Identification of novel acetylcholinesterase inhibitors through 3D-QSAR, molecular docking, and molecular dynamics simulation targeting Alzheimer’s disease

2021 ◽  
Vol 27 (10) ◽  
Author(s):  
Khalil El Khatabi ◽  
Reda El-Mernissi ◽  
Ilham Aanouz ◽  
Mohammed Aziz Ajana ◽  
Tahar Lakhlifi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Dynamics ◽  
Molecular Docking ◽  
Molecular Dynamics Simulation ◽  
Acetylcholinesterase Inhibitors ◽  
3D Qsar ◽  
Dynamics Simulation

scholarly journals Simulation studies, 3D QSAR and molecular docking on a point mutation of protein kinase B with flavonoids targeting ovarian Cancer

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Suchitra Maheswari Ajjarapu ◽  
Apoorv Tiwari ◽  
Gohar Taj ◽  
Dev Bukhsh Singh ◽  
Sakshi Singh ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Molecular Dynamics ◽  
Molecular Docking ◽  
Molecular Dynamics Simulation ◽  
Protein Kinase ◽  
Point Mutation ◽  
Protein Kinase B ◽  
3D Qsar ◽  
Dynamics Simulation ◽  
Simulation Studies

Abstract Background Ovarian cancer is the world’s dreaded disease and its prevalence is expanding globally. The study of integrated molecular networks is crucial for the basic mechanism of cancer cells and their progression. During the present investigation, we have examined different flavonoids that target protein kinases B (AKT1) protein which exerts their anticancer efficiency intriguing the role in cross-talk cell signalling, by metabolic processes through in-silico approaches. Method Molecular dynamics simulation (MDS) was performed to analyze and evaluate the stability of the complexes under physiological conditions and the results were congruent with molecular docking. This investigation revealed the effect of a point mutation (W80R), considered based on their frequency of occurrence, with AKT1 protein. Results The ligand with high docking scores and favourable behaviour on dynamic simulations are proposed as potential W80R inhibitors. A virtual screening analysis was performed with 12,000 flavonoids satisfying Lipinski’s rule of five according to which drug-likeness is predicted based on its pharmacological and biological properties to be active and taken orally. The pharmacokinetic ADME (adsorption, digestion, metabolism, and excretion) studies featured drug-likeness. Subsequently, a statistically significant 3D-QSAR model of high correlation coefficient (R2) with 0.822 and cross-validation coefficient (Q2) with 0.6132 at 4 component PLS (partial least square) were used to verify the accuracy of the models. Taxifolin holds good interactions with the binding domain of W80R, highest Glide score of − 9.63 kcal/mol with OH of GLU234 and H bond ASP274 and LEU156 amino acid residues and one pi-cation interaction and one hydrophobic bond with LYS276. Conclusion Natural compounds have always been a richest source of active compounds with a wide variety of structures, therefore, these compounds showed a special inspiration for medical chemists. The present study has aimed molecular docking and molecular dynamics simulation studies on taxifolin targeting W80R mutant protein of protein kinase B/serine- threonine kinase/AKT1 (EC:2.7.11.1) protein of ovarian cancer for designing therapeutic intervention. The expected result supported the molecular cause in a mutant form which resulted in a gain of ovarian cancer. Here we discussed validations computationally and yet experimental evaluation or in vivo studies are endorsed for further study. Several of these compounds should become the next marvels for early detection of ovarian cancer.

scholarly journals Environmentally Friendly Fluoroquinolone Derivatives with Lower Plasma Protein Binding Rate Designed Using 3D-QSAR, Molecular Docking and Molecular Dynamics Simulation

2020 ◽  
Vol 17 (18) ◽  
pp. 6626 ◽  
Author(s):  
Yilin Hou ◽  
Yuanyuan Zhao ◽  
Yu Li
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Molecular Dynamics Simulation ◽  
Protein Binding ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
3D Qsar ◽  
Dynamics Simulation ◽  
Target Molecule ◽  
Binding Rate

Comparative molecular similarity index analysis (CoMSIA) was used to establish a three-dimensional quantitative structure–activity relationship (3D-QSAR) model with structural parameters of quinolones as the independent variables and plasma protein binding rate (logfb) as the dependent variable to predict the logfb values of remaining quinolones in this study. In addition, the mono-substituted and bis-substituted reaction schemes that significantly influenced the plasma protein binding rate of quinolones were determined through an analysis of the 3D-QSAR contour maps. It was found that the replacement of small groups, hydrophobic groups, electronegative groups, or hydrogen bond acceptor groups at the substitution sites significantly reduce the logfb values of quinolone derivatives. Furthermore, the mechanism of decrease in binding rate between trovafloxacin (TRO) derivatives and plasma protein was revealed qualitatively and quantitatively based on molecular docking and molecular dynamics simulation. After modification of the target molecule, 11 TRO derivatives with low plasma protein binding rates were screened (reduced by 0.50–24.18%). Compared with the target molecule, the molecular genotoxicity and photodegradability of the TRO derivatives was higher (genotoxicity increased by 4.89–21.36%, and photodegradability increased by 9.04–20.56%), and their bioconcentration was significantly lower (by 36.90–61.41%).

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.

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