Molecular Dynamics and Free Energy Landscape Study of SARS-CoV-2 Omicron M-pro Boswellic acid Compounds of Boswellia Serrata Inhibitors

This work sheds light on the effect of boswellic acid compounds (Alpha boswellic acid, Beta boswellic acid, 11-keto beta boswellic acid and 3-Acetyl-11-keto beta boswellic acid) upon inhibiting SARS-CoV-2 M-pro and O-M-pro (Main protease). A good docking score (-8.4 kcal/mol) is found in the case of 3-Acetyl-11-keto beta boswellic acid as compared to the reference and three other boswellic acid compounds. ADMET results suggest that all these compounds are nontoxic and their pharmacokinetic properties are satisfactory. Moreover, a stability analysis with M-pro/O-M-pro through RMSD, RMSF, hydrogen bonds and Rg parameters in MD simulations is made and we found better values than the reference case. Pre and post-MD structures of Ligands-M-pro show a similar binding site whereas a drift can be noted for L-O-M-pro. 3-Acetyl-11-keto beta boswellic acid shows an average of five hydrogen bonds and it remains stable within the binding pocket of M-pro during the simulation period in comparison to other boswellic acids compounds. Various metastable conformations are observed for all compounds in FEL (free energy landscape), however, Acyclovir-M-pro, Alpha boswellic acid-M-pro and Beta boswellic acid-O-M-pro display only one global minimum. The results suggest that these compounds can be used as potential lead molecules for breakthroughs in drug discovery.

Diversifying the chloroquinoline scaffold against SARS-CoV-2 main protease: Virtual screening approach using cross-docking, SiteMap analysis and molecular dynamics simulation

The absence of designated remedies for coronavirus disease 19 (Covid-19) and the lack of treatment protocols drove scientists to propose new small molecules and to attempt to repurpose existing drugs against various targets of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in order to bring forward efficient solutions. The main protease (Mpro) is one of the most promising drug targets due to its crucial role in fighting viral replic-ation. Several antiviral drugs have been used in an attempt to overcome the pandemic, such as hydroxychloroquine (HCQ). Despite its perceived positive outcomes in the beginning of the disease, HCQ was associated with several drawbacks, such as insolubility, toxicity, and cardiac adverse effects. There-fore, in the present study, a structure-based virtual screening approach was performed to identify structurally modified ligands of the chloroquinoline (CQ) scaffold with good solubility, absorption, and permeation aimed at eventually suggesting a more dependable alternative. PDB ID:7BRP Mpro was chosen as the most reliable receptor after cross-docking calculation using 30 crystal struc-tures. Then, a SiteMap analysis was performed and a total of 231,456 structur-ally modified compounds of the CQ scaffold were suggested. After Lipinski criteria filtration, 64,312 molecules were docked and their MM-GBSA free binding energy were calculated. Next, ADME descriptors were calculated, and 12 molecules with ADME properties better than that of HCQ were identified. The resulting molecules were subjected to molecular dynamics (MD) simul-ation for 100 ns. The results of the study indicate that 3 molecules (CQ_22;CQ_2 and CQ_5) show better interactions and stability with the Mpro receptor. Binding interaction analysis indicates that GLU143, THR26, and HIS41 amino acids are potential binding hot-spot residues for the remaining 3 ligands.

Phytochemicals from Annona muricata (Sour Sop) as potential inhibitors of SARS-CoV-2 main protease (Mpro) and spike receptor protein: A structure-based drug design studies and chemoinformatics analyses

As the fight against SARS-CoV-2 remains undefeated despite available vaccines, continuous efforts to curtail this deadly and highly spreading virus remain a world priority. In this research, we have investigated the antiviral properties of the phytochemicals from Annona muricata (Sour Sop) as potential inhibitors of SARS-CoV-2 main protease (Mpro) and Spike Receptor Protein. Pharmacokinetic analyses such as in-silicoADME, drug-likeness, PASS prediction, oral-bioavailability and bioactivity were carried out to screen the phytochemicals, 9 out of the 131 ligands satisfied the screening. A molecular docking approach was used to obtain the binding energies of the 9 ligands, and the result showed that Roseoside (-7.50 » kcal/mol) and Coreximine (-7.0 » kcal/mol) displayed the best docking score and have predicted to have stable interactions with SARS-CoV-2 main protease and Spike Glycoprotein. Data from this study could be further explored in developing multi-target drugs against SARS-CoV-2. © 2023 Walter de Gruyter GmbH, Berlin/Boston 2023.

Naphtho[2,1-b]furan derived triazole-pyrimidines as highly potential InhA and Cytochrome c peroxidase inhibitors: Synthesis, DFT calculations, drug-likeness profile, molecular docking and dynamic studies

Napthofuran and its fused heterocyclic derivatives evaluated with varied biological activity functional groups comprise an important class of compounds for new chemical entities. We here in reporting synthesis of new 3-(4-substituted phenyl)naphtho[1′,2′:4,5]furo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidines 6(a-f). Structures of the newly synthesized compounds were confirmed by making use of spectroscopic techniques like IR, NMR and Mass. The DFT calculations were taken for the selected molecules using B3LYP hybrid functional with a 6–31+G (d, p) all-electron basis set using the Gaussian 09 package. The bioactivity predictions were evaluated for the synthesized compounds. The In vitro biological activities were reported for the all compounds 6(a-f). The compound 6a showed high activity of anti-TB and antioxidant activity with at MIC 1.6 μg/ml and at percentage of inhibition (72.54±0.21) at 10μg/ml respectively. The compound 6f (73.21±0.11) showed antioxidant activity better than standard drug BHA (71.32±0.13) at 10 μg/ml. Furthermore, the docking studies for the newly synthesized molecules were carried out by Auto dock software with proteins InhA (4TZK),Cytochrome c peroxidase (2 × 08) and protease (Mpro) of SARS-CoV-2 Omicron (PDB ID: 7TOB). All the compounds showed a strong binding affinity for the docked proteins. The outcome of docking results showed that compound 6ahad excellent binding energies -10.8, -9.4, and -9.0 kcal/mol with 4TZK, 2 × 08, and 7TOB respectively. Lastly, the protein stability, fluctuations of APO-Protein, protein-ligand complexes were investigated through Molecular Dynamics (MD) simulations studies using Desmond Maestro 11.3 and potential lead molecules were identified. © 2023

Comprehensive In silico Investigation Validates Two Flavonoid Compounds of Derris robusta (Roxb. ex DC.) Benth. to Supplant Remdesivir as Natural Therapeutic Remedy Against a Range of Coronaviruses

Diversified Coronaviruses like MERS-CoV, SARS-CoV-1, SARS-CoV-2, etc., have badly affected human life by causing various respiratory syndromes. Natural bioactive products like flavonoids are well-known for their anti-viral property. Derris robusta (Roxb. ex DC.) Benth. is a reservoir of flavonoids, which encouraged the in silico study of the signature flavonoid compounds in it towards investigating the possible inhibitory effect of those flavonoid compounds against the viral replication of MERS-CoV, SARS-CoV-1, and SARS-CoV-2. Therefore, investigating the treatment methodology for alleviating these types of diseases is the ultimate priority for public health. In our in silico study, Flavonoids like Isosinensetin and Retusin inhibited the replication of all three viruses with greater binding affinity compared to the control drug Remdesivir in multiple instances. Physicochemical characterization of the compounds by following Lipinski's rule of fi ve and the ADMET study have helped recognize these compounds as a probable natural therapeutic drug against Coronaviruses. The present study exhibits the potential of alternative drug molecules as anti-viral compounds against these three types of Coronaviruses. Further in vitro and in vivo evaluation followed by clinical trials for developing and successfully implementing these two compounds as an effective inhibitory agents against Coronaviruses can be initiated. © 2022 by the authors.

Novel pyrimidines as COX-2 selective inhibitors: synthesis, DFT analysis, molecular docking and dynamic simulation studies.

Pyrimidine and its derivatives are associated with varieties of biological properties. Therefore, we herein reported the synthesis of four novel pyrimidines (2, 3, and 4a, b) derivatives. The structure of these molecules is confirmed by spectroscopic methods such as IR, NMR, and Mass analysis. The electronic behavior of synthesized compounds 4a, b and in silico drug design 4 c, d was explained by Density Functional Theory estimations at the DFT/B3LYP level via 6-31 G++ (d, p) replicates the structure and geometry. All the synthesized compounds were screened for their in vitro COX-1 and COX-2 inhibitory activity compared to standards Celecoxib and Ibuprofen. Compounds 3 and 4a afforded excellent COX-1 and COX-2 inhibitory activities at IC50 = 5.50 and 5.05 µM against COX-1, 0.85 and 0.65 µM against COX-2, respectively. The standard drugs Celecoxib and Ibuprofen showed inhibitory activity at IC50 = 6.34 and 3.1 µM against COX-1, 0.56 and 1.2 µM against COX-2, respectively. Further, these compounds showed high potential docking with SARS-CoV-2 Omicron protease & COX-2 and predicted drug-likeness for the pyrimidine analogs by using Molinspiration. The protein stability, fluctuations of APO-protein, protein-ligand complexes were investigated through Molecular Dynamics simulations studies using Desmond Maestro 11.3 and potential lead molecules were identified.Communicated by Ramaswamy H. Sarma.

Revisiting the South Indian Traditional Plants against Several Targets of SARS-CoV-2 - An in silico Approach.

BACKGROUND: The south Indian Telugu states will celebrate a new year called 'Ugadi' which is a south Indian traditional festival. The ingredients used in ugadi pachadi have often also been used in food as well as traditional Ayurveda and Siddha medicinal preparations. Coronaviruses (CoVs) are a diverse family of enveloped positive-sense single-stranded RNA viruses which can infect humans and have the potential to cause large-scale outbreaks. OBJECTIVE: Considering the benefits of ugadi pachadi, we investigated the binding modes of various phytochemical constituents reported from its ingredients against five targets of SARS-CoV-2. METHODS: Flexible-ligand docking simulations were achieved through AutoDock version 1.5.6. Following 50ns of molecular dynamics simulation using GROMACS 2018.1 software and binding free energy (ΔGbind) of the protein-ligand complexes were calculated using the g_mmpbsa tool. ADME prediction was done using Qikprop of Schrodinger. RESULTS: From the molecular docking and MM/PBSA results compound Eriodictin exhibited the highest binding energy when complexed with nucleocapsid N protein (6M3M) (-6.8 kcal/mol, - 82.46 kJ/mol), bound SARS-CoV-2-hACE2 complex (6M0J) (-7.4 kcal/mol, -71.10 kJ/mol) and Mpro (6XR3) (-8.6 kcal/mol, -140.21 kJ/mol). Van der Waal and electrostatic energy terms highly favored total free energy binding. CONCLUSION: The compounds Eriodictin, Vitexin, Cycloart-3, 24, 27-triol, Agigenin, Mangiferin, Mangiferolic acid, Schaftoside, 27-Hydroxymangiferonic acid, Quercetin, Azadirachtol, Cubebin, Isomangiferin, Isoquercitrin, Malicarpin, Orientin and procyanidin dimer exhibited satisfactory binding energy values when compared with standard molecules. The further iterative optimization of high-ranked compounds following validation by in vitro and in vivo techniques assists in discovering therapeutic anti-SARS-CoV-2 molecules.

Discovery of Highly Potent Small Molecule Pan-Coronavirus Fusion Inhibitors.

The unprecedented pandemic of COVID-19, caused by a novel coronavirus, SARS-CoV-2, and its highly transmissible variants, led to massive human suffering, death, and economic devastation worldwide. Recently, antibody-evasive SARS-CoV-2 subvariants, BQ and XBB, have been reported. Therefore, the continued development of novel drugs with pan-coronavirus inhibition is critical to treat and prevent infection of COVID-19 and any new pandemics that may emerge. We report the discovery of several highly potent small-molecule inhibitors. One of which, NBCoV63, showed low nM potency against SARS-CoV-2 (IC50: 55 nM), SARS-CoV-1 (IC50: 59 nM), and MERS-CoV (IC50: 75 nM) in pseudovirus-based assays with excellent selectivity indices (SI > 900), suggesting its pan-coronavirus inhibition. NBCoV63 showed equally effective antiviral potency against SARS-CoV-2 mutant (D614G) and several variants of concerns (VOCs) such as B.1.617.2 (Delta), B.1.1.529/BA.1 and BA.4/BA.5 (Omicron), and K417T/E484K/N501Y (Gamma). NBCoV63 also showed similar efficacy profiles to Remdesivir against authentic SARS-CoV-2 (Hong Kong strain) and two of its variants (Delta and Omicron), SARS-CoV-1, and MERS-CoV by plaque reduction in Calu-3 cells. Additionally, we show that NBCoV63 inhibits virus-mediated cell-to-cell fusion in a dose-dependent manner. Furthermore, the absorption, distribution, metabolism, and excretion (ADME) data of NBCoV63 demonstrated drug-like properties.

Structure Based Drug Design Approach to Identify Potential SARS-CoV-2 Polymerase Inhibitors

Aims: The research work aims to apply the current virtual screening approaches for rapid screening of available compounds as inhibitors of the novel coronavirus (COVID-19). Background(s): The worldwide pandemic, uncontrolled spread, and lack of effective therapeutics demand novel SARS-CoV-2 inhibitory anti-viral agents. Objective(s): The major objectives of the present work are - i) effective utilization of open-source com-puter-aided drug design (CADD) tools;ii) to prepare a database according to chemical structure similarity to the reported anti-viral drug, Favipiravir;and iii) to investigate potential inhibitors of the novel coronavirus. Method(s): The dataset was prepared based on the chemical structure similarity feature of ChemSpider. The virtual screening was carried out using molecular docking and ADMET properties. For performing molecular docking studies, the standard docking protocol of iGEMDOCK was used. Result(s): Based on chemical structure similarity search to Favipiravir, a small library of 40 compounds was designed. The docking score and ADMET properties were analyzed to prioritize the compounds. Conclusion(s): The virtual screening resulted in the identification of potential anti-viral compounds. Among the designed library of compounds based on structural similarity to Favipiravir, 70% of compounds were found to possess docking scores more than that of Favipiravir. The amino acid residues involved in binding at the RNA dependent RNA polymerase (RdRp) were identified. The compounds have shown acceptable ADME properties and are potentially non-toxic. Other: The study has successfully applied the open-source CADD tools to investigate the novel SARS-CoV-2 polymerase inhibitors.Copyright © 2021 Bentham Science Publishers.

Discovery and development of lead compounds from natural sources using computational approaches

Natural products have a significant role in drug discovery. Their unique chemical structures have led to compounds in clinical use to treat different diseases. Also, natural products are significant sources of inspiration or starting points to develop new therapeutic agents. There are also unique natural products such as peptides and macrocycles that offer sources or starting points to address complex diseases. Computational approaches that used chemoinformatics and molecular modeling methods contribute to assisting and accelerating natural product-based drug discovery. Several research groups have recently used computational methodologies to organize data, interpret results, generate and test hypotheses, filter large chemical databases before the experimental screening, and design experiments. Herein, we discuss chemoinformatics and molecular modeling applications to uncover bioactive natural products. We also discuss in silico methods to optimize the biological activity and anticipate potential toxicity issues of natural products. As case studies, we discuss the role of natural products for COVID-19 drug discovery and their impact on the identification of compounds with activity against DNA methyltransferase, an epigenetic target with relevance in cancer and other diseases. © 2022 Elsevier Inc. All rights reserved.

AIDrugApp: artificial intelligence-based Web-App for virtual screening of inhibitors against SARS-COV-2

Currently, there is no effective cure for SARS-COVID-19 diseases. The identification of novel therapeutic targets and drug-like compounds is required for the development of anti-COVID-19 drugs. Virtual screening is currently the most significant component for identifying drug-like molecules from large datasets for drug design and development. However, there are no effective easily available and user-friendly applications for virtual screening of drug leads against SARS-COV-2. Therefore, we have developed a user-friendly web-app named ‘AIDrugApp' for the virtual screening of inhibitor molecules against SARS-CoV-2. AIDrugApp is a novel open-access, deep learning AI-based inhibitory activity prediction and data statistics visualisation platform. Users can predict the inhibitory activities (Active/Inactive) and pIC-50 values of new compounds against SARS-CoV-2 replicase polyprotein, 3CLpro and human angiotensin-converting enzymes. It is also useful for virtual screening of chemical features of molecules towards SARS-COVID-19 clinical trial bioactivities. This paper presents the development and architecture of AIDrugApp. We also present two case studies where large sets of molecules were screened using the ‘Bioactivity Prediction' module of our app. Screened molecules were analysed further for validation by molecular docking and ADME analysis to identify the potential drug candidates.

In Silico Identification of Potential Inhibitors of SARS-CoV-2 Papain-like Protease From Natural Sources: A Natural Weapon to Fight COVID-19

Background: The rapid spread of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) globally has created unprecedented health care and economic crisis. The ever-in-creasing death toll highlights an urgent need for the development of specific antiviral to combat Novel Coronavirus Disease 2019 (COVID-19). Objective(s): In the present study, we aimed to identify potential SARS-CoV-2 papain-like protease inhibitors from regularly used spices. Method(s): A structure-based virtual screening (VS) of our in-house databank of 1152 compounds was employed to identify small molecule inhibitors of SARS-CoV-2 papain-like protease (PLpro), which are important protease for virus replication. The databank was built of the compounds from ten spices and two medicinal plants. Result(s): The top three potential hits that resulted from VS were myricetin (1) available in Alium cepa and Mentha piperita;alpha-hydroxyhydrocaffeic acid (2) available in M. Piperita;and luteolin (3) available in M. Piperita, Curcuma longa, A. cepa, and Trigonella foenum-graecum, which showed fair binding affinity to PLpro of SARS-CoV-2 compared to known SARS-CoV PLpro in-hibitors. The predicted Absorption, Distribution, Metabolism, and Excretion (ADME) properties of the selected hits showed that all are drug-like. The compounds bind to biologically critical regions of the target protein, indicating their potential to inhibit the functionality of this component. Conclusion(s): There are only a few reports available in the literature on the in-silico identification of PLpro inhibitors and most of them used homology modeling of protein. Here, we used the recently uploaded X-ray crystal structure of PLpro (PDB ID: 6WX4) with a well-defined active site. Our computational approach has resulted in the identification of effective inhibitors of SARS-CoV-2PL-pro. The reported edible spices may be useful against COVID-19 as a home remedy after an in--vitro study.Copyright © 2021 Bentham Science Publishers.

N-Heterocycles as Privileged Scaffolds in FDA Approved Different NMEs of 2021: A Review

The presence of N-heterocyclic ring systems as promising features in the molecular skele-ton of FDA-approved drugs, underlie the remarkable contributions of these heterocyclic nuclei in the field of medicine. Despite instability risks associated with the COVID pandemic, the US FDA approved 50 drugs (36 NMEs and 14 biological products) in the year 2021. The active ingredients of 32 drugs out of these 36 NMEs (almost 89%) contain saturated, partially unsaturated and aromatic N-heterocyclic moieties in their molecular assemblies, hence dominating the medicinal approvals. While 27 molecules (75% of these NMEs drugs) are prominent small NMEs. Herein, we have considered profiling those FDA-approved 27 small-molecule drugs which are decorated with N-heterocycles as privileged scaffolds. These drugs are grouped on the basis of a number of N-heterocycles present in their structural framework. The spectrum of these drugs in terms of their structural features and medicinal importance is summarized in this review. Also, the pertinent analyses of their drug-likeliness conferring some general pharmacokinetic principles are highlighted. © 2023 Bentham Science Publishers.

Molecular Docking Studies of Ocimum Americanum Secondary Metabolites Against SARS-Cov-2 Spike Protein

Introduction and Aim: The outbreak of Covid-19 pandemic since December 2019 has raised serious global health concern. Because of rapid human to human transmission and non-availability of clinically proven drugs or vaccines, this Covid-19 pandemic has created a great threat to mankind. Many naturally derived molecules are being investigated for the treatment of Covid-19. Ocimum americanum is one such significant medicinal plant possessing a variety of biological activities. Material(s) and Method(s): In the present study, seven phytochemicals were selected from O. americanum and were docked against SARS-CoV-2 spike protein which is an important site for virus to enter the host cell. Docking was performed using Autodock Vina and the ADME properties of all these seven ligands were predicted using the Swiss-ADME tool. The bioactivity score was also predicted using the Molinspiration tool. Besides the secondary metabolites, all these analyses were also performed for well-known antiviral drugs namely lopinavir and ritonavir. Result(s): The binding energy obtained from the docking studies of SARS-CoV-2 spike protein with Lopinavir, Ritonavir, Alpha-farnesene, Beta-farnesene, Eugenol, Linalool, Estragole, Limonene and 1,8-Cineole was found to be-5.2,-5.1,-4.7,-4.5,-4.3,-4.1,-4,-3.9 and-3.8 Kcal/Mol respectively. Swiss-ADME results also suggest that all the selected ligands follow the drug likeness properties and hence they could be taken for further drug discovery process. Conclusion(s): From the present in silico study, it can be concluded that secondary metabolites of O. americanum have potential inhibiting activity against spike protein of SARS-CoV-2. Isolation and efficacy studies in vitro may provide an insight into the drug discovery to fight Covid-19.Copyright © 2023, Indian Association of Biomedical Scientists. All rights reserved.

In-Silico Structure-Based Drug Discovery of Candidate Drugs Against Novel Protein Receptor Complex Nsp10-Nsp16 of SARS-CoV-2 Using Drug Repurposing Approach

Background: Several therapeutic possibilities have been explored against Severe Acute Respiratory Syndrome-2 (SARS-CoV-2), such as convalescent plasma (CP), intravenous immunoglobulin (IVIG) and monoclonal antibodies. Compounds such as hydroxychloroquine have also been found to have fatal drawbacks. Repurposing of existing antiviral drugs can be an effective strategy, which could fasten up the process of drug discovery. Objective(s): The present study is designed to predict the computational efficacy of pre-existing antiviral drugs as inhibitors for the Nsp10-Nsp16 complex protein of SARS-CoV-2. Method(s): Twenty-six known antiviral drugs along with their similar structures based on Tanimoto simi-larity, were screened towards the Nsp10-Nsp16 complex's active site. Result(s): Our study reports competitive binding of 1-[3-[2-(2-Ethoxyphenoxy) ethylamino]-2-hydroxypropyl]-9H-carbazol-4-ol against AdoMet binding site in Nsp10-Nsp16 complex. Formation of the stable ligand-receptor complex with 1-[3-[2-(2-Ethoxyphenoxy) ethylamino]-2-hydroxypropyl]-9H-carbazol-4-ol could functionally inhibit the Nsp10-Nsp16 complex, thereby making the SARS-CoV-2 vulnerable to host immuno-surveillance mechanisms. Conclusion(s): We conclude that these computational hits can display positive results in in-vitro trials against SARS-CoV-2.Copyright © 2021 Bentham Science Publishers.

Virtual Screening of the Flavonoids Compounds with the SARS-CoV-2 3C-like Protease as the Lead Compounds for the COVID-19

As of 1st of September 2020, the COVID-19 pandemic has reached an unprecedented level of more than 25 million cases with more than 850,000 deaths. Moreover, all the drug candidates are still undergoing testing in clinical trials. In this regard, a breakthrough in drug design is neces-sary. One strategy to devise lead compounds is leveraging natural products as a lead source. Sever-al companies and research institutes are currently developing anti-SARS-CoV-2 lead from natural products. Flavonoids are well known as a class of antiviral compounds library. The objective of this research is to employ virtual screening methods for obtaining the best lead compounds from the library of flavonoid compounds. This research employed virtual screening methods that com-prised of downloading the protein and lead compound structures, QSAR analysis prediction, itera-tions of molecular docking simulation, and ADME-TOX simulation for toxicity prediction. The QSAR analysis found that the tested compounds have broad-spectrum antiviral activity, and some of them exhibit specific binding to the 3C-like Protease of the Coronavirus. Moreover, juglanin was found as the compound with the fittest binding with the Protease enzyme of SARS-CoV-2. Al-though most of the tested compounds are deemed toxic by the ADME-Tox test, further research should be conducted to comprehend the most feasible strategy to deliver the drug to the infected lung cells. The juglanin compound is selected as the fittest candidate as the SARS-CoV-2 lead compound in the tested flavonoid samples. However, further research should be conducted to observe the lead delivery method to the cell.Copyright © 2021 Bentham Science Publishers.

Ebselen suitably interacts with the potential SARS-CoV-2 targets: an in-silico approach.

Ebselen (SPI-1005) is an active selenoorganic compound that can be found potential inhibitory activity against different types of viral infections such as zika virus, influenza A virus, HCV, and HIV-1; and also be found to exhibit promising antiviral activity against SARS-CoV-2 in cell-based assays but its particular target action against specific non-structural and structural proteins of SARS-CoV-2 is unclear to date. The purpose of this study is to evaluate the anti-SARS-CoV-2 efficacy of Ebselen along with the determination of the specific target among the 12 most common target proteins of SARS-CoV-2. AutoDock Vina in PyRx platform was used for docking analysis against the 12 selected SARS-CoV-2 encoded drug targets. ADME profiling was examined by using SwissADME online server. The stability of binding mode in the target active sites was evaluated using molecular dynamics (MD) simulation studies through NAMD and Desmond package software application. In this docking study, we recognized that Ebselen possesses the highest affinity to N protein (C domain) (PDB ID: 6YUN) and PLpro (PDB ID: 6WUU) among the selected SARS-CoV-2 targets showing -7.4 kcal/mol binding energy. The stability of Ebselen-6YUN and Ebselen-6WUU was determined by a 100 ns trajectory of all-atom molecular dynamics simulation. Structural conformation of these two complexes displayed stable root mean square deviation (RMSD), while root mean square fluctuations (RMSF) were also found to be consistent. This molecular docking study may propose the efficiency of Ebselen against SARS-CoV-2 to a significant extent which makes it a candidature of COVID-19 treatment.Communicated by Ramaswamy H. Sarma.

Combined molecular docking and dynamics simulations studies of natural compounds as potent inhibitors against SARS-CoV-2 main protease.

Main protease (Mpro) of SARS-CoV-2 is a key CoV enzyme that plays a pivotal role in mediating viral replication and transcription, making it an attractive drug target for SARS-CoV-2 the new strain of coronavirus. In this study, we evaluated biologically active compounds present in medicinal plants as potential SARS-CoV-2 Mpro inhibitors, using a molecular docking study with Autodock Vina software. Top seven compounds Afzelin, Phloroglucinol, Myricetin-3-O- rutinosid Tricin 7-neohesperidoside, Silybin, Kaempferol and Silychristin among 50 molecules of natural Origin (Algerian Medicinal plants) were selected which had better and significantly low binding energy as compared to the reference molecule with binding affinities of -9.3, -9.3, -9, -8.9, -8.5, 8.3 and -8.3 kcal mol-1 respectively. Then, we analyzed the ADME properties of the best 7 ligands using the Web server SwissADME. Two of small molecules have been shown to be the ideal candidates for further drug development. Finally, the stability of the both compounds complexed with Mpro was validated through molecular dynamics (MD) simulation, they displayed stable trajectory (RMSD, RMSF) and molecular properties with consistent interaction profile in molecular dynamics simulations, moreover, Silybin could form more stable complex with Mpro than Silychristin.Communicated by Ramaswamy H. Sarma.

Identification and structural studies of natural inhibitors against SARS-CoV-2 viral RNA methyltransferase (NSP16).

Pathogenic RNA viruses are emerging as one of the major threats and posing challenges to human community. RNA viruses have an exceptionally shorter generation time and easy to adapt in host cells. The recent emergence of SARS-CoV-2, a long RNA virus, has shown us how difficult it is to overcome this kind of pandemic without understanding the viral infection and replication mechanisms. It is essential to comprehend replications of the viral genome, including RNA polymerization and the final capping process. The mRNAs of SARS-CoV-2 coronaviruses are protected at their 5'-ends by cap structure. The cap-like system plays a significant role in viral translational process, viral RNA stability, and scatting in detecting innate immune recognition in host cells. Two coronavirus enzymes, Nsp14 and Nsp16, critically help in the formation of capping and are considered as potential drug targets for antiviral therapy. Natural and herbal medicines have a past record of treating various acute respiratory diseases. In this work, we have exploited 56000 natural compounds to screen potential inhibitors against NSP16. In silico virtual screening, docking and Molecular Dynamics (MD) simulation studies were performed to understand how these potential inhibitors are bound to NSP16. We observed that the most highly screened compound binds to protein molecules with a high dock score, primarily through hydrophobic interactions and hydrogen bonding, as previously reported for NSP16. Compound-13 (2-hydroxy-N-({1-[2-hydroxy-1-(hydroxymethyl)ethyl]piperidin-3-yl}methyl)-5-methylbenzamide) and compound-51 (N-(2-isobutoxybenzyl)-N,2-dimethyl-2,8-diazaspiro[4.5]decane-3-carboxamide) occupied in active site along with good pharmokinetices properties. In conclusion, the selected compounds could be used as a novel therapeutic against SARS-CoV-2.Communicated by Ramaswamy H. Sarma.

Discovery of potential SARS-CoV 3CL protease inhibitors from approved antiviral drugs using: virtual screening, molecular docking, pharmacophore mapping evaluation and dynamics simulation.

The spread of corona-virus disease 2019 (COVID-19) has been faster than any other corona-viruses that have succeeded in crossing the animal-human barrier. This disease, caused by the severe acute respiratory syndrome corona-virus 2 (SARS-CoV-2/2019-nCoV) posing a serious threat to global public health and local economies. There are three responsible for this disease; SARS-CoV-2, SARS-CoV and MERS-CoV. Whereas our goal is to test the affinity for a new class of compounds obtained from a hybridization of Chloroquine, Amodiaquine and Mefloquine with three targets SARS-CoV-2, SARS-CoV and MERS-CoV, in order to find new compounds as new inhibitors against Covid-19. In this work, we first used: the molecular docking/dynamics methods and ADME properties to study interaction and affinity between eight new compounds against three targets involved in the Covid-19. The results of the docking simulations and dynamics revealed that inhibitor of the malaria (Ligand 87) has an affinity to interact with SARS-CoV-2, SARS-CoV and MERS-CoV targets and they can be good inhibitors for treatment of Covid-19. Moreover, they give best affinity compared to the Remdesivir and Chloroquine and other clinical tests. The Pharmacokinetics was justified by means of lipophilicity and high coefficient of skin permeability. The in silico evaluation of ADME and drug-likeness revealed that L87 has higher absorption in the intestines with good bioavailability. However, an additional in vitro and/or in vivo experimental study should make it possible to verify the theoretical results obtained in silico.Communicated by Ramaswamy H. Sarma.