scholarly journals Structure-based virtual screening suggests inhibitors of 3-Chymotrypsin-Like Protease of SARS-CoV-2 from Vernonia amygdalina and Occinum gratissimum

2021 ◽  
Author(s):  
Gideon A. Gyebi ◽  
Abdo A. Elfiky ◽  
Oludare M. Ogunyemi ◽  
Ibrahim M. Ibrahim ◽  
Adegbenro P. Adegunloye ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
In Silico ◽  
Hydrophobic Interactions ◽  
Binding Free Energy ◽  
Intermediate Formation ◽  
Binding Energies ◽  
Dynamics Simulation ◽  
Energy Calculation ◽  
Vernonia Amygdalina

Abstract An in-house library of 173 phytocompound structures from Vernonia amygdalina and Occinum gratissimum was screened against the active region of 3-Chymotrypsin-Like Protease (3CLpro) of SARS-CoV-2 in silico. Based on docking scores and reference inhibitors, a hit- list of 21 phytocompounds, with binding energies ranging from − 7.2 to -8.0 kcal/mol, was initially generated. Further docking against the 3CLpro of related coronaviruses (SARS-CoV and MERS-CoV), docking to 5 different representative conformations generated from the cluster analysis of SARS-CoV-2 3CLpro molecular dynamics simulation (MDS) trajectories, and in silico drug-likeness analyses, revealed two drug-like terpenoid structures as promising non-covalent inhibitors of SARS-CoV-2 3CLPro viz: neoandrographolide and vernolide. These terpenoid structures are accommodated within the substrate-binding pocket, and interacted with the catalytic dyad, the oxyanion loop (residues 138–145), and the S1/S2 subsites of the enzyme active site. With the aid of an array of hydrogen bonds and hydrophobic interactions with residues 142–145, these phytocompounds may stabilize the conformation of the flexible oxyanion loop; and thereby interfere with the tetrahedral oxyanion intermediate formation during proteolytic cleavage. Molecular dynamics simulation and binding free energy calculation further revealed that the terpenoid-enzyme complexes exhibit strong interactions and structural stability, which could be adapted for experimental models.

scholarly journals Prediction of Drug Potencies of BACE1 Inhibitors: A Molecular Dynamics Simulation and MM_GB(PB)SA Scoring

2020 ◽  
Author(s):  
Mazen Hamed
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Electrostatic Interactions ◽  
Binding Energies ◽  
Dynamics Simulation ◽  
Energy Calculation ◽  
Brain Disorder ◽  
Kd Values

Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder. One of the important therapeutic approaches of AD is the inhibition of β‐site APP cleaving enzyme‐1 (BACE1). This enzyme plays a central role in the synthesis of the pathogenic β-amyloid peptides (Aβ) in Alzheimer's disease. A group of potent BACE1 inhibitors with known x-ray structures (PDB ID 5i3X, 5i3Y, 5iE1, 5i3V, 5i3W, 4LC7, 3TPP) were studied by molecular dynamics simulation and binding energy calculation employing MM_GB(PB)SA. The calculated binding energies gave Kd values 0.139 µM, 1.39 nM, 4.39 mM, 24.3 nM, 1.39 mM, 29.13 mM and 193.07 nM, respectively. These inhibitors showed potent inhibitory activities in enzymatic and cell assays. The Kd values were compared with experimental values, the structures were discussed in view of the energy contributions to binding. Drug likeness of these inhibitors is also discussed. Accommodation of ligands in the catalytic site of BACE1 is discussed depending on the type of fragment involved in each structure. Molecular dynamics (MD) simulations and energy studies were used to explore the recognition of the selected BACE1 inhibitors by Asp 32, Asp228 and the hydrophobic flap. The results show that selective BACE1 inhibition may be due to the formation of strong electrostatic interactions with Asp32 and Asp228 and a large number of hydrogen bonds, π-π and Van der Waals interactions with the amino acid residues located inside the catalytic cavity. Interactions with the ligands show a similar binding mode with BACE1. These results help to rationalize the design of selective BACE1 inhibitors.

scholarly journals Hydrogen Bond Stability of Quinazoline Derivatives Compounds in Complex against EGFR using Molecular Dynamics Simulation

2019 ◽  
Vol 19 (2) ◽  
pp. 461
Author(s):  
Herlina Rasyid ◽  
Bambang Purwono ◽  
Thomas S Hofer ◽  
Harno Dwi Pranowo
Keyword(s):  
Molecular Dynamics ◽  
Hydrogen Bond ◽  
Free Energy ◽  
Molecular Dynamics Simulation ◽  
Binding Free Energy ◽  
Dynamics Simulation ◽  
Inhibition Mechanism ◽  
Energy Calculation ◽  
Protein Receptor ◽  
The Stability

Lung cancer was a second common cancer case due to the high cigarette smoking activity both in men and women. One of protein receptor which plays an important role in the growth of the tumor is Epidermal Growth Factor Receptor (EGFR). EGFR protein is the most frequent protein mutation in cancer and promising target to inhibit the cancer growth. In this work, the stability of the hydrogen bond as the main interaction in the inhibition mechanism of cancer will be evaluated using molecular dynamics simulation. There were two compounds (A1 and A2) as new potential inhibitors that were complexed against the EGFR protein. The dynamic properties of each complexed were compared with respect to erlotinib against EGFR. The result revealed that both compounds had an interaction in the main catalytic area of protein receptor which is at methionine residue. Inhibitor A1 showed additional interactions during simulation time but the interactions tend to be weak. Inhibitor A2 displayed a more stable interaction. Following dynamics simulation, binding free energy calculation was performed by two scoring techniques MM/GB(PB)SA method and gave a good correlation with the stability of the complex. Furthermore, potential inhibitor A2 had a lower binding free energy as a direct consequence of the stability of hydrogen bond interaction.

scholarly journals Identification of Potential SARS-CoV-2 Main Protease and Spike Protein Inhibitors from the Genus Aloe: An In Silico Study for Drug Development

Molecules ◽  
2021 ◽  
Vol 26 (6) ◽  
pp. 1767
Author(s):  
Mohamed E. Abouelela ◽  
Hamdy K. Assaf ◽  
Reda A. Abdelhamid ◽  
Ehab S. Elkhyat ◽  
Ahmed M. Sayed ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Drug Development ◽  
Root Mean Square ◽  
In Silico ◽  
Dynamics Simulation ◽  
Spike Protein ◽  
Energy Calculation ◽  
Mean Square ◽  
Main Protease

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) disease is a global rapidly spreading virus showing very high rates of complications and mortality. Till now, there is no effective specific treatment for the disease. Aloe is a rich source of isolated phytoconstituents that have an enormous range of biological activities. Since there are no available experimental techniques to examine these compounds for antiviral activity against SARS-CoV-2, we employed an in silico approach involving molecular docking, dynamics simulation, and binding free energy calculation using SARS-CoV-2 essential proteins as main protease and spike protein to identify lead compounds from Aloe that may help in novel drug discovery. Results retrieved from docking and molecular dynamics simulation suggested a number of promising inhibitors from Aloe. Root mean square deviation (RMSD) and root mean square fluctuation (RMSF) calculations indicated that compounds 132, 134, and 159 were the best scoring compounds against main protease, while compounds 115, 120, and 131 were the best scoring ones against spike glycoprotein. Compounds 120 and 131 were able to achieve significant stability and binding free energies during molecular dynamics simulation. In addition, the highest scoring compounds were investigated for their pharmacokinetic properties and drug-likeness. The Aloe compounds are promising active phytoconstituents for drug development for SARS-CoV-2.

scholarly journals Antiviral Activity of Metabolites from Peruvian Plants against SARS-CoV-2: An In Silico Approach

Molecules ◽  
2021 ◽  
Vol 26 (13) ◽  
pp. 3882
Author(s):  
Luis Daniel Goyzueta-Mamani ◽  
Haruna Luz Barazorda-Ccahuana ◽  
Karel Mena-Ulecia ◽  
Miguel Angel Chávez-Fumagalli
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
In Silico ◽  
High Stability ◽  
Native Plants ◽  
Binding Free Energy ◽  
Dynamics Simulation ◽  
Pharmacological Properties ◽  
Potential Candidate ◽  
In Silico Screening

(1) Background: The COVID-19 pandemic lacks treatments; for this reason, the search for potential compounds against therapeutic targets is still necessary. Bioinformatics tools have allowed the rapid in silico screening of possible new metabolite candidates from natural resources or repurposing known ones. Thus, in this work, we aimed to select phytochemical candidates from Peruvian plants with antiviral potential against three therapeutical targets of SARS-CoV-2. (2) Methods: We applied in silico technics, such as virtual screening, molecular docking, molecular dynamics simulation, and MM/GBSA estimation. (3) Results: Rutin, a compound present in Peruvian native plants, showed affinity against three targets of SARS-CoV-2. The molecular dynamics simulation demonstrated the high stability of receptor–ligand systems during the time of the simulation. Our results showed that the Mpro-Rutin system exhibited higher binding free energy than PLpro-Rutin and N-Rutin systems through MM/GBSA analysis. (4) Conclusions: Our study provides insight on natural metabolites from Peruvian plants with therapeutical potential. We found Rutin as a potential candidate with multiple pharmacological properties against SARS-CoV-2.

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