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• W308724932 abstract "Hypertension, also referred as high blood pressure, is a chronical condition that affects nearly 25% of adults worldwide. The increasing prevalence of this illness has contributed to the pandemic of cardiovascular and renal diseases, which are responsible for a large number of deaths every year [1]. Therefore, it is fundamental to develop new antihypertensive drugs, in order to control and prevent the complications associated with high blood pressure. The Renin-Angiotensin System (RAS) is the major regulating system of the blood pressure and it consists of a two-step cascade. Firstly, the aspartic protease renin cleaves its only known substrate, angiotensinogen, in a rate limiting step, leading to the formation of the decapeptide angiotensin I (Ang I). Secondly, Ang I is transformed by angiotensinconverting enzyme (ACE) to produce the octapeptide angiotensin II (Ang II), which binds to angiotensin II receptors (AT receptors) and mediates the blood pressure control. Effective antihypertensive drugs involving different RAS targets have already been developed. However, it is believed that the inhibition of renin would offer better results in blood pressure control, due to its specificity for only one substrate and the fewer adverse treatment side effects [2, 3]. Therefore, the main goal of the present work is to describe, with computational methods, the atomistic details of the catalytic mechanism of human renin, to allow future studies on its inhibition. In order to achieve the purpose of this work the initial system (renin + angiotensinogen) was divided in two layers that were studied at different theoretical levels (Density functional theory (DFT) and Molecular Mechanics (MM)). The geometries were optimized with the ONIOM methodology, at the B3LYP/6-31G(d):Amber) level. The energies of the stationary points were recalculated with single-point calculations, using a large basis set (6-311++G(2d,2p)) and a progressive increase in the number of atoms in the DFT layer. Molecular dynamics (MD) simulations were also performed in order to understand the behavior of the system along the time. Our results suggest that the angiotensinogen hydrolysis by renin occurs by an acid/base mechanism, through three elementary steps. It begins with the formation of a stable gemdiol intermediate, followed by the scissile bond nitrogen protonation and it ends with the viii FCUP/ICBAS Elucidating the catalytic mechanism of human renin with hybrid QM/MM studies completely cleavage of the peptide bond. The final reaction products are two peptides with carboxylic acid and amine extremities. We observed that the formation of the gem-diol intermediate is rate limiting, with a barrier near 20 kcal.mol. We also conclude that the residues around the active center greatly influence the catalytic mechanism of this enzyme. In addition, we also confirm that human renin catalytic mechanism is very similar to the mouse one [4]. The data obtained in the present work provides important clues about renin catalytic mechanism, which will enable further studies on its inhibition and, consequently, the development of new antihypertensive drugs." @default.
• W308724932 created "2016-06-24" @default.
• W308724932 creator A5082347936 @default.
• W308724932 date "2013-11-06" @default.
• W308724932 modified "2023-09-26" @default.
• W308724932 title "Elucidating the catalytic mechanism of human renin with hybrid quantum mechanics and molecular m echanics studies" @default.
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