scholarly journals Binding Mode Knowledge of New Possible Anti-Hypertensive Compounds Designed In Silico Using Neutral Endopeptidase (NEP) as a Target

2020 ◽  
Author(s):  
Emilio Lamazares ◽  
Yudith Cañizares-Carmenate ◽  
Juan A. Castillo-Garit ◽  
Karel Mena-Ulecia
Keyword(s):  
Arterial Hypertension ◽  
In Silico ◽  
Neutral Endopeptidase ◽  
Binding Mode ◽  
Dynamics Simulation ◽  
Energy Decomposition ◽  
Simulation Tools ◽  
Free Energy Decomposition ◽  
Key Enzyme ◽  
New Compounds

Arterial hypertension is a health problem that affects millions of people around the world. Particularly in Chile, according to the last health survey in 2019, 28.7% of the population had this condition, and arterial hypertension complications cause one in three deaths per year. In this work, we have used molecular simulation tools to evaluate new compounds designed in silico by our group as possible anti-hypertensive agents, taking Neutral Endopeptidase (NEP) as a target, a key enzyme in the arterial hypertension regulation at the level kidney. We use docking experiments, molecular dynamics simulation, free energy decomposition calculations (by MM-PBSA method), and ligand efficiency analysis to identify the best anti-hypertensive agent pharmacokinetic and toxicological predictions (ADME-Tox). The energetic components that contribute to the complexes stability are the electrostatic and Van der Waals components; however, when the ADME-Tox properties were analyzed, we conclude that the best anti-hypertensive candidate agents are Lig783 and Lig3444, taking Neutra Endopeptidase as a target.

scholarly journals Insight Into the Binding Mode Knowledge of New Possible Anti-Hypertensive Compounds Designed in Silico Using Neutral Endopeptidase (NEP) As A Target.

2021 ◽  
Author(s):  
Emilio Lamazares ◽  
Yudith Cañizares-Carmenate ◽  
Juan Castillo-Garit ◽  
Karel Mena-Ulecia
Keyword(s):  
Arterial Hypertension ◽  
In Silico ◽  
Neutral Endopeptidase ◽  
Binding Mode ◽  
Dynamics Simulation ◽  
Active Centre ◽  
Simulation Tools ◽  
Free Energy Decomposition ◽  
Key Enzyme ◽  
Poisson Boltzmann

Abstract Arterial hypertension is a health problem that affects millions of people around the world. Particularly in Chile, according to the last health survey in 2019, 28.7% of the population had this condition, and arterial hypertension complications cause one in three deaths per year. In this work, we have used molecular simulation tools to evaluate new compounds designed in silico by our group as possible anti-hypertensive agents, taking Neutral Endopeptidase (NEP) as a target, a key enzyme in the arterial hypertension regulation at the level kidney. We use docking experiments, molecular dynamics simulation, free energy decomposition calculations means of Molecular Mechanics Poisson–Boltzmann (MM-PBSA) method and ligand efficiency analysis. To identify the best anti-hypertensive agent we realized pharmacokinetic and toxicological predictions (ADME-Tox). The principal results obtained shown the ligands designed in silico were adequately oriented in the thermolysin active centre. The Lig783, Lig2177, and Lig3444 compounds were those with better dynamic behaviour. The energetic components that contribute to the complexes stability are the electrostatic and Van der Waals components; however, when the ADME-Tox properties were analyzed, we conclude that the best anti-hypertensive candidate agents are Lig783 and Lig3444, taking Neutra Endopeptidase as a target.

scholarly journals In silico Study of Potential Non-oxime Reactivator for Sarin-inhibited Human Acetylcholinesterase

2021 ◽  
Vol 29 (3) ◽  
Author(s):  
Rauda A. Mohamed ◽  
Keat Khim Ong ◽  
Norhana Abdul Halim ◽  
Noor Azilah Mohd Kasim ◽  
Siti Aminah Mohd Noor ◽  
...  
Keyword(s):  
Binding Energy ◽  
In Silico ◽  
Docking Study ◽  
Dynamics Simulation ◽  
Nucleophilic Attack ◽  
Organophosphate Poisoning ◽  
Nipecotic Acid ◽  
Computational Screening ◽  
The Stability ◽  
New Compounds

The search for new compounds other than oxime as potential reactivator that is effective upon organophosphate poisoning treatments is desired. The less efficacy of oxime treatment has been the core factor. Fourteen compounds have been screened via in silico approach for their potential as sarin-inhibited human acetylcholinesterase poisoning antidotes. The selection of the compounds to be synthesized based on this computational screening, reduces the time and cost needed. To perform the docking study of sarin-inhibited acetylcholinesterase and reactivator-sarin inhibited acetylcholinesterase complexations, a bioinformatics tool was used. Estimation of the nucleophilic attack distance and binding energy of fourteen potential compounds with sarin inhibited acetylcholinesterase complexes to determine their antidote capacities was carried out using Autodock. A commercially available antidote, 2-PAM was used for the comparison. The best docked-pose was further examined with molecular dynamics simulation. Apart from being lipophilic, a compound with a carboxylic acid, (R)-Boc-nipecotic acid is shown to exhibit 6.29 kcal/mol binding energy with 8.778 Å distance of nucleophilic attack. The stability and flexibility of the sarin-inhibited acetylcholinesterase, complexed with (R)-Boc-nipecotic acid suggests this compound should be tested experimentally as a new, promising antidote for sarin-inhibited acetylcholinesterase poisoning.

scholarly journals Polyphenolic Profile of Callistemon viminalis Aerial Parts: Antioxidant, Anticancer and In Silico 5-LOX Inhibitory Evaluations

Molecules ◽  
2021 ◽  
Vol 26 (9) ◽  
pp. 2481
Author(s):  
Shahenda Mahgoub ◽  
Nashwa Hashad ◽  
Sahar Ali ◽  
Reham Ibrahim ◽  
Ahmed M. Said ◽  
...  
Keyword(s):  
Ascorbic Acid ◽  
In Silico ◽  
Enzyme Inhibitor ◽  
In Silico Analysis ◽  
Binding Mode ◽  
Strong Activity ◽  
Aerial Parts ◽  
Callistemon Viminalis ◽  
Polyphenolic Profile ◽  
New Compounds

Five new compounds viz kaempferol 3-O-(4″-galloyl)-β-d-glucopyranosyl-(1‴→6″)-O-β-d-glucopyranoside (1), kaempferol 3-O-β-d-mannuronopyranoside (2), kaempferol 3-O-β-d-mannopyranoside (3), quercetin 3-O-β-d-mannuronopyranoside (4), 2, 3 (S)- hexahydroxydiphenoyl]-d-glucose (5) along with fifteen known compounds were isolated from 80% aqueous methanol extract (AME) of C. viminalis. AME and compounds exerted similar or better antioxidant activity to ascorbic acid using DPPH, O2−, and NO inhibition methods. In addition, compounds 16, 4, and 7 showed cytotoxic activity against MCF-7 cell lines while 3, 7 and 16 exhibited strong activity against HepG2. An in silico analysis using molecular docking for polyphenolic compounds 2, 3, 7, 16 and 17 against human stable 5-LOX was performed and compared to that of ascorbic acid and quercetin. The binding mode as well as the enzyme-inhibitor interactions were evaluated. All compounds occupied the 5-LOX active site and showed binding affinity greater than ascorbic acid or quercetin. The data herein suggest that AME, a source of polyphenols, could be used against oxidative-stress-related disorders.

scholarly journals MOLECULAR DOCKING AND ADMET PREDICTION OF 5-BENZYLOXYTRYPTOPHAN AS A POTENTIAL RADIOPHARMACEUTICAL KIT FOR MOLECULAR IMAGING OF CANCER

2021 ◽  
pp. 171-175
Author(s):  
FAISAL MAULANA IBRAHIM ◽  
HOLIS ABDUL HOLIK ◽  
GHIFARI FARHAN HASIBUAN ◽  
ACHMAD HUSSEIN SUNDAWA KARTAMIHARDJA
Keyword(s):  
Molecular Docking ◽  
Molecular Imaging ◽  
In Silico ◽  
Research Method ◽  
Chelating Agents ◽  
Binding Mode ◽  
Inhibition Effect ◽  
Theranostic Agent ◽  
In Silico Study ◽  
New Compounds

Objective: This in silico study aims to determine the inhibition effect of 5-BOTP with various bifunctional chelating agents (BFCA); NOTA, DOTA, TETA, CTPA, H2CB-DO2A, H2CBTE2A against the antiporter site of the LAT1. Methods: The research method consisted of the binding mode of 5-BOTP and its derivatives with LAT1, the docking score, the analysis of preADMET, and the overview of Ro5 compatibility. Results: The results showed that 5-BOTP-NOTA and 5-BOTP-DOTA had interactions with the gating residue (Phe252, Trp257, Asn258, and Tyr259) on the antiporter site of LAT1. 5-BOTP-NOTA and 5-BOTP-DOTA affinity are around-11.50 and-9.14 kcal/mol, respectively. Conclusion: Based on this study, 5-BOTP-NOTA and 5-BOTP-DOTA are the new compounds that have the potential as a theranostic agent of cancer by inhibiting LAT1.

scholarly journals In silico and saturation transfer difference NMR approaches to unravel the binding mode of an andrographolide derivative to K-Ras oncoprotein

2020 ◽  
Vol 12 (18) ◽  
pp. 1611-1631
Author(s):  
Shun Ying Quah ◽  
Michelle Siying Tan ◽  
Kok Lian Ho ◽  
Nizar Abdul Manan ◽  
Alemayehu Abebe Gorfe ◽  
...  
Keyword(s):  
In Silico ◽  
Hydrophobic Interactions ◽  
Binding Pocket ◽  
Binding Mode ◽  
Dynamics Simulation ◽  
Saturation Transfer ◽  
In Silico Docking ◽  
Saturation Transfer Difference ◽  
Major Interest ◽  
Ras Oncoprotein

Background: Andrographolide and its benzylidene derivatives, SRJ09 and SRJ23, potentially bind oncogenic K-Ras to exert anticancer activity. Their molecular interactions with K-Ras oncoproteins that lead to effective biological activity are of major interest. Methods & results: In silico docking and molecular dynamics simulation were performed using Glide and Desmond, respectively; while saturation transfer difference NMR was performed using GDP-bound K-RasG12V. SRJ23 was found to bind strongly and selectively to K-RasG12V, by anchoring to a binding pocket (namely p2) principally via hydrogen bond and hydrophobic interactions. The saturation transfer difference NMR analysis revealed the proximity of protons of functional moieties in SRJ23 to K-RasG12V, suggesting positive binding. Conclusion: SRJ23 binds strongly and interacts stably with K-RasG12V to exhibit its inhibitory activity.

Binding Modes of Ligands Using Enhanced Sampling (BLUES): Rapid Decorrelation of Ligand Binding Modes Using Nonequilibrium Candidate Monte Carlo

2017 ◽  
Author(s):  
Samuel Gill ◽  
Nathan M. Lim ◽  
Patrick Grinaway ◽  
Ariën S. Rustenburg ◽  
Josh Fass ◽  
...  
Keyword(s):  
Monte Carlo ◽  
Ligand Binding ◽  
Binding Mode ◽  
Free Energy Calculations ◽  
Dynamics Simulation ◽  
Binding Modes ◽  
Enhanced Sampling ◽  
Recent Success ◽  
Multiple Binding ◽  
Proper Sampling

<div>Accurately predicting protein-ligand binding is a major goal in computational chemistry, but even the prediction of ligand binding modes in proteins poses major challenges. Here, we focus on solving the binding mode prediction problem for rigid fragments. That is, we focus on computing the dominant placement, conformation, and orientations of a relatively rigid, fragment-like ligand in a receptor, and the populations of the multiple binding modes which may be relevant. This problem is important in its own right, but is even more timely given the recent success of alchemical free energy calculations. Alchemical calculations are increasingly used to predict binding free energies of ligands to receptors. However, the accuracy of these calculations is dependent on proper sampling of the relevant ligand binding modes. Unfortunately, ligand binding modes may often be uncertain, hard to predict, and/or slow to interconvert on simulation timescales, so proper sampling with current techniques can require prohibitively long simulations. We need new methods which dramatically improve sampling of ligand binding modes. Here, we develop and apply a nonequilibrium candidate Monte Carlo (NCMC) method to improve sampling of ligand binding modes.</div><div><br></div><div>In this technique the ligand is rotated and subsequently allowed to relax in its new position through alchemical perturbation before accepting or rejecting the rotation and relaxation as a nonequilibrium Monte Carlo move. When applied to a T4 lysozyme model binding system, this NCMC method shows over two orders of magnitude improvement in binding mode sampling efficiency compared to a brute force molecular dynamics simulation. This is a first step towards applying this methodology to pharmaceutically relevant binding of fragments and, eventually, drug-like molecules. We are making this approach available via our new Binding Modes of Ligands using Enhanced Sampling (BLUES) package which is freely available on GitHub.</div>

Binding Modes of Ligands Using Enhanced Sampling (BLUES): Rapid Decorrelation of Ligand Binding Modes Using Nonequilibrium Candidate Monte Carlo

2018 ◽  
Author(s):  
Samuel Gill ◽  
Nathan M. Lim ◽  
Patrick Grinaway ◽  
Ariën S. Rustenburg ◽  
Josh Fass ◽  
...  
Keyword(s):  
Monte Carlo ◽  
Ligand Binding ◽  
Binding Mode ◽  
Free Energy Calculations ◽  
Dynamics Simulation ◽  
Binding Modes ◽  
Enhanced Sampling ◽  
Recent Success ◽  
Multiple Binding ◽  
Proper Sampling

<div>Accurately predicting protein-ligand binding is a major goal in computational chemistry, but even the prediction of ligand binding modes in proteins poses major challenges. Here, we focus on solving the binding mode prediction problem for rigid fragments. That is, we focus on computing the dominant placement, conformation, and orientations of a relatively rigid, fragment-like ligand in a receptor, and the populations of the multiple binding modes which may be relevant. This problem is important in its own right, but is even more timely given the recent success of alchemical free energy calculations. Alchemical calculations are increasingly used to predict binding free energies of ligands to receptors. However, the accuracy of these calculations is dependent on proper sampling of the relevant ligand binding modes. Unfortunately, ligand binding modes may often be uncertain, hard to predict, and/or slow to interconvert on simulation timescales, so proper sampling with current techniques can require prohibitively long simulations. We need new methods which dramatically improve sampling of ligand binding modes. Here, we develop and apply a nonequilibrium candidate Monte Carlo (NCMC) method to improve sampling of ligand binding modes.</div><div><br></div><div>In this technique the ligand is rotated and subsequently allowed to relax in its new position through alchemical perturbation before accepting or rejecting the rotation and relaxation as a nonequilibrium Monte Carlo move. When applied to a T4 lysozyme model binding system, this NCMC method shows over two orders of magnitude improvement in binding mode sampling efficiency compared to a brute force molecular dynamics simulation. This is a first step towards applying this methodology to pharmaceutically relevant binding of fragments and, eventually, drug-like molecules. We are making this approach available via our new Binding Modes of Ligands using Enhanced Sampling (BLUES) package which is freely available on GitHub.</div>

In silico Mapping and Structure Analysis of Key Enzyme Genes in Fatty Acid Synthesis of Soybean

2009 ◽  
Vol 35 (10) ◽  
pp. 1942-1947
Author(s):  
Wan-Kun SONG ◽  
Ming-Xi ZHU ◽  
Yang-Lin ZHAO ◽  
Jing WANG ◽  
Wen-Fu LI ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Structure Analysis ◽  
Fatty Acid Synthesis ◽  
In Silico ◽  
Acid Synthesis ◽  
In Silico Mapping ◽  
Key Enzyme
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