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The most important mechanisms in the blood pressure regulation, fluid volume and sodium-potassium balance in humans is the renin-angiotensin-aldosterone system (RAAS). This regulatory pathway plays a critical role in modulating cardiac function and vascular tone. An alteration in any of the molecules that make up this system (RAAS) could contribute to the development of arterial hypertension. In this important mechanisms, the neutral endopeptidase, also called Neprilysin (NEP) is the main enzyme for the degradation of natriuretic, therefore, it is essential proteins in controlling blood pressure. In this work, we have used docking methodology, molecular dynamics simulationa and free energy calculations method (MM-PBSA), to comprehensively evaluate the inhibitory behavior of some ligands obteined from consulted literature. The principal results obtained shown these ligands were adequately oriented in the NEP pocket. The Lig783, Lig2177, and Lig3444 compounds were those with better dynamic behavior. The energetic components that contribute to the complex's stability are the electrostatic and Van der Waals components; however, when the ADME-Tox properties were analyzed, we conclude that the best possible anti-hypertensive candidate are Lig783 and Lig3444. [ABSTRACT FROM AUTHOR]

The 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 silico against a protein target. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]