title: Conformational Properties and Energetic Analysis of Aliskiren in Solution and Receptor Site.
abstract: 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.
authors.affiliation: Department of Chemistry, Laboratory of Organic Chemistry, University of Athens, Zographou, Athens 15771, Greece.|National Hellenic Research Foundation, Institute of Organic and Pharmaceutical Chemistry, 48 Vas. Constantinou, Athens 11635, Greece.
authors.forename: Aggeliki
authors.initials: A
authors.lastname: Politi
authors.affiliation: National Hellenic Research Foundation, Institute of Organic and Pharmaceutical Chemistry, 48 Vas. Constantinou, Athens 11635, Greece. gleonis@eie.gr.
authors.forename: Georgios
authors.initials: G
authors.lastname: Leonis
authors.affiliation: Department of Chemistry, Laboratory of Organic Chemistry, University of Athens, Zographou, Athens 15771, Greece.|National Hellenic Research Foundation, Institute of Organic and Pharmaceutical Chemistry, 48 Vas. Constantinou, Athens 11635, Greece.
authors.forename: Haralambos
authors.initials: H
authors.lastname: Tzoupis
authors.affiliation: Department of Chemistry, University of Patras, Patras 26500, Greece.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Ntountaniotis
authors.affiliation: National Hellenic Research Foundation, Institute of Organic and Pharmaceutical Chemistry, 48 Vas. Constantinou, Athens 11635, Greece.
authors.forename: Manthos G
authors.initials: MG
authors.lastname: Papadopoulos
authors.affiliation: Laboratory of Biomolecular Structure, National Institute of Chemistry, Hajdrihova 19, SI-1001 Ljubljana, Slovenia.|EN-FIST Centre of Excellence, Dunajska cesta 156, SI-1000 Ljubljana, Slovenia.
authors.forename: Simona Golic
authors.initials: SG
authors.lastname: Grdadolnik
authors.affiliation: Department of Chemistry, Laboratory of Organic Chemistry, University of Athens, Zographou, Athens 15771, Greece. tmavrom@chem.uoa.gr.|National Hellenic Research Foundation, Institute of Organic and Pharmaceutical Chemistry, 48 Vas. Constantinou, Athens 11635, Greece. tmavrom@chem.uoa.gr.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mavromoustakos
keywords: Aliskiren; Conformational analysis; Molecular dynamics; NMR spectroscopy; Renin