Plant-derived active compounds as a potential nucleocapsid protein inhibitor of SARS-CoV-2: an in-silico study.

The coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2. This virus has a high mismatch repair proofreading ability due to its unique exonuclease activity, making it knotty to treat. The nucleocapsid protein can serve as a potential antiviral drug target, as this protein is responsible for multiple captious functions during the viral life cycle. Herein, we have investigated the potential to repurpose active antiviral compounds of plant origins for treating the SARS-CoV-2 infection. In the present study, we followed the molecular docking methodology to screen druggable natural plants' active compounds against the nucleocapsid protein of SARS-CoV-2. The virtual screening of all 68 compounds revealed that the top seven active compounds, such as withanolide D, hypericin, silymarin, oxyacanthine, withaferin A, Acetyl aleuritolic acid, and rhein, exhibit good binding affinity with druggable ADME properties, toxicity, and Pass prediction. The stability of the docked complexes was studied by conducting molecular simulations of 100 ns. MM-GBSA calculated the binding free energy uncovered that withanolide D, hypericin, and silymarin result in highly stable binding conformations in three different sites of the nucleocapsid protein. However, further investigation is needed in order to validate the candidacy of these inhibitors for clinical trials. HighlightsNatural plants' active compounds may aid in the inhibition of SARS-CoV-2 replication and COVID-19 therapeutics.Hypericin, silymarin, withanolide D, oxyacanthine, withaferin A, Acetyl aleuritolic acid, and rhein are effective against SARS-CoV-2 N protein.Studied natural plants' active compounds could be useful against COVID-19 and its associated organs comorbidities.ADMET properties of selected compounds favor these compounds as druggable candidates.Communicated by Ramaswamy H. Sarma.

Identification of FDA-approved drugs against SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) through computational virtual screening.

The SARS-CoV-2 coronavirus is responsible for the COVID-19 outbreak, which overwhelmed millions of people worldwide; hence, there is an urgency to identify appropriate antiviral drugs. This study focuses on screening compounds that inhibit RNA-dependent RNA-polymerase (RdRp) essential for RNA synthesis required for replication of positive-strand RNA viruses. Computational screening against RdRp using Food and Drug Administration (FDA)-approved drugs identified ten prominent compounds with binding energies of more than - 10.00 kcal/mol, each a potential inhibitor of RdRp. These compounds' binding energy is comparable to known RdRp inhibitors remdesivir (IC50 = 10.09 µM, SI = 4.96) and molnupiravir (EC50 = 0.67 - 2.66 µM) and 0.32-2.03 µM). Remdesivir and molnupiravir have been tested in clinical trial and remain authorized for emergency use in the treatment of COVID-19. In docking simulations, selected compounds are bound to the substrate-binding pocket of RdRp and showed hydrophobic and hydrogen bond interaction. For molecular dynamics simulation, capmatinib, pralsetinib, ponatinib, and tedizolid phosphate were selected from the initial ten candidate compounds. MD simulation indicated that these compounds are stable at 50-ns MD simulation when bound to RdRp protein. The screen hit compounds, remdesivir, molnupiravir, and GS-441524, are bound in the substrate binding pocket with good binding-free energy. As a consequence, capmatinib, pralsetinib, ponatinib, and tedizolid phosphate are potential new inhibitors of RdRp protein with potential of limiting COVID-19 infection by blocking RNA synthesis. Supplementary Information: The online version contains supplementary material available at 10.1007/s11224-022-02072-1.

Computational Drug Designing, Synthesis, Characterization and Anti-bacterial Activity Evaluation of Some Mixed Ligand–Metal Complexes of 2-hydroxybenzaldehydethiosemicarbazone as Primary Ligand

This paper reports the mixed ligand–metal complexes of CuSO4·5H2O and ZnSO4·7H2O with salicylaldehyde thiosemicarbazone (2-hydroxybenzaldehyde thiosemicarbazone) as primary ligand and imidazole (im), pyridine (py) and triphenylphosphine (PPh3) as secondary ligands through a general preparatory route. The ligand and complexes were characterized by FTIR, UV, 1H-NMR and molar conductance techniques. Computational studies to know the physicochemical parameters, bioactivity scores, absorption, distribution, metabolism, excretion and toxicity (ADMET) properties were carried out through Molinspiration, SwissADME and admetSAR softwares. Molecular docking was perfomed with Mproof SARS-CoV-2 (PDB i.d.6LU7), Aspartate Kinase (PDB i.d.5YEI) and Transforming Growth Factor β (PDB i.d. 3KFD) using PyRx automated docking software. The antibacterial activity was tested using Agar well method. Computational findings revealed that almost all the complexes had clogP values less than 5 indicating their bioavailability. The bioactivity scores of the complexes were between moderate to good. The mixed ligand complexes having imidazole as secondary ligand displayed relatively high FCsp3, indicating their potential as lead candidates. [Zn(C8H9N3OS)(PPh3)2(SO4)] and [Cu(C8H9N3OS)(im)2(SO4)] exhibited appreciable binding affinity against the selected proteins. Furthermore, the molecular simulation findings with the ligated [Cu(C8H9N3OS)(im)2(SO4)] and aspartate kinase showed compact folding, less deviations and significant stability. The stability of the ligand was further confirmed by the frontier molecular orbitals (FMOs) gap. The energy gap (− 0.423 eV) indicated molecular stability. The ligand was active against L. monocytogenes, S. aureus and E.coli having zone of inhibition of 11, 11 and 10 mm respectively. Among the complexes, [Cu(C8H9N3OS)(im)2(SO4)] had the minimum inhibitory concentrations (MIC) ranging between 32 and 128 µg/mL against the selecetd bacterial strains. Graphical : [Figure not available: see fulltext.] © 2023, The Tunisian Chemical Society and Springer Nature Switzerland AG.

Structural insights into the effect of mutations in the spike protein of SARS-CoV-2 on the binding with human furin protein.

The SARS COV-2 and its variants are spreading around the world at an alarming speed, due to its higher transmissibility and the conformational changes caused by mutations. The resulting COVID-19 pandemic has imposed severe health consequences on human health. Several countries of the world including Pakistan have studied its genome extensively and provided productive findings. In the current study, the mCSM, DynaMut2, and I-Mutant servers were used to analyze the effect of identified mutations on the structural stability of spike protein however, the molecular docking and simulations approaches were used to evaluate the dynamics of the bonding network between the wild-type and mutant spike proteins with furin. We addressed the mutational modifications that have occurred in the spike protein of SARS-COV-2 that were found in 215 Pakistani's isolates of COVID-19 patients to study the influence of mutations on the stability of the protein and its interaction with the host cell. We found 7 single amino acid substitute mutations in various domains that reside in spike protein. The H49Y, N74K, G181V, and G446V were found in the S1 domain while the D614A, V622F, and Q677H mutations were found in the central helices of the spike protein. Based on the observation, G181V, G446V, D614A, and V622F mutants were found highly destabilizing and responsible for structural perturbation. Protein-protein docking and molecular simulation analysis with that of furin have predicted that all the mutants enhanced the binding efficiency however, the V622F mutant has greatly altered the binding capacity which is further verified by the KD value (7.1 E-14) and therefore may enhance the spike protein cleavage by Furin and increase the rate of infectivity by SARS-CoV-2. On the other hand, the total binding energy for each complex was calculated which revealed -50.57 kcal/mol for the wild type, for G181V -52.69 kcal/mol, for G446V -56.44 kcal/mol, for D614A -59.78 kcal/mol while for V622F the TBE was calculated to be -85.84 kcal/mol. Overall, the current finding shows that these mutations have increased the binding of Furin for spike protein and shows that D614A and V622F have significant effects on the binding and infectivity.

Repurposing immune boosting and anti-viral efficacy of Parkia bioactive entities as multi-target directed therapeutic approach for SARS-CoV-2: exploration of lead drugs by drug likeness, molecular docking and molecular dynamics simulation methods.

The COVID-19 pandemic has caused adverse health (severe respiratory, enteric and systemic infections) and environmental impacts that have threatened public health and the economy worldwide. Drug repurposing and small molecule multi-target directed herbal medicine therapeutic approaches are the most appropriate exploration strategies for SARS-CoV-2 drug discovery. This study identified potential multi-target-directed Parkia bioactive entities against SARS-CoV-2 receptors (S-protein, ACE2, TMPRSS2, RBD/ACE2, RdRp, MPro, and PLPro) using ADMET, drug-likeness, molecular docking (AutoDock, FireDock and HDOCK), molecular dynamics simulation and MM-PBSA tools. One thousand Parkia bioactive entities were screened out by virtual screening and forty-five bioactive phytomolecules were selected based on favorable binding affinity and acceptable pharmacokinetic and pharmacodynamics properties. The binding affinity values of Parkia phyto-ligands (AutoDock: -6.00--10.40 kcal/mol; FireDock: -31.00--62.02 kcal/mol; and HDOCK: -150.0--294.93 kcal/mol) were observed to be higher than the reference antiviral drugs (AutoDock: -5.90--9.10 kcal/mol; FireDock: -35.64--59.35 kcal/mol; and HDOCK: -132.82--211.87 kcal/mol), suggesting a potent modulatory action of Parkia bioactive entities against the SARS-CoV-2. Didymin, rutin, epigallocatechin gallate, epicatechin-3-0-gallate, hyperin, ursolic acid, lupeol, stigmasta-5,24(28)-diene-3-ol, ellagic acid, apigenin, stigmasterol, and campesterol strongly bound with the multiple targets of the SARS-CoV-2 receptors, inhibiting viral entry, attachment, binding, replication, transcription, maturation, packaging and spread. Furthermore, ACE2, TMPRSS2, and MPro receptors possess significant molecular dynamic properties, including stability, compactness, flexibility and total binding energy. Residues GLU-589, and LEU-95 of ACE2, GLN-350, HIS-186, and ASP-257 of TMPRSS2, and GLU-14, MET-49, and GLN-189 of MPro receptors contributed to the formation of hydrogen bonds and binding interactions, playing vital roles in inhibiting the activity of the receptors. Promising results were achieved by developing multi-targeted antiviral Parkia bioactive entities as lead and prospective candidates under a small molecule strategy against SARS-CoV-2 pathogenesis. The antiviral activity of Parkia bioactive entities needs to be further validated by pre-clinical and clinical trials.

In Silico molecular docking and dynamic analysis of natural compounds against major non-structural proteins of SARS-COV-2.

COVID-19 has infected millions and significantly affected the global economy and healthcare systems. Despite continuous lockdowns, symptomatic management with currently available medications, and numerous vaccination drives, it is still far more difficult to control. Against COVID-19 infection, the pressure to develop vaccines and drugs has led to using some currently available medications like remdesivir, azithromycin, hydroxychloroquine and ritonavir. Understanding the importance and potential of harmless molecules to tackle SARS-COV-2, we designed the present study to identify potential natural phytocompounds. In the present study, we docked natural compounds and standard drugs against SARS-COV-2 proteins: papain-like protease, main protease and helicase. ADME/T and ProTox-II analyses were used to determine the toxicity of phytocompounds and drugs. The docking analysis revealed that podophyllotoxin gave the highest binding affinity scores of -8.1, -7.1 and -7.4 kcal/mol against PLpro, Mpro and helicase, respectively. Among the control drugs, doxycycline hydrochloride showed the highest binding affinity of -10.5, -8.4 and -8.8 kcal/mol against PLpro, Mpro and helicase. The results of this study revealed that podophyllotoxin and doxycycline hydrochloride could be promising inhibitors against SARS-Cov-2. Molecular dynamic simulations were executed for the best docked (PLpro-podophyllotoxin) complex, and the results displayed stable conformation and convergence. Energy plot results predicted a global minima average energy of -95 kcal/mol and indicated podophyllotoxin's role in stabilizing protein and making it compact and complex. FarPPI server used MM/GBSA approach to determine free binding affinity, and helicase-gallic acid complex showed the highest affinity, respectively. Therefore, it can be concluded that there is still a need for in vitro and in vivo studies to support further and validate these findings and validate these findings.Communicated by Ramaswamy H. Sarma.

Pollution caused by nanoplastics: adverse effects and mechanisms of interaction via molecular simulation.

The continuous increase in the production of synthetic plastics for decades and the inadequate disposal of plastic waste have resulted in a considerable increase of these materials in aquatic environments, which has developed into a major environmental concern. In addition to conventional parameters, the relevance of the environmental monitoring of microplastics (MPs) and nanoplastics (NPs) has been highlighted by the scientific community due to the potential adverse effects these materials pose to the ecosystem as well as to human health. The literature has registered an increasing interest in understanding the mechanisms, at the molecular level, of the interaction between NPs and other compounds using molecular simulation techniques. The present review aims to: (i) summarize the force fields conventionally used to describe NPs by molecular simulations; (ii) discuss the effects of NPs in the structural and dynamical properties of biological membranes; (iii) evaluate how NPs affect the folding of proteins; (iv) discuss the mechanisms by which NPs adsorb contaminants from the environment. NPs can affect the secondary structure of proteins and change the lateral organization and diffusion of lipid membranes. As a result, they may alter the lipid digestion in the gastrointestinal system representing a risk to the assimilation of the nutrients by humans. The adsorption of contaminants on MPs and NPs can potentiate their harmful effects on human health, due to a possible synergism. Therefore, understanding the mechanisms involved in these interactions is crucial to predict dangerous combinations and outline action strategies that reduce negative impacts on ecosystems and human health. Depending on the chemical properties of contaminants and NPs, electrostatic and/or van der Waals interactions can be more relevant in explaining the adsorption process. Finally, we conclude by highlighting gaps in the literature and the critical aspects for future investigations.

Propolis efficacy on SARS-COV viruses: a review on antimicrobial activities and molecular simulations.

This current study review provides a brief review of a natural bee product known as propolis and its relevance toward combating SARS-CoV viruses. Propolis has been utilized in medicinal products for centuries due to its excellent biological properties. These include anti-oxidant, immunomodulatory, anti-inflammatory, anti-viral, anti-fungal, and bactericidal activities. Furthermore, studies on molecular simulations show that flavonoids in propolis may reduce viral replication. While further research is needed to validate this theory, it has been observed that COVID-19 patients receiving propolis show earlier viral clearance, enhanced symptom recovery, quicker discharge from hospitals, and a reduced mortality rate relative to other patients. As a result, it appears that propolis could probably be useful in the treatment of SARS-CoV-2-infected patients. Therefore, this review sought to explore the natural properties of propolis and further evaluated past studies that investigated propolis as an alternative product for the treatment of COVID-19 symptoms. In addition, the review also highlights the possible mode of propolis action as well as molecular simulations of propolis compounds that may interact with the SARS-CoV-2 virus. The activity of propolis compounds in decreasing the impact of COVID-19-related comorbidities, the possible roles of such compounds as COVID-19 vaccine adjuvants, and the use of nutraceuticals in COVID-19 treatment, instead of pharmaceuticals, has also been discussed.

Exploring the Potential of Chromones as Inhibitors of Novel Coronavirus Infection Based on Molecular Docking and Molecular Dynamics Simulation Studies

The COVID-19 has been declared a global pandemic by the WHO. There are no approved drugs to treat the disease in the present scenario, by which there is an urgent need for best-suited antiviral therapy against COVID-19. Natural compounds (Chromone) have a significant effect on treating COVID-19 and other diseases. Chromone compounds can be used as an adjunctive treatment for SARS‐CoV‐2 infection. Herein, we have applied a bioinformatics approach to check out the lead molecule's binding capabilities to that of H-Bonding with THE 638 and TYR 612, PI Bonding with VAL622 VAL 610 and PRO 295, that interact with specifically defined residues in substrate binding cavity. Further, molecular simulation studies have been performed that revealed that the ligand's binding made the substrate more fluctuating and dynamic. The study affirms that the Chromone may serve as an effective tool to fight COVID-19 disease having promising binding activities. © 2022 by the authors.

Optimizing peptide inhibitors of SARS-Cov-2 nsp10/nsp16 methyltransferase predicted through molecular simulation and machine learning.

Coronaviruses, including the recent pandemic strain SARS-Cov-2, use a multifunctional 2'-O-methyltransferase (2'-O-MTase) to restrict the host defense mechanism and to methylate RNA. The nonstructural protein 16 2'-O-MTase (nsp16) becomes active when nonstructural protein 10 (nsp10) and nsp16 interact. Novel peptide drugs have shown promise in the treatment of numerous diseases and new research has established that nsp10 derived peptides can disrupt viral methyltransferase activity via interaction of nsp16. This study had the goal of optimizing new analogous nsp10 peptides that have the ability to bind nsp16 with equal to or higher affinity than those naturally occurring. The following research demonstrates that in silico molecular simulations can shed light on peptide structures and predict the potential of new peptides to interrupt methyltransferase activity via the nsp10/nsp16 interface. The simulations suggest that misalignments at residues F68, H80, I81, D94, and Y96 or rotation at H80 abrogate MTase function. We develop a new set of peptides based on conserved regions of the nsp10 protein in the Coronaviridae species and test these to known MTase variant values. This results in the prediction that the H80R variant is a solid new candidate for potential new testing. We envision that this new lead is the beginning of a reputable foundation of a new computational method that combats coronaviruses and that is beneficial for new peptide drug development.

Active site prediction of phosphorylated SARS-CoV-2 N-Protein using molecular simulation.

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) nucleocapsid protein (N-protein) is responsible for viral replication by assisting in viral RNA synthesis and attaching the viral genome to the replicase-transcriptase complex (RTC). Numerous studies suggested the N-protein as a drug target. However, the specific N-protein active sites for SARS-CoV-2 drug treatments are yet to be discovered. The purpose of this study was to determine active sites of the SARS-CoV-2 N-protein by identifying torsion angle classifiers for N-protein structural changes that correlated with the respective angle differences between the active and inactive N-protein. In the study, classifiers with a minimum accuracy of 80% determined from molecular simulation data were analyzed by Principal Component Analysis and cross-validated by Logistic Regression, Support Vector Machine, and Random Forest Classification. The ability of torsion angles ψ252 and φ375 to differentiate between phosphorylated and unphosphorylated structures suggested that residues 252 and 375 in the RNA binding domain might be important in N-protein activation. Furthermore, the φ and ψ angles of residue S189 correlated to a 90.7% structural determination accuracy. The key residues involved in the structural changes identified here might suggest possible important functional sites on the N-protein that could be the focus of further study to understand their potential as drug targets.

Discovery of a Natural Product with Potent Efficacy Against SARS-CoV-2 by Drug Screening.

The novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide for almost 2 years. It starts from viral adherence to host cells through an interaction between spike glycoprotein 1 (S1) containing a receptor-binding domain (RBD) and human angiotensin-converting enzyme-2 (ACE2). One of the useful strategies to prevent SARS-CoV-2 infection is to inhibit the attachment of RBD to ACE2. Therefore, the current work proposed potent peptides against SARS-CoV-2 infection by carrying out MM-PBSA calculation based on the binding of 52 antiviral peptides (AVPs) to RBD. Considering the binding free energies of AVPs to RBD, cyanovirin-N (CV-N) showed the strongest RBD binding affinity among 52 AVPs. Upon structural analysis of RBD complex with CV-N, it was observed that 12 of the 13 key residues of RBD binding to ACE2 were hijacked by CV-N. CV-N bound to RBD at a smaller affinity of 14.9 nM than that of ACE2 and inhibited the recruitment of S1 to human alveolar epithelial cells. Further analysis revealed that CV-N suppressed SARS-CoV-2 S pseudovirion infection with a half-maximal inhibitory concentration (IC50) of 18.52 µg/mL. This study demonstrated a drug screening for AVPs against SARS-CoV-2 and discovered a peptide with inspiring antiviral properties, which provided a promising strategy for the COVID-19 therapeutic approach.

HD5 and LL-37 Inhibit SARS-CoV and SARS-CoV-2 Binding to Human ACE2 by Molecular Simulation.

The coronavirus (COVID-19) pandemic is still spreading all over the world. As reported, angiotensin-converting enzyme-2 (ACE2) is a receptor of SARS-CoV-2 spike protein that initializes viral entry into host cells. Previously, the human defensin 5 (HD5) has been experimentally confirmed to be functional against the SARS-CoV-2. The present study proposes a human cathelicidin known as LL37 that strongly binds to the carboxypeptidase domain of human ACE2 compared to HD5. Therefore, LL37 bears a great potential to be tested as an anti-SARS-CoVD-2 peptide. We investigated the molecular interactions formed between the LL37 and ACE2 as well as HD5 and ACE2 tailed by their thermodynamic stability. The MM-PBSA and free energy landscape analysis outcomes confirmed its possible inhibitory effect against the SARS-CoV-2. The results obtained here could help propose a promising therapeutic strategy against the havoc caused by SARS-CoV-2 infections.

Potential inhibitors of the main protease of SARS-CoV-2 and modulators of arachidonic acid pathway: Non-steroidal anti-inflammatory drugs against COVID-19.

The main protease of SARS-CoV-2 is one of the key targets to develop and design antiviral drugs. There is no general agreement on the use of non-steroidal anti-inflammatory drugs (NSAIDs) in COVID-19. In this study, we investigated NSAIDs as potential inhibitors for chymotrypsin-like protease (3CLpro) and the main protease of the SARS-CoV-2 to find out the best candidates, which can act as potent inhibitors against the main protease. We also predicted the effect of NSAIDs on the arachidonic pathway and evaluated the hepatotoxicity of the compounds using systems biology techniques. Molecular docking was conducted via AutoDock Vina to estimate the interactions and binding affinities between selected NSAIDs and the main protease. Molecular docking results showed the presence of 10 NSAIDs based on lower binding energy (kcal/mol) toward the 3CLpro inhibition site compared to the co-crystal native ligand Inhibitor N3 (-6.6 kcal/mol). To validate the docking results, molecular dynamic (MD) simulations on the top inhibitor, Talniflumate, were performed. To obtain differentially-expressed genes under the 27 NSAIDs perturbations, we utilized the L1000 final Z-scores from the NCBI GEO repository (GSE92742). The obtained dataset included gene expression profiling signatures for 27 NSAIDs. The hepatotoxicity of NSAIDs was studied by systems biology modeling of Disturbed Metabolic Pathways. This study highlights the new application of NSAIDs as anti-viral drugs used against COVID-19. NSAIDs may also attenuate the cytokine storm through the downregulation of inflammatory mediators in the arachidonic acid pathway.

A potential antiviral activity of Esculentoside A against binding interactions of SARS-COV-2 spike protein and angiotensin converting enzyme 2 (ACE2).

The recent emergence of the novel coronavirus (SARS-CoV-2) has resulted in a devastating pandemic with global concern. However, to date, there are no regimens to prevent and treat SARS-CoV-2 virus. There is an urgent need to identify novel leads with anti-viral properties that impede viral pathogenesis in the host system. Esculentoside A (EsA), a saponin isolated from the root of Phytolacca esculenta, is known to exhibit diverse pharmacological properties, especially anti-inflammatory activity. To our knowledge, SARS-CoV-2 uses angiotensin converting enzyme 2 (ACE2) to enter host cells. This is mediated through the proteins of SARS-CoV-2, especially the spike glycoprotein receptor binding domain. Thus, our primary goal is to prevent virus replication and binding to the host, which allows us to explore the efficiency of EsA on key surface drug target proteins using the computational biology paradigm approach. Here, the anti-coronavirus activity of EsA in vitro and its potential mode of inhibitory action on the S-protein of SARS-CoV-2 were investigated. We found that EsA inhibited the HCoV-OC43 coronavirus during the attachment and penetration stage. Molecular docking results showed that EsA had a strong binding affinity with the spike glycoprotein from SARS-CoV-2. The results of the molecular dynamics simulation revealed that EsA had higher stable binding with the spike protein. These results demonstrated that Esculentoside A can act as a spike protein blocker to inhibit SARS-CoV-2. Considering the poor bioavailability and low toxicity of EsA, it is suitable as novel lead for the inhibitor against binding interactions of SARS-CoV-2 of S-protein and ACE2.

Molecular simulation studies of the interactions between the human/pangolin/cat/bat ACE2 and the receptor binding domain of the SARS-CoV-2 spike protein.

The recent outbreak of SARS-CoV-2 has had a profound effect on the world. Similar to that in SARS-CoV, the entry receptor of SARS-CoV-2 is ACE2. The binding of SARS-CoV-2 spike protein to ACE2 is the critical to the virus infection. Recently multiple species (human, Chinese chrysanthemum, Malay pangolin and cat) have been reported to be susceptible to the virus infection. However, the binding capacity and the detailed binding mechanism of SARS-CoV-2 spike protein to ACE2 of these species remains unexplored. Herein free energy calculations with MM-GBSA and Potential of Mean Forces together reveal that the Human-SARS-CoV-2 has a higher stability tendency than Human-SARS-CoV. Meanwhile, we uncover that SARS-CoV-2 has an enhanced ability to bind with the ACE2 in humans, pangolins and cats compared to that in bats. Analysis of key residues with energy decomposition and residue contact maps reveal several important consensus sites in ACE2s among the studied species, and determined the more favorable specified residues among the different types of amino acids. These results provide important implications for understanding SARS-CoV-2 host range which will make it possible to control the spread of the virus and use of animal models, targeted drug screening and vaccine candidates against SARS-CoV-2.

Proposal of novel natural inhibitors of severe acute respiratory syndrome coronavirus 2 main protease: Molecular docking and ab initio fragment molecular orbital calculations.

This paper proposes natural drug candidate compounds for the treatment of coronavirus disease 2019 (COVID-19). We investigated the binding properties between the compounds in the Moringa oleifera plant and the main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 using molecular docking and ab initio fragment molecular orbital calculations. Among the 12 compounds, niaziminin was found to bind the strongest to Mpro. We furthermore proposed novel compounds based on niaziminin and investigated their binding properties to Mpro. The results reveal that the introduction of a hydroxyl group into niaziminin enhances its binding affinity to Mpro. These niaziminin derivatives can be promising candidate drugs for the treatment of COVID-19.

Computational exploration of natural peptides targeting ACE2.

Interaction between the SARS-COV-2 (2019 novel coronavirus) spike protein and ACE2 receptors expressed on cellular surfaces initialises viral attachment and consequent infection. Blocking this interaction shows promise for blocking or ameliorating the virus' pathological effects on the body. By contrast to work focusing on the coronavirus, which has significant potential diversity through possible accumulation of mutations during transmission, targeting the conserved ACE2 protein expressed on human cells offers an attractive alternative route to developing pharmacological prophylactics against viral invasion. In this study, we screened a virtual database of natural peptides in silico, with ACE2 as the target, and performed structural analyses of the interface region in the SARS-COV-2 RBD/ACE2 complex. These analyses have identified 15 potentially effective compounds. Analyses of ACE2/polypeptide interactions suggest that these peptides can block viral invasion of cells by stably binding in the ACE2 active site pocket. Molecular simulation results for Complestatin and Valinomycin indicate that they may share this mechanism. The discovery of this probable binding mechanism provides a frame of reference for further optimization, and design of high affinity ACE2 inhibitors that could serve as leads for production of drugs with preventive and therapeutic effects against SARS-COV-2. Communicated by Ramaswamy H. Sarma.

In silico inquest reveals the efficacy of Cannabis in the treatment of post-Covid-19 related neurodegeneration.

Coronavirus (SARS-CoV-2), the causative agent of the Covid-19 pandemic has proved itself as the deadliest pathogen. A major portion of the population has become susceptible to this strain. Scientists are pushing their limits to formulate a vaccine against Covid-19 with the least side effects. Although the recent discoveries of vaccines have shown some relief from the covid infection rate, however, physical fatigue, mental abnormalities, inflammation and other multiple organ damages are arising as post-Covid symptoms. The long-term effects of these symptoms are massive. Patients with such symptoms are known as long-haulers and treatment strategy against this condition is still unknown. In this study, we tried to explore a strategy to deal with the post-Covid symptoms. We targeted three human proteins namely ACE2, Interleukin-6, Transmembrane serine protease and NRP1 which are already reported to be damaged via Covid-19 proteins and upregulated in the post-Covid stage. Our target plant in this study is Cannabis (popularly known as 'Ganja' in India). The molecular docking and simulation studies revealed that Cannabidiol (CBD) and Cannabivarin (CVN) obtained from Cannabis can bind to post-Covid symptoms related central nervous system (CNS) proteins and downregulate them which can be beneficial in post-covid symptoms treatment strategy. Thus we propose Cannabis as an important therapeutic plant against post-Covid symptoms.Communicated by Ramaswamy H. Sarma.