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Evaluation of new antihypertensive drugs designed in silico using Thermolysin as a target

dc.contributor.authorMacLeod-Carey D.
dc.contributor.authorSolis-Céspedes E.
dc.contributor.authorLamazares E.
dc.contributor.authorMena-Ulecia K.
dc.date.accessioned2020-09-02T22:21:55Z
dc.date.available2020-09-02T22:21:55Z
dc.date.issued2020
dc.identifier10.1016/j.jsps.2020.03.010
dc.identifier.citation28, 5, 582-592
dc.identifier.issn13190164
dc.identifier.urihttps://hdl.handle.net/20.500.12728/5149
dc.descriptionThe search for new therapies for the treatment of Arterial hypertension is a major concern in the scientific community. Here, we employ a computational biochemistry protocol to evaluate the performance of six compounds (Lig783, Lig1022, Lig1392, Lig2177, Lig3444 and Lig6199) to act as antihypertensive agents. This protocol consists of Docking experiments, efficiency calculations of ligands, molecular dynamics simulations, free energy, pharmacological and toxicological properties predictions (ADME-Tox) of the six ligands against Thermolysin. Our results show that the docked structures had an adequate orientation in the pocket of the Thermolysin enzymes, reproducing the X-ray crystal structure of Inhibitor-Thermolysin complexes in an acceptable way. The most promising candidates to act as antihypertensive agents among the series are Lig2177 and Lig3444. These compounds form the most stable ligand-Thermolysin complexes according to their binding free energy values obtained in the docking experiments as well as MM-GBSA decomposition analysis calculations. They present the lowest values of Ki, indicating that these ligands bind strongly to Thermolysin. Lig2177 was oriented in the pocket of Thermolysin in such a way that both OH of the dihydroxyl-amino groups to establish hydrogen bond interactions with Glu146 and Glu166. In the same way, Lig3444 interacts with Asp150, Glu143 and Tyr157. Additionally, Lig2177 and Lig3444 fulfill all the requirements established by Lipinski Veber and Pfizer 3/75 rules, indicating that these compounds could be safe compounds to be used as antihypertensive agents. We are confident that our computational biochemistry protocol can be used to evaluate and predict the behavior of a broad range of compounds designed in silicoagainst a protein target. © 2020 The Author(s)
dc.language.isoen
dc.publisherElsevier B.V.
dc.subjectADME-Tox
dc.subjectAntihypertensive
dc.subjectLigand efficiency
dc.subjectMM-GBSA
dc.subjectMolecular dynamics
dc.subjectantihypertensive agent
dc.subjectlig 1022
dc.subjectlig 1392
dc.subjectlig 2177
dc.subjectlig 3444
dc.subjectlig 6199
dc.subjectlig 783
dc.subjectthermolysin
dc.subjectunclassified drug
dc.subjectArticle
dc.subjectcomputer model
dc.subjectcrystal structure
dc.subjectdrug targeting
dc.subjecthuman
dc.subjectmolecular docking
dc.subjectX ray crystallography
dc.titleEvaluation of new antihypertensive drugs designed in silico using Thermolysin as a target
dc.typeArticle


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