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Conformational Properties and Energetic Analysis of Aliskiren in Solution and Receptor Site
Author(s) -
Politi Aggeliki,
Leonis Georgios,
Tzoupis Haralambos,
Ntountaniotis Dimitrios,
Papadopoulos Manthos G.,
Grdadolnik Simona Golic,
Mavromoustakos Thomas
Publication year - 2011
Publication title -
molecular informatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.481
H-Index - 68
eISSN - 1868-1751
pISSN - 1868-1743
DOI - 10.1002/minf.201100077
Subject(s) - aliskiren , chemistry , molecular mechanics , molecular dynamics , solvation , van der waals force , hydrogen bond , renin inhibitor , computational chemistry , stereochemistry , renin–angiotensin system , molecule , organic chemistry , medicine , blood pressure , radiology
Aliskiren is the first orally active, direct renin inhibitor to be approved for the treatment of hypertension. Its structure elucidation and conformational analysis were explored using 1D and 2D NMR spectroscopy, as well as random search and molecular dynamics (MD) simulations. For the first time, MD calculations have also been performed for aliskiren at the receptor site, in order to reveal its molecular basis of action. It is suggested that aliskiren binds in an extended conformation and is involved in several stabilizing hydrogen bonding interactions with binding cavity (Asp32/255, Gly34) and other binding‐cavity (Arg74, Ser76, Tyr14) residues. Of paramount importance is the finding of a loop consisting of residues around Ser76 that determines the entrapping of aliskiren into the active site of renin. The details of this mechanism will be the subject of a subsequent study. Additionally molecular mechanics Poisson–Boltzmann surface area (MM–PBSA) free energy calculations for the aliskiren‐renin complex provided insight into the binding mode of aliskiren by identifying van der Waals and nonpolar contribution to solvation as the main components of favorable binding interactions.