scholarly journals Identification of Natural Inhibitors Against SARS-CoV-2 Drugable Targets Using Molecular Docking, Molecular Dynamics Simulation, and MM-PBSA Approach

2021 ◽  
Vol 11 ◽  
Author(s):  
Prem Prakash Kushwaha ◽  
Atul Kumar Singh ◽  
Tanya Bansal ◽  
Akansha Yadav ◽  
Kumari Sunita Prajapati ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Docking ◽  
Active Site ◽  
Md Simulation ◽  
Dynamics Simulation ◽  
Stable Complex ◽  
Kcal Mole ◽  
Hydrogen Bond Formation ◽  
Docking Score

The present study explores the SARS-CoV-2 drugable target inhibition efficacy of phytochemicals from Indian medicinal plants using molecular docking, molecular dynamics (MD) simulation, and MM-PBSA analysis. A total of 130 phytochemicals were screened against SARS-CoV-2 Spike (S)-protein, RNA-dependent RNA polymerase (RdRp), and Main protease (Mpro). Result of molecular docking showed that Isoquercetin potentially binds with the active site/protein binding site of the Spike, RdRP, and Mpro targets with a docking score of -8.22, -6.86, and -9.73 kcal/mole, respectively. Further, MS 3, 7-Hydroxyaloin B, 10-Hydroxyaloin A, showed -9.57, -7.07, -8.57 kcal/mole docking score against Spike, RdRP, and Mpro targets respectively. The MD simulation was performed to study the favorable confirmation and energetically stable complex formation ability of Isoquercetin and 10-Hydroxyaloin A phytochemicals in Mpro-unbound/ligand bound/standard inhibitor bound system. The parameters such as RMSD, RMSF, Rg, SASA, Hydrogen-bond formation, energy landscape, principal component analysis showed that the lead phytochemicals form stable and energetically stabilized complex with the target protein. Further, MM-PBSA analysis was performed to compare the Gibbs free energy of the Mpro-ligand bound and standard inhibitor bound complexes. The analysis revealed that the His-41, Cys145, Met49, and Leu27 amino acid residues were majorly responsible for the lower free energy of the complex. Drug likeness and physiochemical properties of the test compounds showed satisfactory results. Taken together, the study concludes that that the Isoquercetin and 10-Hydroxyaloin A phytochemical possess significant efficacy to bind SARS-Cov-2 Mpro active site. The study necessitates further in vitro and in vivo experimental validation of these lead phytochemicals to assess their anti-SARS-CoV-2 potential.

scholarly journals High-Throughput Virtual Screening, Molecular Dynamics Simulation, and Enzyme Kinetics Identified ZINC84525623 as a Potential Inhibitor of NDM-1

2019 ◽  
Vol 20 (4) ◽  
pp. 819 ◽  
Author(s):  
Md Rehman ◽  
Mohamed AlAjmi ◽  
Afzal Hussain ◽  
Gulam Rather ◽  
Meraj Khan
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Virtual Screening ◽  
Enzyme Kinetics ◽  
High Throughput ◽  
Md Simulation ◽  
Dynamics Simulation ◽  
Multi Drug Resistance ◽  
Stable Complex ◽  
High Throughput Virtual Screening

The bacteria expressing New Delhi Metallo-β-lactamase-1 (NDM-1) can hydrolyze all β-lactam antibiotics including carbapenems, causing multi-drug resistance. The worldwide emergence and dissemination of gene blaNDM-1 (produces NDM-1) in hospital and community settings, rising problems for public health. Indeed, there is an urgent need for NDM-1 inhibitors to manage antibiotic resistance. Here, we have identified novel non-β-lactam ring-containing inhibitors of NDM-1 by applying a high-throughput virtual screening of lead-like subset of ZINC database. The screened compounds were followed for the molecular docking, the molecular dynamics simulation, and then enzyme kinetics assessment. The adopted screening procedure funnels out five novel inhibitors of NDM-1 including ZINC10936382, ZINC30479078, ZINC41493045, ZINC7424911, and ZINC84525623. The molecular mechanics-generalized born surface area and molecular dynamics (MD) simulation showed that ZINC84525623 formed the most stable complex with NDM-1. Furthermore, analyses of the binding pose after MD simulation revealed that ZINC84525623 formed two hydrogen bonds (electrostatic and hydrophobic interaction) with key amino acid residues of the NDM-1 active site. The docking binding free energy and docking binding constant for the ZINC84525623 and NDM-1 interaction were estimated to be −11.234 kcal/mol, and 1.74 × 108 M−1 respectively. Steady-state enzyme kinetics in the presence of ZINC84525623 show the decreased catalytic efficiency (i.e., kcat/Km) of NDM-1 on various antibiotics. The findings of this study would be helpful in identifying novel inhibitors against other β-lactamases from a pool of large databases. Furthermore, the identified inhibitor (ZINC84525623) could be developed as efficient drug candidates.

scholarly journals Phytochemicals from Leucas zeylanica Targeting Main Protease of SARS-CoV-2: Chemical Profiles, Molecular Docking, and Molecular Dynamics Simulations

Biology ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 789
Author(s):  
Mycal Dutta ◽  
Abu Montakim Tareq ◽  
Ahmed Rakib ◽  
Shafi Mahmud ◽  
Saad Ahmed Sami ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Molecular Dynamics Simulation ◽  
Surface Area ◽  
Dynamics Simulation ◽  
Solvent Accessible Surface Area ◽  
Gas Chromatography Mass Spectrometry ◽  
Radius Of Gyration ◽  
Hydrogen Bond Formation ◽  
Main Protease

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a contemporary coronavirus, has impacted global economic activity and has a high transmission rate. As a result of the virus’s severe medical effects, developing effective vaccinations is vital. Plant-derived metabolites have been discovered as potential SARS-CoV-2 inhibitors. The SARS-CoV-2 main protease (Mpro) is a target for therapeutic research because of its highly conserved protein sequence. Gas chromatography–mass spectrometry (GC-MS) and molecular docking were used to screen 34 compounds identified from Leucas zeylanica for potential inhibitory activity against the SARS-CoV-2 Mpro. In addition, prime molecular mechanics–generalized Born surface area (MM-GBSA) was used to screen the compound dataset using a molecular dynamics simulation. From molecular docking analysis, 26 compounds were capable of interaction with the SARS-CoV-2 Mpro, while three compounds, namely 11-oxa-dispiro[4.0.4.1]undecan-1-ol (−5.755 kcal/mol), azetidin-2-one 3,3-dimethyl-4-(1-aminoethyl) (−5.39 kcal/mol), and lorazepam, 2TMS derivative (−5.246 kcal/mol), exhibited the highest docking scores. These three ligands were assessed by MM-GBSA, which revealed that they bind with the necessary Mpro amino acids in the catalytic groove to cause protein inhibition, including Ser144, Cys145, and His41. The molecular dynamics simulation confirmed the complex rigidity and stability of the docked ligand–Mpro complexes based on the analysis of mean radical variations, root-mean-square fluctuations, solvent-accessible surface area, radius of gyration, and hydrogen bond formation. The study of the postmolecular dynamics confirmation also confirmed that lorazepam, 11-oxa-dispiro[4.0.4.1]undecan-1-ol, and azetidin-2-one-3, 3-dimethyl-4-(1-aminoethyl) interact with similar Mpro binding pockets. The results of our computerized drug design approach may assist in the fight against SARS-CoV-2.

scholarly journals Discovery of New Hydroxyethylamine Analogs Against 3CLpro Protein Target of SARS-CoV-2: Molecular Docking, Molecular Dynamics Simulation and Structure-Activity Relationship Studies

2020 ◽  
Author(s):  
Sumit Kumar ◽  
Prem Prakash Sharma ◽  
Uma Shankar ◽  
Dhruv Kumar ◽  
Sanjeev K Joshi ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Cysteine Protease ◽  
Binding Pocket ◽  
Structure Activity Relationship ◽  
Dynamics Simulation ◽  
Activity Relationship ◽  
Docking Score ◽  
Structure Activity ◽  
Novel Coronavirus

<p><br></p> <p>A novel coronavirus, SARS-CoV-2 has caused a recent pandemic called COVID-19 and a severe health threat around the world. In the current situation, the virus is rapidly spreading worldwide, and the discovery of vaccine and potential therapeutics are critically essential. The crystal structure for main protease (M<sup>pro</sup>) of SARS-CoV-2, 3-chymotrypsin-like cysteine protease (3CL<sup>pro</sup>) was recently made available and is considerably similar to previously reported SARS-CoV. Due to its essentiality in viral replication, it represents a potential drug target. Herein, computer-aided drug design (CADD) approach was implemented for the initial screening of 13 approved antiviral drugs. Molecular docking of 13 antivirals against 3-chymotrypsin-like cysteine protease (3CL<sup>pro</sup>) enzyme was accomplished and indinavir was described as a lead drug with a docking score of -8.824 and a XP Gscore of -9.466 kcal/mol. Indinavir possesses an important pharmacophore, hydroxyethylamine (HEA), and thus a new library of HEA compounds (>2500) was subjected to virtual screening that led to 25 hits with a docking score more than indinavir. Exclusively, compound <b>16</b> with docking score of -8.955 adhered to drug like parameters, and the Structure-Activity Relationship (SAR) analysis was demonstrated to highlight the importance of chemical scaffolds therein. Molecular Dynamics (MD) simulation studies carried out at 100ns supported the stability of <b>16</b> within the binding pocket. Largly, our results supported that this novel compound <b>16</b> binds to the domain I & II, and domain II-III linker of 3CL<sup>pro</sup> protein, suggesting its suitablity as strong candidate for therapeutic discovery against COVID-19. Lead compound <b>16</b> could pave incredible directions for the design of novel 3CL<sup>pro</sup> inhibitors and ultimately therapeutics against COVID-19 disease.</p> <p><br></p> <p> </p>

scholarly journals Molecular Docking and Molecular Dynamics Studies of SARS-CoV-2 Inhibitors: Crocin, Digitoxigenin, Beta-Eudesmol and Favipiravir: Comparative Study

2021 ◽  
Vol 12 (4) ◽  
pp. 5591-5600
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Molecular Dynamics Simulation ◽  
Comparative Study ◽  
Active Site ◽  
Antiviral Treatment ◽  
Docking Study ◽  
The Other ◽  
Dynamics Simulation ◽  
Main Protease

In this study, Crocin, Digitoxigenin, Beta-Eudesmol, and Favipiravir were docked in the active site of SARS-CoV-2 main protease (PDB code: 6LU7). The docking study was followed by Molecular Dynamics simulation. The result indicates that Crocin and Digitoxigenin are the structures with the best affinity in the studied enzyme's binding site. Still, Molecular Dynamics simulation showed that Digitoxigenin is the molecule that fits better in the active site of the main protease. Therefore, this molecule could have a more potent antiviral treatment of COVID-19 than the other three studied compounds.

scholarly journals Discovery of New Hydroxyethylamine Analogs Against 3CLpro Protein Target of SARS-CoV-2: Molecular Docking, Molecular Dynamics Simulation and Structure-Activity Relationship Studies

2020 ◽  
Author(s):  
Sumit Kumar ◽  
Prem Prakash Sharma ◽  
Uma Shankar ◽  
Dhruv Kumar ◽  
Sanjeev K Joshi ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Cysteine Protease ◽  
Binding Pocket ◽  
Structure Activity Relationship ◽  
Dynamics Simulation ◽  
Activity Relationship ◽  
Docking Score ◽  
Structure Activity ◽  
Novel Coronavirus

<p><br></p> <p>A novel coronavirus, SARS-CoV-2 has caused a recent pandemic called COVID-19 and a severe health threat around the world. In the current situation, the virus is rapidly spreading worldwide, and the discovery of vaccine and potential therapeutics are critically essential. The crystal structure for main protease (M<sup>pro</sup>) of SARS-CoV-2, 3-chymotrypsin-like cysteine protease (3CL<sup>pro</sup>) was recently made available and is considerably similar to previously reported SARS-CoV. Due to its essentiality in viral replication, it represents a potential drug target. Herein, computer-aided drug design (CADD) approach was implemented for the initial screening of 13 approved antiviral drugs. Molecular docking of 13 antivirals against 3-chymotrypsin-like cysteine protease (3CL<sup>pro</sup>) enzyme was accomplished and indinavir was described as a lead drug with a docking score of -8.824 and a XP Gscore of -9.466 kcal/mol. Indinavir possesses an important pharmacophore, hydroxyethylamine (HEA), and thus a new library of HEA compounds (>2500) was subjected to virtual screening that led to 25 hits with a docking score more than indinavir. Exclusively, compound <b>16</b> with docking score of -8.955 adhered to drug like parameters, and the Structure-Activity Relationship (SAR) analysis was demonstrated to highlight the importance of chemical scaffolds therein. Molecular Dynamics (MD) simulation studies carried out at 100ns supported the stability of <b>16</b> within the binding pocket. Largly, our results supported that this novel compound <b>16</b> binds to the domain I & II, and domain II-III linker of 3CL<sup>pro</sup> protein, suggesting its suitablity as strong candidate for therapeutic discovery against COVID-19. Lead compound <b>16</b> could pave incredible directions for the design of novel 3CL<sup>pro</sup> inhibitors and ultimately therapeutics against COVID-19 disease.</p> <p><br></p> <p> </p>

scholarly journals Interaction between β-lactoglobulin and EGCG under high-pressure by molecular dynamics simulation

2021 ◽  
Author(s):  
yechuan huang ◽  
Xicai Zhang ◽  
huayi suo
Keyword(s):  
Molecular Dynamics ◽  
High Pressure ◽  
Free Energy ◽  
Molecular Docking ◽  
Small Molecules ◽  
Binding Free Energy ◽  
Dynamics Simulation ◽  
Solvent Accessible Surface Area ◽  
Α Helix ◽  
Β Lactoglobulin

The binding between β-lactoglobulin and epigallocatechin gallate (EGCG) under the pressure of 600 MPa was explored using molecular docking and molecular dynamics (MD) simulation. EGCG bound mainly in two regions with site 1 in internal cavity of the β-barrel and site 2 on the surface of protein. 150 ns MD was performed starting from the structure with the lowest binding energy at the two sites in molecular docking, respectively, it was found that the system fluctuated greatly when small molecule bound to site 2 at 0.1 MPa. The protein fluctuation and solvent accessible surface area became smaller under high-pressure. The binding of small molecules made the protein structure more stable with increasing of α-helix and β-sheet, while high-pressure destroyed α-helix of protein. The binding free energy of small molecules at site 1was higher than that at site 2 under 0.1 MPa, with higher van der Waals and hydrophobic interaction at site 1 while more hydrogen bonds at site 2. The binding free energy of both sites decreased under high-pressure, especially at site 1, causing binding free energy at site 1 was lower than that at site 2 under high-pressure.

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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