 in-clinical and FDA approved drugs were filtered out from nearly 0.5 million protomers of relatively large compounds (MW > 500, and LogP ≤ 5). Our results depict plausible mechanistic aspects related to the blockage of SARS-CoV-2 spike RBD by the top hits discovered. We found that the most promising candidates, namely, ZINC95628821, ZINC95617623, ZINC3979524, and ZINC261494658, strongly bind to the spike RBD and interfere with the human ACE2 receptor. These findings accelerate the rational design of selective inhibitors targeting the spike RBD protein of SARS-CoV-2.Communicated by Ramaswamy H. Sarma.

In Silico Analysis of Bacteriocins from Lactic Acid Bacteria Against SARS-CoV-2.

The COVID-19 pandemic caused by a novel coronavirus (SARS-CoV-2) is a serious health concern in the twenty-first century for scientists, health workers, and all humans. The absence of specific biotherapeutics requires new strategies to prevent the spread and prophylaxis of the novel virus and its variants. The SARS-CoV-2 virus shows pathogenesis by entering the host cells via spike protein and Angiotensin-Converting Enzyme 2 receptor protein. Thus, the present study aims to compute the binding energies between a wide range of bacteriocins with receptor-binding domain (RBD) on spike proteins of wild type (WT) and beta variant (lineage B.1.351). Molecular docking analyses were performed to evaluate binding energies. Upon achieving the best bio-peptides with the highest docking scores, further molecular dynamics (MD) simulations were performed to validate the structure and interaction stability. Protein-protein docking of the chosen 22 biopeptides with WT-RBD showed docking scores lower than -7.9 kcal/mol. Pediocin PA-1 and salivaricin P showed the lowest (best) docking scores of - 12 kcal/mol. Pediocin PA-1, salivaricin B, and salivaricin P showed a remarkable increase in the double mutant's predicted binding affinity with -13.8 kcal/mol, -13.0 kcal/mol, and -12.5 kcal/mol, respectively. Also, a better predicted binding affinity of pediocin PA-1 and salivaricin B against triple mutant was observed compared to the WT. Thus, pediocin PA-1 binds stronger to mutants of the RBD, particularly to double and triple mutants. Salivaricin B showed a better predicted binding affinity towards triple mutant compared to WT, showing that it might be another bacteriocin with potential activity against the SARS-CoV-2 beta variant. Overall, pediocin PA-1, salivaricin P, and salivaricin B are the most promising candidates for inhibiting SARS-CoV-2 (including lineage B.1.351) entrance into the human cells. These bacteriocins derived from lactic acid bacteria hold promising potential for paving an alternative way for treatment and prophylaxis of WT and beta variants.

Reversal of the unique Q493R mutation increases the affinity of Omicron S1-RBD for ACE2.

The SARS-CoV-2 Omicron variant containing 15 mutations, including the unique Q493R, in the spike protein receptor binding domain (S1-RBD) is highly infectious. While comparison with previously reported mutations provide some insights, the mechanism underlying the increased infections and the impact of the reversal of the unique Q493R mutation seen in BA.4, BA.5, BA.2.75, BQ.1 and XBB lineages is not yet completely understood. Here, using structural modelling and molecular dynamics (MD) simulations, we show that the Omicron mutations increases the affinity of S1-RBD for ACE2, and a reversal of the unique Q493R mutation further increases the ACE2-S1-RBD affinity. Specifically, we performed all atom, explicit solvent MD simulations using a modelled structure of the Omicron S1-RBD-ACE2 and compared the trajectories with the WT complex revealing a substantial reduction in the Cα-atom fluctuation in the Omicron S1-RBD and increased hydrogen bond and other interactions. Residue level analysis revealed an alteration in the interaction between several residues including a switch in the interaction of ACE2 D38 from S1-RBD Y449 in the WT complex to the mutated R residue (Q493R) in Omicron complex. Importantly, simulations with Revertant (Omicron without the Q493R mutation) complex revealed further enhancement of the interaction between S1-RBD and ACE2. Thus, results presented here not only provide insights into the increased infectious potential of the Omicron variant but also a mechanistic basis for the reversal of the Q493R mutation seen in some Omicron lineages and will aid in understanding the impact of mutations in SARS-CoV-2 evolution.

Investigating the binding affinity of andrographolide against human SARS-CoV-2 spike receptor-binding domain through docking and molecular dynamics simulations.

SARS-CoV-2 is a positive-sense single-stranded RNA virus that causes a deadly coronavirus disease (COVID-19) in humans. The infection of SARS-CoV-2 in humans involves a viral surface spike glycoprotein containing the receptor-binding domain (RBD). The interactions of SARS-CoV-2 with the host angiotensin-converting enzyme 2 (ACE2) receptor are mediated by RBD. It binds to the host ACE2 and influences viral replication and disease pathogenesis. Therefore, targeting the RBD to prevent SARS-CoV-2 infections is of utmost importance. In this study, we used docking and molecular dynamics simulations to understand the binding effect of andrographolide on the SARS-CoV-2 spike protein. During docking, a strong binding affinity was observed between the ligand and the target receptor protein. MD results demonstrated higher conformational fluctuations in the ligand-free protein compared to the bound form. Several residues in the active sites make conformational rearrangements for the S protein to interact with the ligand. While RBD experiences conformational transition to gain more stability upon binding with the ligand. This binding is strengthened via several non-covalent interactions that make the complex structure more stable with higher binding affinity. Overall findings of the study may shed some valuable insights concerning the development of potential therapeutics in the strategies for COVID-19 prevention.

A benzimidazole scaffold as a promising inhibitor against SARS-CoV-2.

The manuscript reports the green-chemical synthesis of a new diindole-substituted benzimidazole compound, B1 through a straightforward route in coupling between indolyl-3-carboxaldehyde and o-phenylenediamine in water medium under the aerobic condition at 75 ºC. The single crystal X-ray structural analysis of B1 suggests that the disubstituted benzimidazole compound crystallizes in a monoclinic system and the indole groups exist in a perpendicular fashion with respect to benzimidazole moiety. The SARS-CoV-2 screening activity has been studied against 1 × 10e4 VeroE6 cells in a dose-dependent manner following Hoechst 33342 and nucleocapsid staining activity with respect to remdesivir. The compound exhibits 92.4% cell viability for 30 h and 35.1% inhibition against VeroE6 cells at non-cytotoxic concentration. Molecular docking studies predict high binding propensities of B1 with the main protease (Mpro) and non-structural (nsp2 and nsp7-nsp8) proteins of SARS-CoV-2 through a number of non-covalent interactions. Molecular dynamics (MD) simulation analysis for 100 ns confirms the formation of stable conformations of B1-docked proteins with significant changes of binding energy, attributing the potential inhibition properties of the synthetic benzimidazole scaffold against SARS-CoV-2.Communicated by Ramaswamy H. Sarma.

Defective ORF8 dimerization in SARS-CoV-2 delta variant leads to a better adaptive immune response due to abrogation of ORF8-MHC1 interaction.

In India, during the second wave of the COVID-19 pandemic, the breakthrough infections were mainly caused by the SARS-COV-2 delta variant (B.1.617.2). It was reported that, among majority of the infections due to the delta variant, only 9.8% percent cases required hospitalization, whereas only 0.4% fatality was observed. Sudden dropdown in COVID-19 infections cases were observed within a short timeframe, suggesting better host adaptation with evolved delta variant. Downregulation of host immune response against SARS-CoV-2 by ORF8 induced MHC-I degradation has been reported earlier. The Delta variant carried mutations (deletion) at Asp119 and Phe120 amino acids which are critical for ORF8 dimerization. The deletions of amino acids Asp119 and Phe120 in ORF8 of delta variant resulted in structural instability of ORF8 dimer caused by disruption of hydrogen bonds and salt bridges as revealed by structural analysis and MD simulation studies. Further, flexible docking of wild type and mutant ORF8 dimer revealed reduced interaction of mutant ORF8 dimer with MHC-I as compared to wild-type ORF8 dimer with MHC-1, thus implicating its possible role in MHC-I expression and host immune response against SARS-CoV-2. We thus propose that mutant ORF8 of SARS-CoV-2 delta variant may not be hindering the MHC-I expression thereby resulting in a better immune response against the SARS-CoV-2 delta variant, which partly explains the possible reason for sudden drop of SARS-CoV-2 infection rate in the second wave of SARS-CoV-2 predominated by delta variant in India.

A hypothesis on designing strategy of effective RdRp inhibitors for the treatment of SARS-CoV-2.

Vaccines are used as one of the major weapons for the eradication of pandemic. However, the rise of different variants of the SARS-CoV-2 virus is creating doubts regarding the end of the pandemic. Hence, there is an urgent need to develop more drug candidates which can be useful for the treatment of COVID-19. In the present research for the scientific hypothesis, emphasis was given on the direct antiviral therapy available for the treatment of COVID-19. In lieu of this, the available molecular targets which include Severe Acute Respiratory Syndrome Chymotrypsin-like Protease (SARS-3CLpro), Papain-Like Cysteine Protease (PLpro), and RNA-Dependent RNA Polymerase (RdRp) were explored. As per the current scientific reports and literature, among all the available molecular targets, RNA-Dependent RNA Polymerase (RdRp) was found to be a crucial molecular target for the treatment of COVID-19. Most of the inhibitors which are reported against this target consisted of the free amine group and carbonyl group which might be playing an important role in the binding interaction with the RdRp protein. Among all the reported RdRp inhibitors, remdesivir, favipiravir, and molnupiravir were found to be the most promising drugs against COVID-19. Overall, the structural features of this RNA-Dependent RNA Polymerase (RdRp) inhibitors proved the importance of pyrrolo-triazine and pyrimidine scaffolds. Previous computational models of these drug molecules indicated that substitution with the polar functional group, hydrogen bond donor, and electronegative atoms on these scaffolds may increase the activity against the RdRp protein. Hence, in line with the proposed hypothesis, in the present research work for the evaluation of the hypothesis, new molecules were designed from the pyrrolo-triazine and pyrimidine scaffolds. Further, molecular docking and MD simulation studies were performed with these designed molecules. All these designed molecules (DM-1, DM-2, and DM-3) showed the results as per the proposed hypothesis. Among all the designed molecules, DM-1 showed promising results against the RdRp protein of SARS-CoV-2. In the future, these structural features can be used for the development of new RdRp inhibitors with improved activity. Also, in the future lead compound DM-1 can be explored against the RdRp protein for the treatment of COVID-19.

Exploration of Potent Antiviral Phytomedicines from Lauraceae Family Plants against SARS-CoV-2 Main Protease.

A new Coronaviridae strain, Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), emerged from Wuhan city of China and caused one of the substantial global health calamities in December 2019. Even though several vaccines and drugs have been developed worldwide since COVID-19, a cost-effective drug with the least side effects is still unavailable. Currently, plant-derived compounds are mostly preferred to develop antiviral therapeutics due to its less toxicity, easy access, and cost-effective characteristics. Therefore, in this study, 124 phytochemical compounds from plants of Lauraceae family with medicinal properties were virtually screened against SARS-CoV-2 Mpro. Identification of four phytomolecules, i.e., cassameridine, laetanine, litseferine and cassythicine, with docking scores -9.3, -8.8, -8.6, and -8.6 kcal/mol, respectively, were undertaken by virtual screening, and molecular docking. Furthermore, the molecular dynamic simulation and essential dynamics analysis have contributed in understanding the stability and inhibitory effect of these selected compounds. These phytomolecules can be considered for further in vitro and in vivo experimental study to develop anti-SARS-CoV-2 therapeutics targeting the main protease (Mpro).

Computational screening of natural products to identify potential inhibitors for human neuropilin-1 (NRP1) receptor to abrogate the binding of SARS-CoV-2 and host cell.

Recently, a new variant B.1.1.529 or Omicron variant and its sub-variants (BA2.75, BA.5) of SARS-CoV-2 (Severe acute respiratory virus 2) have been reported with a larger number of mutations in the spike protein and particularly in the RBD (receptor-binding domain). The omicron (B.1.1.529) variant has aggravated the pandemic situation further and needs more analysis for therapeutic development. Keeping in view the urgency of the required data, the current study used molecular modeling and simulation-based methods to target the NRP1 (Neuropilin 1) protein to halt the entry into the host cell. Employing a molecular screening approach to screen the North-East African natural compounds database (NEANCDB) revealed Subereamine B with a docking score of -8.44 kcal/mol, Zinolol with the docking score of -8.05 while Subereamine A with a docking score of -7.88 kcal/mol as the best hits against NRP1. Molecular simulation-based further validation revealed stable dynamics, good structural packing, and dynamic residues flexibility index. Moreover, hydrogen bonding fraction analysis demonstrated the interactions remained sustained during the simulation. Furthermore, the total binding free energy for Subereamine B was -44.24 ±0.91 kcal/mol, for Zinolol -34.32 ±0.40 kcal/mol while for Subereamine A the TBE was calculated to be -41.78 ± 0.36 kcal/mol respectively. This shows that the two arginine-based alkaloids, i.e. Subereamine B and Subereamine A could inhibit the NRP1 more strongly than Zinolol. In conclusion, this study provides a basis for the development of novel drugs against SARS-CoV-2.Communicated by Ramaswamy H. Sarma.

Insights into the structural properties of SARS-CoV-2 main protease.

SARS-CoV-2 is the infectious agent responsible for the coronavirus disease since 2019, which is the viral pneumonia pandemic worldwide. The structural knowledge on SARS-CoV-2 is rather limited. These limitations are also applicable to one of the most attractive drug targets of SARS-CoV-2 proteins - namely, main protease Mpro, also known as 3C-like protease (3CLpro). This protein is crucial for the processing of the viral polyproteins and plays crucial roles in interfering viral replication and transcription. In fact, although the crystal structure of this protein with an inhibitor was solved, Mpro conformational dynamics in aqueous solution is usually studied by molecular dynamics simulations without special sampling techniques. We conducted replica exchange molecular dynamics simulations on Mpro in water and report the dynamic structures of Mpro in an aqueous environment including root mean square fluctuations, secondary structure properties, radius of gyration, and end-to-end distances, chemical shift values, intrinsic disorder characteristics of Mpro and its active sites with a set of computational tools. The active sites we found coincide with the currently known sites and include a new interface for interaction with a protein partner.