The Experts below are selected from a list of 68883 Experts worldwide ranked by ideXlab platform
Ashok Sharma - One of the best experts on this subject based on the ideXlab platform.
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Docking Molecular dynamics binding energy mm pbsa studies of naphthofuran derivatives to identify potential dual inhibitors against bace 1 and gsk 3β
Journal of Biomolecular Structure & Dynamics, 2019Co-Authors: Akhil Kumar, Gaurava Srivastava, Arvind S. Negi, Ashok SharmaAbstract:BACE-1 and GSK-3β both are potential therapeutic drug targets for Alzheimer’s disease. Recently, both these targets received attention for designing dual inhibitors. Till now only two scaffolds (tr...
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Docking, Molecular dynamics, binding energy-MM-PBSA studies of naphthofuran derivatives to identify potential dual inhibitors against BACE-1 and GSK-3β
2018Co-Authors: Akhil Kumar, Gaurava Srivastava, Arvind S. Negi, Ashok SharmaAbstract:BACE-1 and GSK-3β both are potential therapeutic drug targets for Alzheimer’s disease. Recently, both these targets received attention for designing dual inhibitors. Till now only two scaffolds (triazinone and curcumin) derivatives have been reported as BACE-1 and GSK-3β dual inhibitors. In our previous work, we have reported first in class dual inhibitor for BACE-1 and GSK-3β. In this study, we have explored other naphthofuran derivatives for their potential to inhibit BACE-1 and GSK-3β through Docking, Molecular dynamics, binding energy (MM-PBSA). These computational methods were performed to estimate the binding affinity of naphthofuran derivatives towards the BACE-1 and GSK-3β. In the Docking results, two derivatives (NS7 and NS9) showed better binding affinity as compared to previously reported inhibitors. Hydrogen bond occupancy of NS7 and NS9 generated from MD trajectories showed good interaction with the flap residues Gln73, Thr72 of BACE-1 and Arg141, Thr138 residues of GSK-3β. MM-PBSA and energy decomposition per residue revealed different components of binding energy and relative importance of amino acid involved in binding. The results showed that the binding of inhibitors was majorly governed by the hydrophobic interactions and suggesting that hydrophobic interactions might be the key to design dual inhibitors for BACE1-1 and GSK-3β. Distance between important pair of amino acid residues indicated that BACE-1 and GSK-3β adopt closed conformation and become inactive after ligand binding. The results suggested that naphthofuran derivatives might act as dual inhibitor against BACE-1 and GSK-3β.
Tingjun Hou - One of the best experts on this subject based on the ideXlab platform.
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binding mechanisms of 1 4 dihydropyridine derivatives to l type calcium channel cav1 2 a Molecular modeling study
Molecular BioSystems, 2016Co-Authors: Li Tao, Yanling Yang, Tingjun HouAbstract:L-type Ca(2+) channels (LTCCs), the heteromultimeric proteins, are associated with electrical signaling and provide the key link between electrical signals and non-electrical processes. 1,4-Dihydropyridine (DHP) derivatives are a major class of blockers for LTCCs, and have experienced widespread use in the treatment of cardiovascular diseases. However, the precise knowledge of the binding mechanism of these ligands to LTCCs at the atomic level has remained unknown because of the unavailability of the crystal structures of LTCCs. In this study, homology modeling, Molecular Docking, Molecular dynamics (MD) simulations, free energy calculations and decomposition were employed to explore the structural requirement of the binding of DHP derivatives to human Cav1.2, a member of LTCCs. The binding conformations of the DHPs in the active site of Cav1.2 were predicted, and the rank of the binding free energies of Cav1.2/DHPs is generally consistent with the experimental data. The structural analysis shows that most studied ligands fit into a hydrophobic pocket formed by Phe1129, Ile1173, Phe1176, Met1177 and Met1509, and form aryl-aryl interaction with Phe1129 or Tyr1508. The consistency between the predictions and experimental data suggest that the developed model is reliable and can be used as a valuable platform for the structure-based design of new potent ligands of Cav1.2.
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discovery and optimization of triazine derivatives as rock1 inhibitors Molecular Docking Molecular dynamics simulations and free energy calculations
Molecular BioSystems, 2013Co-Authors: Mingyun Shen, Peichen Pan, Shunye Zhou, Liling Zhang, Tingjun HouAbstract:Rho-associated protein kinases (ROCK1 and ROCK2) are promising targets for a number of diseases, including cardiovascular disorders, nervous system diseases, cancers, etc. Recently, we have successfully identified a ROCK1 inhibitor (1) with the triazine core. In order to gain a deeper insight into the microscopic binding of this inhibitor with ROCK1 and design derivatives with improved potency, the interactions between ROCK1 and a series of triazine/pyrimidine-based inhibitors were studied by using an integrated computational protocol that combines Molecular Docking, Molecular dynamics (MD) simulations, binding free energy calculations, and binding energy decomposition analysis. First, three Docking protocols, rigid receptor Docking, induced fit Docking, QM-polarized ligand Docking, were used to determine the binding modes of the studied inhibitors in the active site of ROCK1. The results illustrate that rigid receptor Docking achieves the best performance to rank the binding affinities of the studied inhibitors. Then, based on the predicted structures from Molecular Docking, MD simulations and MM/GBSA free energy calculations were employed to determine the dynamic binding process and compare the binding modes of the inhibitors with different activities. The binding free energies predicted by MM/GBSA are in good agreement with the experimental bioactivities, and the analysis of the individual energy terms suggests that the van der Waals interaction is the major driving force for ligand binding. In addition, the residue–inhibitor interaction spectra were obtained by the MM/GBSA free energy decomposition analysis, and the important residues for achieving strong binding were highlighted, which affords important guidance for the rational design of novel ROCK inhibitors. Finally, a variety of derivatives of inhibitor 1 were designed and four of them showed promising potency according to the predictions. We expect that our study can provide significant insight into the development of improved inhibitors of ROCK1.
Sugunadevi Sakkiah - One of the best experts on this subject based on the ideXlab platform.
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Elucidation of Agonist and Antagonist Dynamic Binding Patterns in ER-α by Integration of Molecular Docking, Molecular Dynamics Simulations and Quantum Mechanical Calculations
'MDPI AG', 2021Co-Authors: Sugunadevi Sakkiah, Chandrabose Selvaraj, Wenjing Guo, Jie Liu, Tucker A. Patterson, Huixiao HongAbstract:Estrogen receptor alpha (ERα) is a ligand-dependent transcriptional factor in the nuclear receptor superfamily. Many structures of ERα bound with agonists and antagonists have been determined. However, the dynamic binding patterns of agonists and antagonists in the binding site of ERα remains unclear. Therefore, we performed Molecular Docking, Molecular dynamics (MD) simulations, and quantum mechanical calculations to elucidate agonist and antagonist dynamic binding patterns in ERα. 17β-estradiol (E2) and 4-hydroxytamoxifen (OHT) were docked in the ligand binding pockets of the agonist and antagonist bound ERα. The best complex conformations from Molecular Docking were subjected to 100 nanosecond MD simulations. Hierarchical clustering was conducted to group the structures in the trajectory from MD simulations. The representative structure from each cluster was selected to calculate the binding interaction energy value for elucidation of the dynamic binding patterns of agonists and antagonists in the binding site of ERα. The binding interaction energy analysis revealed that OHT binds ERα more tightly in the antagonist conformer, while E2 prefers the agonist conformer. The results may help identify ERα antagonists as drug candidates and facilitate risk assessment of chemicals through ER-mediated responses
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Identification of Inhibitor Binding Site in Human Sirtuin 2 Using Molecular Docking and Dynamics Simulations
2016Co-Authors: Sugunadevi Sakkiah, Mahreen Arooj, Manian Rajesh Kumar, Soo Hyun Eom, Keun Woo LeeAbstract:The ability to identify the site of a protein that can bind with high affinity to small, drug-like compounds has been an important goal in drug design. Sirtuin 2 (SIRT2), histone deacetylase protein family, plays a central role in the regulation of various pathways. Hence, identification of drug for SIRT2 has attracted great interest in the drug discovery community. To elucidate the Molecular basis of the small molecules interactions to inhibit the SIRT2 function we employed the Molecular Docking, Molecular dynamics simulations, and the Molecular mechanism Poisson-Boltzmann/surface area (MM-PBSA) calculations. Five well know inhibitors such as suramin, mol-6, sirtinol, 67, and nf675 were selected to establish the nature of the binding mode of the inhibitors in the SIRT2 active site. The Molecular Docking and dynamics simulations results revealed that the hydrogen bonds between Arg97 and Gln167 are crucial to inhibit the function of SIRT2. In addition, the MM-PBSA calculations revealed that binding of inhibitors to SIRT2 is mainly driven by van der Waals/non-polar interactions. Although the five inhibitors are very different in structure, shape, and electrostatic potential, they are able to fit in the same binding pocket. These findings from this study provide insights to elucidate the binding pattern of SIRT2 inhibitors and help in th
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identification of inhibitor binding site in human sirtuin 2 using Molecular Docking and dynamics simulations
PLOS ONE, 2013Co-Authors: Mahreen Arooj, Sugunadevi Sakkiah, Manian Rajesh KumarAbstract:The ability to identify the site of a protein that can bind with high affinity to small, drug-like compounds has been an important goal in drug design. Sirtuin 2 (SIRT2), histone deacetylase protein family, plays a central role in the regulation of various pathways. Hence, identification of drug for SIRT2 has attracted great interest in the drug discovery community. To elucidate the Molecular basis of the small molecules interactions to inhibit the SIRT2 function we employed the Molecular Docking, Molecular dynamics simulations, and the Molecular mechanism Poisson-Boltzmann/surface area (MM-PBSA) calculations. Five well know inhibitors such as suramin, mol-6, sirtinol, 67, and nf675 were selected to establish the nature of the binding mode of the inhibitors in the SIRT2 active site. The Molecular Docking and dynamics simulations results revealed that the hydrogen bonds between Arg97 and Gln167 are crucial to inhibit the function of SIRT2. In addition, the MM-PBSA calculations revealed that binding of inhibitors to SIRT2 is mainly driven by van der Waals/non-polar interactions. Although the five inhibitors are very different in structure, shape, and electrostatic potential, they are able to fit in the same binding pocket. These findings from this study provide insights to elucidate the binding pattern of SIRT2 inhibitors and help in the rational structure-based design of novel SIRT2 inhibitors with improved potency and better resistance profile.
Akhil Kumar - One of the best experts on this subject based on the ideXlab platform.
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Docking Molecular dynamics binding energy mm pbsa studies of naphthofuran derivatives to identify potential dual inhibitors against bace 1 and gsk 3β
Journal of Biomolecular Structure & Dynamics, 2019Co-Authors: Akhil Kumar, Gaurava Srivastava, Arvind S. Negi, Ashok SharmaAbstract:BACE-1 and GSK-3β both are potential therapeutic drug targets for Alzheimer’s disease. Recently, both these targets received attention for designing dual inhibitors. Till now only two scaffolds (tr...
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Docking, Molecular dynamics, binding energy-MM-PBSA studies of naphthofuran derivatives to identify potential dual inhibitors against BACE-1 and GSK-3β
2018Co-Authors: Akhil Kumar, Gaurava Srivastava, Arvind S. Negi, Ashok SharmaAbstract:BACE-1 and GSK-3β both are potential therapeutic drug targets for Alzheimer’s disease. Recently, both these targets received attention for designing dual inhibitors. Till now only two scaffolds (triazinone and curcumin) derivatives have been reported as BACE-1 and GSK-3β dual inhibitors. In our previous work, we have reported first in class dual inhibitor for BACE-1 and GSK-3β. In this study, we have explored other naphthofuran derivatives for their potential to inhibit BACE-1 and GSK-3β through Docking, Molecular dynamics, binding energy (MM-PBSA). These computational methods were performed to estimate the binding affinity of naphthofuran derivatives towards the BACE-1 and GSK-3β. In the Docking results, two derivatives (NS7 and NS9) showed better binding affinity as compared to previously reported inhibitors. Hydrogen bond occupancy of NS7 and NS9 generated from MD trajectories showed good interaction with the flap residues Gln73, Thr72 of BACE-1 and Arg141, Thr138 residues of GSK-3β. MM-PBSA and energy decomposition per residue revealed different components of binding energy and relative importance of amino acid involved in binding. The results showed that the binding of inhibitors was majorly governed by the hydrophobic interactions and suggesting that hydrophobic interactions might be the key to design dual inhibitors for BACE1-1 and GSK-3β. Distance between important pair of amino acid residues indicated that BACE-1 and GSK-3β adopt closed conformation and become inactive after ligand binding. The results suggested that naphthofuran derivatives might act as dual inhibitor against BACE-1 and GSK-3β.
Seung Joo Cho - One of the best experts on this subject based on the ideXlab platform.
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Designing of the N-ethyl-4-(pyridin-4-yl)benzamide based potent ROCK1 inhibitors using Docking, Molecular dynamics, and 3D-QSAR
'PeerJ', 2021Co-Authors: Suparna Ghosh, Seketoulie Keretsu, Seung Joo ChoAbstract:Rho-associated kinase-1 (ROCK1) has been recognized for its pivotal role in heart diseases, different types of malignancy, and many neurological disorders. Hyperactivity of ROCK phosphorylates the protein kinase-C (PKC), which ultimately induces smooth muscle cell contraction in the vascular system. Inhibition of ROCK1 has been shown to be a promising therapy for patients with cardiovascular disease. In this study, we have conducted Molecular modeling techniques such as Docking, Molecular dynamics (MD), and 3-Dimensional structure-activity relationship (3D-QSAR) on a series of N-ethyl-4-(pyridin-4-yl)benzamide-based compounds. Docking and MD showed critical interactions and binding affinities between ROCK1 and its inhibitors. To establish the structure-activity relationship (SAR) of the compounds, 3D-QSAR techniques such as Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) were used. The CoMFA (q2 = 0.774, r2 = 0.965, ONC = 6, and ${r}_{pred}^{2}$ r p r e d 2 = 0.703) and CoMSIA (q2 = 0.676, r2 = 0.949, ONC = 6, and ${r}_{pred}^{2}$ r p r e d 2 = 0.548) both models have shown reasonable external predictive activity, and contour maps revealed favorable and unfavorable substitutions for chemical group modifications. Based on the contour maps, we have designed forty new compounds, among which, seven compounds exhibited higher predictive activity (pIC50). Further, we conducted the MD study, ADME/Tox, and SA score prediction using the seven newly designed compounds. The combination of Docking, MD, and 3D-QSAR studies helps to understand the coherence modification of existing molecules. Our study may provide valuable insight into the development of more potent ROCK1 inhibitors
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rational approach toward covid 19 main protease inhibitors via Molecular Docking Molecular dynamics simulation and free energy calculation
Scientific Reports, 2020Co-Authors: Seketoulie Keretsu, Swapnil P Bhujbal, Seung Joo ChoAbstract:In the rapidly evolving coronavirus disease (COVID-19) pandemic, repurposing existing drugs and evaluating commercially available inhibitors against druggable targets of the virus could be an effective strategy to accelerate the drug discovery process. The 3C-Like proteinase (3CLpro) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been identified as an important drug target due to its role in viral replication. The lack of a potent 3CLpro inhibitor and the availability of the X-ray crystal structure of 3CLpro (PDB-ID 6LU7) motivated us to perform computational studies to identify commercially available potential inhibitors. A combination of modeling studies was performed to identify potential 3CLpro inhibitors from the protease inhibitor database MEROPS ( https://www.ebi.ac.uk/merops/index.shtml ). Binding energy evaluation identified key residues for inhibitor design. We found 15 potential 3CLpro inhibitors with higher binding affinity than that of an α-ketoamide inhibitor determined via X-ray structure. Among them, saquinavir and three other investigational drugs aclarubicin, TMC-310911, and faldaprevir could be suggested as potential 3CLpro inhibitors. We recommend further experimental investigation of these compounds.