Excavating phytochemicals from plants possessing antiviral activities for identifying SARS-CoV hemagglutinin-esterase inhibitors by diligent computational workflow.

Coronaviruses (CoVs) belong to a group of RNA viruses that cause diseases in vertebrates including. Newer and deadlier than SARS CoV-2 are sought to appear in future for which the scientific community must be prepared with the strategies for their control. Spike protein (S-protein) of all the CoVs require angiotensin-converting enzyme2 (ACE2), while CoVs also require hemagglutinin-acetylesterase (HE) glycoprotein receptor to simultaneously interact with O-acetylated sialic acids on host cells, both these interactions enable viral particle to enter host cell leading to its infection. Target inhibition of viral S-protein and HE glycoprotein receptor can lead to a development of therapy against the SARS CoV-2. The proposition is to recognize molecules from the bundle of phytochemicals of medicinal plants known to possess antiviral potentials as a lead that could interact and mask the active site of, HE glycoprotein which would ideally bind to O-acetylated sialic acids on human host cells. Such molecules can be addressed as 'HE glycoprotein blockers'. A library of 110 phytochemicals from Withania somnifera, Asparagus racemosus, Zinziber officinalis, Allium sativum, Curcuma longa and Adhatoda vasica was constructed and was used under present study. In silico analysis was employed with plant-derived phytochemicals. The molecular docking, molecular dynamics simulations over the scale of 1000 ns (1 µs) and ADMET prediction revealed that the Withania somnifera (ashwagandha) and Asparagus racemosus (shatavari) plants possessed various steroidal saponins and alkaloids which could potentially inhibit the COVID-19 virus and even other CoVs targeted HE glycoprotein receptor.

Molecular insights into the interaction of eighteen different variants of SARS-CoV-2 spike proteins with sixteen therapeutically important phytocompounds: in silico approach.

SARS-CoV-2 has mutated many times among different populations. We analyzed wild-type spike protein and 18 different variants of SARS-CoV-2 spike protein known until the beginning of 2022 (alpha, beta, B.1.429, B.1.616, B.1.620, B.1.617.3, C.1.2, delta, epsilon, eta, gamma, iota, kappa, lambda, mu, omicron, theta, and zeta) for their interaction with 16 phytocompounds and remdesivir, resulting into 425 combinations. The largest number of mutations has been reported in the omicron followed by delta variant. However, the virulence of the delta variant has been reported higher as compared to omicron. Mutations at a few locations (D215G, K417N, E484K, N501Y, D614G, and P681H) were common in most of the variants. 3 D structures of all the 18 spike proteins were created using SWISS-MODEL to test the binding affinities with caffeine theophylline, emodin, vitexin, berberine, curcumin, piperine, quercetin, artemisinin, carvacrol, capsaicin, tetrahydrocannabinol, cannabidiol, α- pinene, ß- pinene and gingerol. Phytocompounds and mutant variants were prepared using AutoDock 4.2.6 software. Binding affinities of the selected phytocompounds with the different mutant spike proteins were achieved using AutoDock Vina. Out of all combinations investigated, the best binding affinities were observed with 3 variants of SAR-CoV-2 with 5 phytocompounds along with remdesivir. The range of best binding energies varied from -9.1 to -8.0 kcal/mol. Further, MD simulation was done for selected 9 phytocompound-spike mutant complexes for analyzing the stability of interactions for 100 ns. ADMET studies via ProTox-II and SwissADME displayed that phytocompounds are safe and less toxic in comparison to remdesivir.Communicated by Ramaswamy H. Sarma.

Computational investigation of natural compounds as potential main protease (Mpro) inhibitors for SARS-CoV-2 virus.

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is significantly impacting human lives, overburdening the healthcare system and weakening global economies. Plant-derived natural compounds are being largely tested for their efficacy against COVID-19 targets to combat SARS-CoV-2 infection. The SARS-CoV-2 Main protease (Mpro) is considered an appealing target because of its role in replication in host cells. We curated a set of 7809 natural compounds by combining the collections of five databases viz Dr Duke's Phytochemical and Ethnobotanical database, IMPPAT, PhytoHub, AromaDb and Zinc. We applied a rigorous computational approach to identify lead molecules from our curated compound set using docking, dynamic simulations, the free energy of binding and DFT calculations. Theaflavin and ginkgetin have emerged as better molecules with a similar inhibition profile in both SARS-CoV-2 and Omicron variants.

Methylxanthines as Potential Inhibitor of SARS-CoV-2: an In Silico Approach.

The aim of the present study was to test the binding affinity of methylxanthines (caffeine/theine, methylxanthine, theobromine, theophylline and xanthine) to three potential target proteins namely Spike protein (6LZG), main protease (6LU7) and nucleocapsid protein N-terminal RNA binding domain (6M3M) of SARS-CoV-2. Proteins and ligand were generated using AutoDock 1.5.6 software. Binding affinity of methylxanthines with SARS-CoV-2 target proteins was determined using Autodock Vina. MD simulation of the best interacting complexes was performed using GROMACS 2018.3 (in duplicate) and Desmond program version 2.0 (academic version) (in triplicate) to study the stabile interaction of protein-ligand complexes. Among the selected methylxanthines, theophylline showed the best binding affinity with all the three targets of SARS-CoV-2 (6LZG - 5.7 kcal mol-1, 6LU7 - 6.5 kcal mol-1, 6M3M - 5.8 kcal mol-1). MD simulation results of 100 ns (in triplicate) showed that theophylline is stable in the binding pockets of all the selected SARS-CoV-2 proteins. Moreover, methylxanthines are safer and less toxic as shown by high LD50 value with Protox II software as compared to drug chloroquine. This research supports the use of methylxanthines as a SARS-CoV-2 inhibitor. It also lays the groundwork for future studies and could aid in the development of a treatment for SARS-CoV-2 and related viral infections. Supplementary Information: The online version contains supplementary material available at 10.1007/s40495-021-00276-3.

Identification of antiviral phytochemicals as a potential SARS-CoV-2 main protease (Mpro) inhibitor using docking and molecular dynamics simulations.

Novel SARS-CoV-2, an etiological factor of Coronavirus disease 2019 (COVID-19), poses a great challenge to the public health care system. Among other druggable targets of SARS-Cov-2, the main protease (Mpro) is regarded as a prominent enzyme target for drug developments owing to its crucial role in virus replication and transcription. We pursued a computational investigation to identify Mpro inhibitors from a compiled library of natural compounds with proven antiviral activities using a hierarchical workflow of molecular docking, ADMET assessment, dynamic simulations and binding free-energy calculations. Five natural compounds, Withanosides V and VI, Racemosides A and B, and Shatavarin IX, obtained better binding affinity and attained stable interactions with Mpro key pocket residues. These intermolecular key interactions were also retained profoundly in the simulation trajectory of 100 ns time scale indicating tight receptor binding. Free energy calculations prioritized Withanosides V and VI as the top candidates that can act as effective SARS-CoV-2 Mpro inhibitors.

Identification of novel inhibitors of SARS-CoV-2 main protease (Mpro ) from Withania sp. by molecular docking and molecular dynamics simulation.

Since December 2019, coronavirus disease (COVID-19) has claimed the lives of millions of people across the globe. To date, no medicine is available for the responsible virus SARS-CoV-2. 3CLpro, that is, 3-chymotrypsin-like protease, the main protease (Mpro ), has an important role in cleaving pp1a and pp1ab polyproteins. This Mpro serves as an important target in drug designing against COVID-19. Herein, the study includes the investigation, screening, and identification of potent leads from (Withania sps.), against SARS-CoV-2, using virtual screening, molecular docking, and molecular dynamics (MD) simulations. Seventy-three natural compounds from this important medicinal plant were screened. The Binding affinity was used to identify the most probable target to inhibit the Mpro , compounds 27-hydroxywithanolide F (W32, -11.5 kcal/mol), withanolide A (W56, -11.4 kcal/mol), and withacoagulin H (W30, -11.1 kcal/mol) showed highest binding energy. Lipinski's rule, followed by drug-likability and likeness screening, resulted in 36 molecules. Further, MD simulation of 50 ns predicted withacoagulin H possessing strong binding affinity and hydrogen-bonding interactions with the active site. The binding free energy calculation showed the most negative energy of withacoagulin H (-63.463 KJ/mol) compared to other selected compounds. The study also compared the bonding energy of already reported repurposed and newly synthesized drugs. Further, absorption, distribution, metabolism, and excretion predictions were made to found a good balance of potency. Hence the following screened compounds from Withania sps. could serve as the potential leads for drug development against COVID-19.

Repurposing of anticancer phytochemicals for identifying potential fusion inhibitor for SARS-CoV-2 using molecular docking and molecular dynamics (MD) simulations.

The viral particle, SARS-CoV-2 is responsible for causing the epidemic of Coronavirus disease 2019 (COVID-19). To combat this situation, numerous strategies are being thought for either creating its antidote, vaccine, or agents that can prevent its infection. For enabling research on these strategies, several target proteins are identified where, Spike (S) protein is of great potential. S-protein interacts with human angiotensin-converting-enzyme-2 (ACE2) for entering the cell. S-protein is a large protein and a portion of it designated as a receptor-binding domain (RBD) is the key region that interacts with ACE2, following to which the viral membrane fuses with the alveolar membrane to enter the human cell. The hypothesis is to identify molecules from the pool of anticancer phytochemicals as a lead possessing the ability to interact and mask the amino acids of RBD, making them unavailable to form associations with ACE2. Such a molecule is termed as 'fusion inhibitor'. We hypothesized to identify fusion inhibitors from the NPACT library of anticancer phytochemicals. For this, all the molecules from the NPACT were screened using molecular docking, the five top hits (Theaflavin, Ginkgetin, Ursolic acid, Silymarin and Spirosolane) were analyzed for essential Pharmacophore features and their ADMET profiles were studied following to which the best two hits were further analyzed for their interaction with RBD using Molecular Dynamics (MD) simulation. Binding free energy calculations were performed using MM/GBSA, proving these phytochemicals containing anticancer properties to serve as fusion inhibitors.Communicated by Ramaswamy H. Sarma.

Pinpointing the potential hits for hindering interaction of SARS-CoV-2 S-protein with ACE2 from the pool of antiviral phytochemicals utilizing molecular docking and molecular dynamics (MD) simulations.

SARS-CoV-2, the viral particle, is responsible for triggering the 2019 Coronavirus disease outbreak (COVID-19). To tackle this situation, a number of strategies are being devised to either create an antidote, a vaccine, or agents capable of preventing its infection. To enable research on these strategies, numerous target proteins are identified where Spike (S) protein is presumed to be of immense potential. S-protein interacts with human angiotensin-converting-enzyme-2 (ACE2) for cell entry. The key region of S-protein that interacts with ACE2 is a portion of it designated as a receptor-binding domain (RBD), following whereby the viral membrane fuses with the alveolar membrane to enter the human cell. The proposition is to recognize molecules from the bundle of phytochemicals of medicinal plants known to possess antiviral potentials as a lead that could interact and mask RBD, rendering them unavailable to form ACE2 interactions. Such a molecule is called the 'S-protein blocker'. A total of 110 phytochemicals from Withania somnifera, Asparagus racemosus, Zinziber officinalis, Allium sativum, Curcuma longa and Adhatoda vasica were used in the study, of which Racemoside A, Ashwagandhanolide, Withanoside VI, Withanoside IV and Racemoside C were identified as top five hits using molecular docking. Further, essential Pharmacophore features and their ADMET profiles of these compounds were studied following to which the best three hits were analyzed for their interaction with RBD using Molecular Dynamics (MD) simulation. Binding free energy calculations were performed using MM/GBSA, proving these phytochemicals can serve as S-protein blocker.

Identification of potential inhibitors of coronavirus hemagglutinin-esterase using molecular docking, molecular dynamics simulation and binding free energy calculation.

The pandemic outbreak of the Corona viral infection has become a critical global health issue. Biophysical and structural evidence shows that spike protein possesses a high binding affinity towards host angiotensin-converting enzyme 2 and viral hemagglutinin-acetylesterase (HE) glycoprotein receptor. We selected HE as a target in this study to identify potential inhibitors using a combination of various computational approaches such as molecular docking, ADMET analysis, dynamics simulations and binding free energy calculations. Virtual screening of NPACT compounds identified 3,4,5-Trihydroxy-1,8-bis[(2R,3R)-3,5,7-trihydroxy-3,4-dihydro-2H-chromen-2-yl]benzo[7]annulen-6-one, Silymarin, Withanolide D, Spirosolane and Oridonin as potential HE inhibitors with better binding energy. Furthermore, molecular dynamics simulations for 100 ns time scale revealed that most of the key HE contacts were retained throughout the simulations trajectories. Binding free energy calculations using MM/PBSA approach ranked the top-five potential NPACT compounds which can act as effective HE inhibitors.

In silico prediction of potential inhibitors for the main protease of SARS-CoV-2 using molecular docking and dynamics simulation based drug-repurposing.

BACKGROUND: The rapidly enlarging COVID-19 pandemic caused by the novel SARS-corona virus-2 is a global public health emergency of an unprecedented level. Unfortunately no treatment therapy or vaccine is yet available to counter the SARS-CoV-2 infection, which substantiates the need to expand research efforts in this direction. The indispensable function of the main protease in virus replication makes this enzyme a promising target for inhibitors screening and drug discovery to treat novel coronavirus infection. The recently concluded α-ketoamide ligand-bound X-ray crystal structure of SARS-CoV-2 Mpro (PDB ID: 6Y2F) from Zhang et al. has revealed the potential inhibitor binding mechanism and the molecular determinants responsible for substrate binding. METHODS: For the study, we have targeted the SARS-CoV-2 Mpro for the screening of FDA approved antiviral drugs and carried out molecular docking based virtual screening. Further molecular dynamic simulation studies of the top three selected drugs carried out to investigated for their binding affinity and stability in the SARS-CoV-2 Mpro active site. The phylogenetic analysis was also performed to know the relatedness between the SARS-CoV-2 genomes isolated from different countries. RESULTS: The phylogenetic analysis of the SARS-CoV-2 genome reveals that the virus is closely related to the Bat-SL-CoV and does not exhibit any divergence at the genomic level. Molecular docking studies revealed that among the 77 drugs, screened top ten drugs shows good binding affinities, whereas the top three drugs: Lopinavir-Ritonavir, Tipranavir, and Raltegravir were undergone for molecular dynamics simulation studies for their conformational stability in the active site of the SARS-CoV-2 Mpro protein. CONCLUSIONS: In the present study among the library of FDA approved antiviral drugs, the top three inhibitors Lopinavir-Ritonavir, Tipranavir, and Raltegravir show the best molecular interaction with the main protease of SARS-CoV-2. However, the in-vitro efficacy of the drug molecules screened in this study further needs to be corroborated by carrying out a biochemical and structural investigation.