An approach to identify new antihypertensive agents using Thermolysin as model: In silico study based on QSARINS and docking

Cañizares-Carmenate, Yudith; Mena-Ulecia, Karel; Perera-Sardiña, Yunier; Torrens, Francisco; Castillo-Garit, Juan A.

doi:10.1016/j.arabjc.2016.10.003

Cited by 22 publications

(18 citation statements)

References 62 publications

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“…Its crystallographic structure was resolved a long time ago, as a result, it is widely used as a disease studies model [ 11 , 12 ]. Our research group has previously designed new thermolysin inhibitors as possible antihypertensive drugs by using a combination of QSARIN and virtual screening methods [ 11 ]. Six compounds were selected from that previous study ( Figure 1 ) and were evaluated as possible antibacterial agents.…”

Section: Introductionmentioning

confidence: 99%

Theoretical Evaluation of Novel Thermolysin Inhibitors from Bacillus thermoproteolyticus. Possible Antibacterial Agents

et al. 2021

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The search for new antibacterial agents that could decrease bacterial resistance is a subject in continuous development. Gram-negative and Gram-positive bacteria possess a group of metalloproteins belonging to the MEROPS peptidase (M4) family, which is the main virulence factor of these bacteria. In this work, we used the previous results of a computational biochemistry protocol of a series of ligands designed in silico using thermolysin as a model for the search of antihypertensive agents. Here, thermolysin from Bacillus thermoproteolyticus, a metalloprotein of the M4 family, was used to determine the most promising candidate as an antibacterial agent. Our results from docking, molecular dynamics simulation, molecular mechanics Poisson–Boltzmann (MM-PBSA) method, ligand efficiency, and ADME-Tox properties (Absorption, Distribution, Metabolism, Excretion, and Toxicity) indicate that the designed ligands were adequately oriented in the thermolysin active site. The Lig783, Lig2177, and Lig3444 compounds showed the best dynamic behavior; however, from the ADME-Tox calculated properties, Lig783 was selected as the unique antibacterial agent candidate amongst the designed ligands.

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Section: Introductionmentioning

confidence: 99%

Theoretical Evaluation of Novel Thermolysin Inhibitors from Bacillus thermoproteolyticus. Possible Antibacterial Agents

et al. 2021

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“…In the previous section, we have obtained five molecules as possible anti-hypertensive agents (18) . The structure of these molecules is represented in Figure 1.…”

Section: Resultsmentioning

confidence: 99%

“…As shown previously, our group has designed a series of ligands as possible anti-hypertensive agents (18,24) , so the fundamental objective of this work is to analyze whether these designed compounds will be good candidates, taking Neutral Endopeptidase (NEP) as the target protein. To this, we have developed a sequential computational protocol, which is shown in Figure 7.…”

Section: Computational Detailsmentioning

confidence: 99%

“…We have designed several compounds as possible anti-hypertensive agents in previous work using the QSAR-IN and virtual screening methods (18). This result is the starting point to evaluate if any of these ligands could have this property.…”

Section: Computational Detailsmentioning

confidence: 99%

“…Because of the arterial hypertension pathological complexity, it is necessary to research, design, and development new compounds to find more safe, innovative, and economic NEP inhibitors for the prevention and remedy of hypertension (17) . For this reason, in previous works, we have computationally designed new ligands as possible anti-hypertensive agents, based on the QSAR-IN methodology (18) , taking Thermolysin as the target, which is a protein of the M4 family and presents structural similarities with NEP (19)(20)(21)(22) . That is why we have performed a set of computational experiments based on molecular mechanics (Docking, Molecular Dynamics Simulation, MM-PBSA, Ligand Efficiency Metrics, and AMDE-Tox calculations) to analyze the compounds.…”

Section: Introductionmentioning

confidence: 99%

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

Lamazares¹,

Cañizares-Carmenate²,

Castillo-Garit³

et al. 2020

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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.

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Computational approach to the discovery of potential neprilysin inhibitors compounds for cardiovascular diseases treatment

et al. 2020

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An approach to identify new antihypertensive agents using Thermolysin as model: In silico study based on QSARINS and docking

Cited by 22 publications

References 62 publications

Theoretical Evaluation of Novel Thermolysin Inhibitors from Bacillus thermoproteolyticus. Possible Antibacterial Agents

Theoretical Evaluation of Novel Thermolysin Inhibitors from Bacillus thermoproteolyticus. Possible Antibacterial Agents

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

Computational approach to the discovery of potential neprilysin inhibitors compounds for cardiovascular diseases treatment

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