scholarly journals Phytochemical Moieties From Indian Traditional Medicine for Targeting Dual Hotspots on SARS-CoV-2 Spike Protein: An Integrative in-silico Approach

2021 ◽  
Vol 8 ◽  
Author(s):  
V. Umashankar ◽  
Sanjay H. Deshpande ◽  
Harsha V. Hegde ◽  
Ishwar Singh ◽  
Debprasad Chattopadhyay
Keyword(s):  
Free Energy ◽  
Binding Energy ◽  
Traditional Medicine ◽  
Binding Affinity ◽  
In Silico ◽  
Binding Free Energy ◽  
Contemporary Literature ◽  
Dynamics Simulation ◽  
Spike Protein ◽  
Syzygium Aromaticum

SARS-CoV-2 infection across the world has led to immense turbulence in the treatment modality, thus demanding a swift drug discovery process. Spike protein of SARS-CoV-2 binds to ACE2 receptor of human to initiate host invasion. Plethora of studies demonstrate the inhibition of Spike-ACE2 interactions to impair infection. The ancient Indian traditional medicine has been of great interest of Virologists worldwide to decipher potential antivirals. Hence, in this study, phytochemicals (1,952 compounds) from eight potential medicinal plants used in Indian traditional medicine were meticulously collated, based on their usage in respiratory disorders, along with immunomodulatory and anti-viral potential from contemporary literature. Further, these compounds were virtually screened against Receptor Binding Domain (RBD) of Spike protein. The potential compounds from each plant were prioritized based on the binding affinity, key hotspot interactions at ACE2 binding region and glycosylation sites. Finally, the potential hits in complex with spike protein were subjected to Molecular Dynamics simulation (450 ns), to infer the stability of complex formation. Among the compounds screened, Tellimagrandin-II (binding energy of −8.2 kcal/mol and binding free energy of −32.08 kcal/mol) from Syzygium aromaticum L. and O-Demethyl-demethoxy-curcumin (binding energy of −8.0 kcal/mol and binding free energy of −12.48 kcal/mol) from Curcuma longa L. were found to be highly potential due to their higher binding affinity and significant binding free energy (MM-PBSA), along with favorable ADMET properties and stable intermolecular interactions with hotspots (including the ASN343 glycosylation site). The proposed hits are highly promising, as these are resultant of stringent in silico checkpoints, traditionally used, and are documented through contemporary literature. Hence, could serve as promising leads for subsequent experimental validations.

scholarly journals Molecular simulation of SARS-CoV-2 spike protein binding to pangolin ACE2 or human ACE2 natural variants reveals altered susceptibility to infection

2020 ◽  
Vol 101 (9) ◽  
pp. 921-924 ◽  
Author(s):  
Jingfang Wang ◽  
Xintian Xu ◽  
Xinbo Zhou ◽  
Ping Chen ◽  
Huiying Liang ◽  
...  
Keyword(s):  
Free Energy ◽  
Protein Binding ◽  
Binding Affinity ◽  
Binding Free Energy ◽  
Virus Transmission ◽  
Dynamics Simulation ◽  
Spike Protein ◽  
Susceptibility To Infection ◽  
Natural Variants ◽  
Complex Models

We constructed complex models of SARS-CoV-2 spike protein binding to pangolin or human ACE2, the receptor for virus transmission, and estimated the binding free energy changes using molecular dynamics simulation. SARS-CoV-2 can bind to both pangolin and human ACE2, but has a significantly lower binding affinity for pangolin ACE2 due to the increased binding free energy (9.5 kcal mol−1). Human ACE2 is among the most polymorphous genes, for which we identified 317 missense single-nucleotide variations (SNVs) from the dbSNP database. Three SNVs, E329G (rs143936283), M82I (rs267606406) and K26R (rs4646116), had a significant reduction in binding free energy, which indicated higher binding affinity than wild-type ACE2 and greater susceptibility to SARS-CoV-2 infection for people with them. Three other SNVs, D355N (rs961360700), E37K (rs146676783) and I21T (rs1244687367), had a significant increase in binding free energy, which indicated lower binding affinity and reduced susceptibility to SARS-CoV-2 infection.

scholarly journals Predicting the Potential Effect of E484K Mutation on the Binding of 28 Antibodies to the Spike Protein of SARS-CoV-2 by Molecular Dynamics Simulation and Free Energy Calculation

2021 ◽  
Author(s):  
Leyun Wu ◽  
Cheng Peng ◽  
Zhijian Xu ◽  
weiliang zhu
Keyword(s):  
Free Energy ◽  
Binding Affinity ◽  
Immune Escape ◽  
Binding Free Energy ◽  
Experimental Studies ◽  
Potential Effect ◽  
Dynamics Simulation ◽  
Spike Protein ◽  
Energy Calculation ◽  
Potential Impact

Vaccines and antibody therapeutic are needed to fight the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that has spread since 2020. Experimental studies have shown that the E484K variant may escape the neutralization of antibodies. To explore the potential impact of E484K mutation on the antibody binding affinity, we calculated the binding free energy of 28 antibodies to the wild type and K484 mutant of the spike protein of SARS-CoV-2. We found that 71% of the antibodies show lower binding affinity to the E484K mutant, indicating the highly possible immune escape risk of the mutated virus. Further analysis revealed that the other mutations, e.g. F490 and V483, are also likely to cause immune escape.

scholarly journals Predicting the Potential Effect of E484K Mutation on the Binding of 28 Antibodies to the Spike Protein of SARS-CoV-2 by Molecular Dynamics Simulation and Free Energy Calculation

2021 ◽  
Author(s):  
Leyun Wu ◽  
Cheng Peng ◽  
Zhijian Xu ◽  
weiliang zhu
Keyword(s):  
Free Energy ◽  
Binding Affinity ◽  
Immune Escape ◽  
Binding Free Energy ◽  
Experimental Studies ◽  
Potential Effect ◽  
Dynamics Simulation ◽  
Spike Protein ◽  
Energy Calculation ◽  
Potential Impact

Vaccines and antibody therapeutic are needed to fight the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that has spread since 2020. Experimental studies have shown that the E484K variant may escape the neutralization of antibodies. To explore the potential impact of E484K mutation on the antibody binding affinity, we calculated the binding free energy of 28 antibodies to the wild type and K484 mutant of the spike protein of SARS-CoV-2. We found that 71% of the antibodies show lower binding affinity to the E484K mutant, indicating the highly possible immune escape risk of the mutated virus. Further analysis revealed that the other mutations, e.g. F490 and V483, are also likely to cause immune escape.

scholarly journals SARS-CoV-2 host cell entry: an in silico investigation of potential inhibitory roles of terpenoids

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Gideon A. Gyebi ◽  
Oludare M. Ogunyemi ◽  
Ibrahim M. Ibrahim ◽  
Olalekan B. Ogunro ◽  
Adegbenro P. Adegunloye ◽  
...  
Keyword(s):  
Free Energy ◽  
In Silico ◽  
Md Simulation ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Cell Entry ◽  
Spike Protein ◽  
Energy Calculations ◽  
Wide Range ◽  
Binding Free Energy Calculations

Abstract Background Targeting viral cell entry proteins is an emerging therapeutic strategy for inhibiting the first stage of SARS-CoV-2 infection. In this study, 106 bioactive terpenoids from African medicinal plants were screened through molecular docking analysis against human angiotensin-converting enzyme 2 (hACE2), human transmembrane protease serine 2 (TMPRSS2), and the spike (S) proteins of SARS-CoV-2, SARS-CoV, and MERS-CoV. In silico absorption-distribution-metabolism-excretion-toxicity (ADMET) and drug-likeness prediction, molecular dynamics (MD) simulation, binding free energy calculations, and clustering analysis of MD simulation trajectories were performed on the top docked terpenoids to respective protein targets. Results The results revealed eight terpenoids with high binding tendencies to the catalytic residues of different targets. Two pentacyclic terpenoids (24-methylene cycloartenol and isoiguesteri) interacted with the hACE2 binding hotspots for the SARS-CoV-2 spike protein, while the abietane diterpenes were found accommodated within the S1-specificity pocket, interacting strongly with the active site residues TMPRSS2. 3-benzoylhosloppone and cucurbitacin interacted with the RBD and S2 subunit of SARS-CoV-2 spike protein respectively. These interactions were preserved in a simulated dynamic environment, thereby, demonstrating high structural stability. The MM-GBSA binding free energy calculations corroborated the docking interactions. The top docked terpenoids showed favorable drug-likeness and ADMET properties over a wide range of molecular descriptors. Conclusion The identified terpenoids from this study provides core structure that can be exploited for further lead optimization to design drugs against SARS-CoV-2 cell-mediated entry proteins. They are therefore recommended for further in vitro and in vivo studies towards developing entry inhibitors against the ongoing COVID-19 pandemic.

scholarly journals Identification of Potential Binders of the SARS-Cov-2 Spike Protein via Molecular Docking, Dynamics Simulation and Binding Free Energy Calculation

2020 ◽  
Author(s):  
Dr. Chirag N. Patel ◽  
Dr. Prasanth Kumar S. ◽  
Dr. Himanshu A. Pandya ◽  
Dr. Rakesh M. Rawal
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Docking ◽  
Molecular Dynamics Simulations ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Dynamics Simulation ◽  
Spike Protein ◽  
Energy Calculations ◽  
Dynamics Simulations

<p>The pandemic outbreak of COVID-19 virus (SARS-CoV-2) has become critical global health issue. The biophysical and structural evidence shows that SARS-CoV-2 spike protein possesses higher binding affinity towards angiotensin-converting enzyme 2 (ACE2) and hemagglutinin-acetylesterase (HE) glycoprotein receptor. Hence, it was selected as a target to generate the potential candidates for the inhibition of HE glycoprotein. The present study focuses on extensive computational approaches which contains molecular docking, ADMET prediction followed by molecular dynamics simulations and free energy calculations. Furthermore, 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 were interact with high affinity. The ADMET prediction revealed pharmacokinetics and drug-likeness properties of top-ranked compounds. Molecular dynamics simulations and binding free energy calculations affirmed that these five NPACT compounds were robust HE inhibitor.</p>

scholarly journals Computational Determination of Potential Multiprotein Targeting Natural Compounds for Rational Drug Design Against SARS-COV-2

Molecules ◽  
2021 ◽  
Vol 26 (3) ◽  
pp. 674
Author(s):  
Ziyad Tariq Muhseen ◽  
Alaa R. Hameed ◽  
Halah M. H. Al-Hasani ◽  
Sajjad Ahmad ◽  
Guanglin Li
Keyword(s):  
Free Energy ◽  
Binding Energy ◽  
Binding Free Energy ◽  
Binding Mode ◽  
Natural Compounds ◽  
Rational Drug Design ◽  
Dynamics Simulation ◽  
Antiviral Compounds ◽  
Rational Drug ◽  
Key Residues

SARS-CoV-2 caused the current COVID-19 pandemic and there is an urgent need to explore effective therapeutics that can inhibit enzymes that are imperative in virus reproduction. To this end, we computationally investigated the MPD3 phytochemical database along with the pool of reported natural antiviral compounds with potential to be used as anti-SARS-CoV-2. The docking results demonstrated glycyrrhizin followed by azadirachtanin, mycophenolic acid, kushenol-w and 6-azauridine, as potential candidates. Glycyrrhizin depicted very stable binding mode to the active pocket of the Mpro (binding energy, −8.7 kcal/mol), PLpro (binding energy, −7.9 kcal/mol), and Nucleocapsid (binding energy, −7.9 kcal/mol) enzymes. This compound showed binding with several key residues that are critical to natural substrate binding and functionality to all the receptors. To test docking prediction, the compound with each receptor was subjected to molecular dynamics simulation to characterize the molecule stability and decipher its possible mechanism of binding. Each complex concludes that the receptor dynamics are stable (Mpro (mean RMSD, 0.93 Å), PLpro (mean RMSD, 0.96 Å), and Nucleocapsid (mean RMSD, 3.48 Å)). Moreover, binding free energy analyses such as MMGB/PBSA and WaterSwap were run over selected trajectory snapshots to affirm intermolecular affinity in the complexes. Glycyrrhizin was rescored to form strong affinity complexes with the virus enzymes: Mpro (MMGBSA, −24.42 kcal/mol and MMPBSA, −10.80 kcal/mol), PLpro (MMGBSA, −48.69 kcal/mol and MMPBSA, −38.17 kcal/mol) and Nucleocapsid (MMGBSA, −30.05 kcal/mol and MMPBSA, −25.95 kcal/mol), were dominated mainly by vigorous van der Waals energy. Further affirmation was achieved by WaterSwap absolute binding free energy that concluded all the complexes in good equilibrium and stability (Mpro (mean, −22.44 kcal/mol), PLpro (mean, −25.46 kcal/mol), and Nucleocapsid (mean, −23.30 kcal/mol)). These promising findings substantially advance our understanding of how natural compounds could be shaped to counter SARS-CoV-2 infection.

scholarly journals In silico comparison of SARS-CoV-2 spike protein-ACE2 binding affinities across species and implications for virus origin

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sakshi Piplani ◽  
Puneet Kumar Singh ◽  
David A. Winkler ◽  
Nikolai Petrovsky
Keyword(s):  
Binding Affinity ◽  
In Silico ◽  
Sequence Similarity ◽  
Homology Modelling ◽  
Protein Docking ◽  
Dynamics Simulation ◽  
Spike Protein ◽  
High Sequence Similarity ◽  
Virus Origin ◽  
Species Specific

AbstractThe devastating impact of the COVID-19 pandemic caused by SARS–coronavirus 2 (SARS-CoV-2) has raised important questions about its origins and the mechanism of its transfer to humans. A further question was whether companion or commercial animals could act as SARS-CoV-2 vectors, with early data suggesting susceptibility is species specific. To better understand SARS-CoV-2 species susceptibility, we undertook an in silico structural homology modelling, protein–protein docking, and molecular dynamics simulation study of SARS-CoV-2 spike protein’s ability to bind angiotensin converting enzyme 2 (ACE2) from relevant species. Spike protein exhibited the highest binding to human (h)ACE2 of all the species tested, forming the highest number of hydrogen bonds with hACE2. Interestingly, pangolin ACE2 showed the next highest binding affinity despite having a relatively low sequence homology, whereas the affinity of monkey ACE2 was much lower despite its high sequence similarity to hACE2. These differences highlight the power of a structural versus a sequence-based approach to cross-species analyses. ACE2 species in the upper half of the predicted affinity range (monkey, hamster, dog, ferret, cat) have been shown to be permissive to SARS-CoV-2 infection, supporting a correlation between binding affinity and infection susceptibility. These findings show that the earliest known SARS-CoV-2 isolates were surprisingly well adapted to bind strongly to human ACE2, helping explain its efficient human to human respiratory transmission. This study highlights how in silico structural modelling methods can be used to rapidly generate information on novel viruses to help predict their behaviour and aid in countermeasure development.

scholarly journals Improved binding affinity of the Omicron's spike protein with hACE2 receptor is the key factor behind its increased virulence

2021 ◽  
Author(s):  
Rajender Kumar ◽  
Murugan Natarajan Arul ◽  
Vaibhav Srivastava
Keyword(s):  
Free Energy ◽  
Hydrogen Bonding ◽  
Binding Affinity ◽  
Electrostatic Interactions ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Spike Protein ◽  
Strong Interactions ◽  
Salt Bridges ◽  
New Variant

The new variant of SARS-CoV-2, Omicron, has been quickly spreading in many countries worldwide. Compared to the original virus, Omicron is characterized by several mutations in its genomic region, including spike protein's receptor-binding domain (RBD). We have computationally investigated the interaction between RBD of both wild-type and omicron variants with hACE2 receptor using molecular dynamics and MM-GBSA based binding free energy calculations. The mode of the interaction between Omicron's RBD to the human ACE2 (hACE2) receptor is similar to the original SARS-CoV-2 RBD except for a few key differences. The bind-ing free energy difference shows that the spike protein of Omicron has increased binding affinity for the hACE-2 receptor. The mutated residues in the RBD showed strong interactions with a few amino acid residues of the hACE2. More specifically, strong electrostatic interactions (salt bridges) and hydrogen bonding were observed between R493 and R498 residues of the Omicron RBD with D30/E35 and D38 residues of the hACE2, respectively. Other mutated amino acids in the Omicron RBD, e.g. S496 and H505, also exhibited hydrogen bonding with the hACE2 receptor. The pi-stacking interaction was also observed between tyrosine residues (RBD-Tyr501: hACE2-Tyr41) in the complex, which contributes majorly to binding free energies suggesting this as one of the key interactions stabilizing the complex formation. The structural insights of RBD:hACE2 complex, their binding mode information and residue wise contributions to binding free energy provide insight on the increased transmissibility of Omicron and pave the way to design and optimize novel antiviral agents.

scholarly journals Virtual screening, molecular dynamics and binding energy-MM-PBSA studies of natural compounds to identify potential EcR inhibitors against Bemisia tabaci Gennadius

2021 ◽  
Author(s):  
Harmilan Kaur Mangat ◽  
Manisha Rani ◽  
Rajesh Kumar Pathak ◽  
Inderjit Singh Yadav ◽  
Divya Utreja ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Binding Energy ◽  
Virtual Screening ◽  
Bemisia Tabaci ◽  
Binding Free Energy ◽  
Insect Pest ◽  
Natural Compounds ◽  
Dynamics Simulation ◽  
Economic Losses

Abstract Whitefly (Bemisia tabaci Gennadius) is a hmpteran phyto polyphagous sucking insect pest which is an important pest of cotton that causes economic losses to the crop by reducing its yield and quality. Ecdysteroids like 20-hydroxy ecdysone (20-E), have significant role in larval moulting, development, and reproduction in pterygota insects. Intending to obstruct these fundamental, developmental physiological processes, the receptor of 20-E, the Ecdysone Receptor (BtEcR) of Bemisia tabaci has been targeted. To identify potent inhibitors of BtEcr, 98,072 natural compounds were retrieved from ZINC database. A structure-based virtual screening of these compounds was conducted for their binding to BtEcR and the top two compounds (ZINC08952607 and ZINC04264850) were selected based on minimum binding energy. 50 ns molecular dynamics simulation (MDS) study was then performed for the prediction of dynamics and stability of BtEcR and top-scoring ligand-BtEcR complexes. Besides, g_mmpbsa tool was used to calculate and analyse binding free energy of BtEcR-ligand complexes. The results revealed that ZINC08952607 and ZINC04264850 had binding free energy of −170.156 kJ/mol and −200.349 kJ/mol, respectively. Thus, these ligands can be utilized as lead compounds for the development of environmentally safe insecticides against the whitefly.

scholarly journals Identification of Potential Binders of the SARS-Cov-2 Spike Protein via Molecular Docking, Dynamics Simulation and Binding Free Energy Calculation

2020 ◽  
Author(s):  
Dr. Chirag N. Patel ◽  
Dr. Prasanth Kumar S. ◽  
Dr. Himanshu A. Pandya ◽  
Dr. Rakesh M. Rawal
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Docking ◽  
Molecular Dynamics Simulations ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Dynamics Simulation ◽  
Spike Protein ◽  
Energy Calculations ◽  
Dynamics Simulations

<p>The pandemic outbreak of COVID-19 virus (SARS-CoV-2) has become critical global health issue. The biophysical and structural evidence shows that SARS-CoV-2 spike protein possesses higher binding affinity towards angiotensin-converting enzyme 2 (ACE2) and hemagglutinin-acetylesterase (HE) glycoprotein receptor. Hence, it was selected as a target to generate the potential candidates for the inhibition of HE glycoprotein. The present study focuses on extensive computational approaches which contains molecular docking, ADMET prediction followed by molecular dynamics simulations and free energy calculations. Furthermore, 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 were interact with high affinity. The ADMET prediction revealed pharmacokinetics and drug-likeness properties of top-ranked compounds. Molecular dynamics simulations and binding free energy calculations affirmed that these five NPACT compounds were robust HE inhibitor.</p>

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