scholarly journals Dieckol and Its Derivatives as Potential Inhibitors of SARS-CoV-2 Spike Protein (UK Strain: VUI 202012/01): A Computational Study

Marine Drugs ◽  
2021 ◽  
Vol 19 (5) ◽  
pp. 242
Author(s):  
Mohammad Aatif ◽  
Ghazala Muteeb ◽  
Abdulrahman Alsultan ◽  
Adil Alshoaibi ◽  
Bachir Yahia Khelif
Keyword(s):  
Electrostatic Interactions ◽  
Hydrophobic Interactions ◽  
Computational Study ◽  
Free Energy Calculations ◽  
High Rate ◽  
Dynamics Simulation ◽  
Spike Protein ◽  
In Vivo Studies ◽  
Binding Potential ◽  
Primary Role

The high risk of morbidity and mortality associated with SARS-CoV-2 has accelerated the development of many potential vaccines. However, these vaccines are designed against SARS-CoV-2 isolated in Wuhan, China, and thereby may not be effective against other SARS-CoV-2 variants such as the United Kingdom variant (VUI-202012/01). The UK SARS-CoV-2 variant possesses D614G mutation in the Spike protein, which impart it a high rate of infection. Therefore, newer strategies are warranted to design novel vaccines and drug candidates specifically designed against the mutated forms of SARS-CoV-2. One such strategy is to target ACE2 (angiotensin-converting enzyme2)–Spike protein RBD (receptor binding domain) interaction. Here, we generated a homology model of Spike protein RBD of SARS-CoV-2 UK strain and screened a marine seaweed database employing different computational approaches. On the basis of high-throughput virtual screening, standard precision, and extra precision molecular docking, we identified BE011 (Dieckol) as the most potent compounds against RBD. However, Dieckol did not display drug-like properties, and thus different derivatives of it were generated in silico and evaluated for binding potential and drug-like properties. One Dieckol derivative (DK07) displayed good binding affinity for RBD along with acceptable physicochemical, pharmacokinetic, drug-likeness, and ADMET properties. Analysis of the RBD–DK07 interaction suggested the formation of hydrogen bonds, electrostatic interactions, and hydrophobic interactions with key residues mediating the ACE2–RBD interaction. Molecular dynamics simulation confirmed the stability of the RBD–DK07 complex. Free energy calculations suggested the primary role of electrostatic and Van der Waals’ interaction in stabilizing the RBD–DK07 complex. Thus, DK07 may be developed as a potential inhibitor of the RBD–ACE2 interaction. However, these results warrant further validation by in vitro and in vivo studies.

scholarly journals Identification of Natural Compounds (Proanthocyanidin and Rhapontin) as High-Affinity Inhibitor of SARS-CoV-2 Mpro and PLpro using Computational Strategies

2021 ◽  
Author(s):  
Mohamed AlAjmi ◽  
Asim Azhar ◽  
Sadaf Hasan ◽  
Abdullah Alshabr ◽  
Afzal Hussain ◽  
...  
Keyword(s):  
Hydrophobic Interactions ◽  
Economic Loss ◽  
Natural Compounds ◽  
Free Energy Calculations ◽  
Dynamics Simulation ◽  
In Vivo Studies ◽  
Protein Inhibitor ◽  
Active Site Residues

IntroductionThe emergence of a new and highly pathogenic coronavirus (SARS-CoV-2) in Wuhan (China) and its spread worldwide has resulted in enormous social and economic loss. Amongst many proteins encoded by SARS-CoV-2 genome, the main protease (Mpro) or chymotrypsin-like cysteine protease (3CLpro) and Papain-like protease (PLpro) serve as an attractive drug target.Material and methodsWe screened a library of 2267 natural compounds against Mpro and PLpro using high throughput virtual screening (HTVS). 50 top-scoring compounds against each protein in HTVS were further evaluated by standard-precision (SP) docking. Compounds with SP docking energy of ≤ -8.0 kcal mol-1 against Mpro and ≤ -5.0 kcal mol-1 against PLpro were subjected to extra-precision (XP) docking. Finally, six compounds against each target proteins were identified and subjected to Prime/MM-GBSA free energy calculations. Compounds with the lowest Prime/MM-GBSA energy were subjected to molecular dynamics simulation to evaluate the stability of protein-ligand complexes.ResultsProanthocyanidin and Rhapontin were identified as the most potent inhibitors of Mpro and PLpro, respectively. Analysis of protein-inhibitor interaction revealed that both protein-inhibitor complexes were stabilized by hydrogen bonding and hydrophobic interactions. Proanthocyanidin interacted with the catalytic residues (His41 and Cys145) of Mpro, while Rhapontin contacted the active site residues (Trp106, His272, Asp286) of PLpro. The docking energies of Proanthocyanidin and Rhapontin towards their respective targets were -10.566 and -10.022 kcal/mol.ConclusionsThis study's outcome may serve Proanthocyanidin and Rhapontin as a scaffold to build more potent inhibitors with desirable drug-like properties. However, it requires further validations by in vitro and in vivo studies.

scholarly journals Screening marine algae metabolites as high-affinity inhibitors of SARS-CoV-2 main protease (3CLpro): an in silico analysis to identify novel drug candidates to combat COVID-19 pandemic

2020 ◽  
Vol 63 (1) ◽  
Author(s):  
Ghazala Muteeb ◽  
Adil Alshoaibi ◽  
Mohammad Aatif ◽  
Md. Tabish Rehman ◽  
M. Zuhaib Qayyum
Keyword(s):  
Hydrophobic Interactions ◽  
In Silico Analysis ◽  
Salt Bridge ◽  
Competitive Inhibitor ◽  
Binding Energies ◽  
Dynamics Simulation ◽  
In Vivo Studies ◽  
Energy Calculation

AbstractThe recent dissemination of SARS-CoV-2 from Wuhan city to all over the world has created a pandemic. COVID-19 has cost many human lives and created an enormous economic burden. Although many drugs/vaccines are in different stages of clinical trials, still none is clinically available. We have screened a marine seaweed database (1110 compounds) against 3CLpro of SARS-CoV-2 using computational approaches. High throughput virtual screening was performed on compounds, and 86 of them with docking score <  − 5.000 kcal mol−1 were subjected to standard-precision docking. Based on binding energies (< − 6.000 kcal mol−1), 9 compounds were further shortlisted and subjected to extra-precision docking. Free energy calculation by Prime-MM/GBSA suggested RC002, GA004, and GA006 as the most potent inhibitors of 3CLpro. An analysis of ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) properties of RC002, GA004, and GA006 indicated that only RC002 (callophysin A, from red alga Callophycus oppositifolius) passed Lipinski’s, Veber’s, PAINS and Brenk’s filters and displayed drug-like and lead-like properties. Analysis of 3CLpro-callophysin A complex revealed the involvement of salt bridge, hydrogen bonds, and hydrophobic interactions. callophysin A interacted with the catalytic residues (His41 and Cys145) of 3CLpro; hence it may act as a mechanism-based competitive inhibitor. Docking energy and docking affinity of callophysin A towards 3CLpro was − 8.776 kcal mol−1 and 2.73 × 106 M−1, respectively. Molecular dynamics simulation confirmed the stability of the 3CLpro-callophysin A complex. The findings of this study may serve as the basis for further validation by in vitro and in vivo studies.

scholarly journals Computational Investigation of Structural Dynamics of SARS-CoV-2 Methyltransferase-Stimulatory Factor Heterodimer Nsp16/nsp10 Bound to the Cofactor SAM

2020 ◽  
Author(s):  
Md Fulbabu Sk ◽  
Nisha Amarnath Jonniya ◽  
Rajarshi Roy ◽  
Sayan Poddar ◽  
Parimal Kar
Keyword(s):  
Protein Interactions ◽  
Electrostatic Interactions ◽  
Immune Escape ◽  
Hydrophobic Interactions ◽  
Conformational Dynamics ◽  
Rna Stability ◽  
Protein Translation ◽  
Dynamics Simulation ◽  
Mtase Activity ◽  
Computational Alanine Scanning

Recently, a highly contagious novel coronavirus (COVID-19 or SARS-CoV-2) has emerged as a global threat in people's health and global economies. Identification of the potential targets and development of a vaccine or antiviral drugs is an urgent demand. The 5’-capping mechanism of eukaryotic mRNA and some viruses such as coronaviruses (CoVs) are essential for maintaining the RNA stability, protein translation, and for viral immune escape. SARSCoV encodes S-adenosyl-L-methionine dependent (SAM) methyltransferase (MTase) enzyme characterized by nsp16 (2’-O-MTase) for generating the capped structure. The present article highlights the binding mechanisms of nsp16 and nsp10 to identify the role of nsp10 in MTase activity. Furthermore, the conformational dynamics and energetic behind the SAM binding to nsp16 in its monomer and dimer form was analyzed by using an extensive molecular dynamics simulation along with the Molecular Mechanics Poisson-Boltzmann Surface Area (MM/PBSA). Our results show that the presence of nsp10 increases the favorable van der Waal and electrostatic interactions between the SAM and nsp16, thus nsp10 acts as a stimulator for its strong binding. The interaction profile suggests that hydrophobic interactions were predominately identified for protein-protein interactions. Also, the stable hydrogen bond between Ala83 (nsp16) and Tyr96 (nsp10), and between Gln87 (nsp16) and Leu45 (nsp10) plays a vital role in the nsp16-nsp10 interface. Further, Computational Alanine Scanning (CAS) mutagenesis was performed, which revealed hotspot mutants, namely I40A, V104A, and R86A for the dimer association. Therefore, the dimer interface of nsp16/nsp10 could also be a potential target to suppress the 2’-O-MTase activity of SARS-CoV-2. Overall, our study provides a comprehensive understanding of the dynamic and thermodynamic process of binding of nsp16 and nsp10 that will contribute to the novel design of peptide inhibitors based on nsp16.

scholarly journals In SilicoInsight into Potent of Anthocyanin Regulation of FKBP52 to Prevent Alzheimer’s Disease

2014 ◽  
Vol 2014 ◽  
pp. 1-20 ◽  
Author(s):  
Tzu-Chieh Hung ◽  
Tung-Ti Chang ◽  
Ming-Jen Fan ◽  
Cheng-Chun Lee ◽  
Calvin Yu-Chian Chen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amino Acids ◽  
Protein Aggregation ◽  
Tau Protein ◽  
Hydrophobic Interactions ◽  
Dynamics Simulation ◽  
Binding Potential ◽  
Ligand Interaction ◽  
Structure Variation

Alzheimer’s disease (AD) is caused by the hyperphosphorylation of Tau protein aggregation. FKBP52 (FK506 binding protein 52) has been found to inhibit Tau protein aggregation. This study found six different kinds of anthocyanins that have high binding potential. After analyzing the docking positions, hydrophobic interactions, and hydrogen bond interactions, several amino acids were identified that play important roles in protein and ligand interaction. The proteins’ variation is described using eigenvectors and the distance between the amino acids during a molecular dynamics simulation (MD). This study investigates the three loops based around Glu85, Tyr113, and Lys121—all of which are important in inducing FKBP52 activation. By performing a molecular dynamic simulation process between unbound proteins and the protein complex with FK506, it was found that ligand targets that docked onto the FK1 domain will decrease the distance between Glu85/Tyr113 and Glu85/Lys121. The FKBP52 structure variation may induce FKBP52 activation and inhibit Tau protein aggregation. The results indicate that anthocyanins might change the conformation of FKBP52 during binding. In addition, the purple anthocyanins, such as cyanidin-3-glucoside and malvidin-3-glucoside, might be better than FK506 in regulating FKBP52 and treating Alzheimer’s disease.

scholarly journals Computational Investigation of Structural Dynamics of SARS-CoV-2 Methyltransferase-Stimulatory Factor Heterodimer Nsp16/nsp10 Bound to the Cofactor SAM

2020 ◽  
Author(s):  
Md Fulbabu Sk ◽  
Nisha Amarnath Jonniya ◽  
Rajarshi Roy ◽  
Sayan Poddar ◽  
Parimal Kar
Keyword(s):  
Protein Interactions ◽  
Electrostatic Interactions ◽  
Immune Escape ◽  
Hydrophobic Interactions ◽  
Conformational Dynamics ◽  
Rna Stability ◽  
Protein Translation ◽  
Dynamics Simulation ◽  
Mtase Activity ◽  
Computational Alanine Scanning

Recently, a highly contagious novel coronavirus (COVID-19 or SARS-CoV-2) has emerged as a global threat in people's health and global economies. Identification of the potential targets and development of a vaccine or antiviral drugs is an urgent demand. The 5’-capping mechanism of eukaryotic mRNA and some viruses such as coronaviruses (CoVs) are essential for maintaining the RNA stability, protein translation, and for viral immune escape. SARSCoV encodes S-adenosyl-L-methionine dependent (SAM) methyltransferase (MTase) enzyme characterized by nsp16 (2’-O-MTase) for generating the capped structure. The present article highlights the binding mechanisms of nsp16 and nsp10 to identify the role of nsp10 in MTase activity. Furthermore, the conformational dynamics and energetic behind the SAM binding to nsp16 in its monomer and dimer form was analyzed by using an extensive molecular dynamics simulation along with the Molecular Mechanics Poisson-Boltzmann Surface Area (MM/PBSA). Our results show that the presence of nsp10 increases the favorable van der Waal and electrostatic interactions between the SAM and nsp16, thus nsp10 acts as a stimulator for its strong binding. The interaction profile suggests that hydrophobic interactions were predominately identified for protein-protein interactions. Also, the stable hydrogen bond between Ala83 (nsp16) and Tyr96 (nsp10), and between Gln87 (nsp16) and Leu45 (nsp10) plays a vital role in the nsp16-nsp10 interface. Further, Computational Alanine Scanning (CAS) mutagenesis was performed, which revealed hotspot mutants, namely I40A, V104A, and R86A for the dimer association. Therefore, the dimer interface of nsp16/nsp10 could also be a potential target to suppress the 2’-O-MTase activity of SARS-CoV-2. Overall, our study provides a comprehensive understanding of the dynamic and thermodynamic process of binding of nsp16 and nsp10 that will contribute to the novel design of peptide inhibitors based on nsp16.

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 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 Non-RBM Mutations Impaired SARS-CoV-2 Spike Protein Regulated to the ACE2 Receptor Based on Molecular Dynamic Simulation

2021 ◽  
Vol 8 ◽  
Author(s):  
Yaoqiang Du ◽  
Hao Wang ◽  
Linjie Chen ◽  
Quan Fang ◽  
Biqin Zhang ◽  
...  
Keyword(s):  
Free Energy ◽  
Receptor Binding ◽  
Electrostatic Interactions ◽  
Hydrophobic Interactions ◽  
Binding Free Energy ◽  
Host Cells ◽  
Dynamics Simulation ◽  
Random Coil ◽  
Binding Motif ◽  
Binding Loop

The emergence of novel coronavirus mutants is a main factor behind the deterioration of the epidemic situation. Further studies into the pathogenicity of these mutants are thus urgently needed. Binding of the spinous protein receptor binding domain (RBD) of SARS-CoV-2 to the angiotensin-converting enzyme 2 (ACE2) receptor was shown to initiate coronavirus entry into host cells and lead to their infection. The receptor-binding motif (RBM, 438–506) is a region that directly interacts with ACE2 receptor in the RBD and plays a crucial role in determining affinity. To unravel how mutations in the non-RBM regions impact the interaction between RBD and ACE2, we selected three non-RBM mutant systems (N354D, D364Y, and V367F) from the documented clinical cases, and the Q498A mutant system located in the RBM region served as the control. Molecular dynamics simulation was conducted on the mutant systems and the wild-type (WT) system, and verified experiments also performed. Non-RBM mutations have been shown not only to change conformation of the RBM region but also to significantly influence its hydrogen bonding and hydrophobic interactions. In particular, the D364Y and V367F systems showed a higher affinity for ACE2 owing to their electrostatic interactions and polar solvation energy changes. In addition, although the binding free energy at this point increased after the mutation of N354D, the conformation of the random coil (Pro384-Asp389) was looser than that of other systems, and the combined effect weakened the binding free energy between RBD and ACE2. Interestingly, we also found a random coil (Ala475-Gly485). This random coil is very sensitive to mutations, and both types of mutations increase the binding free energy of residues in this region. We found that the binding loop (Tyr495-Tyr505) in the RBD domain strongly binds to Lys353, an important residue of the ACE2 domain previously identified. The binding free energy of the non-RBM mutant group at the binding loop had positive and negative changes, and these changes were more obvious than that of the Q498A system. The results of this study elucidate the effect of non-RBM mutation on ACE2-RBD binding, and provide new insights for SARS-CoV-2 mutation research.

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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