title: Elucidation of the binding mechanism of renin using a wide array of computational techniques and biological assays.
abstract: We investigate the binding mechanism in renin complexes, involving three drugs (remikiren, zankiren and enalkiren) and one lead compound, which was selected after screening the ZINC database. For this purpose, we used ab initio methods (the effective fragment potential, the variational perturbation theory, the energy decomposition analysis, the atoms-in-molecules), docking, molecular dynamics, and the MM-PBSA method. A biological assay for the lead compound has been performed to validate the theoretical findings. Importantly, binding free energy calculations for the three drug complexes are within 3 kcal/mol of the experimental values, thus further justifying our computational protocol, which has been validated through previous studies on 11 drug-protein systems. The main elements of the discovered mechanism are: (i) minor changes are induced to renin upon drug binding, (ii) the three drugs form an extensive network of hydrogen bonds with renin, whilst the lead compound presented diminished interactions, (iii) ligand binding in all complexes is driven by favorable van der Waals interactions and the nonpolar contribution to solvation, while the lead compound is associated with diminished van der Waals interactions compared to the drug-bound forms of renin, and (iv) the environment (H2O/Na(+)) has a small effect on the renin-remikiren interaction.
authors.affiliation: Institute of Biology, Pharmaceutical Chemistry and Biotechnology, National Hellenic Research Foundation, 48 Vas. Constantinou Ave., Athens 11635, Greece; Department of Chemistry, National and Kapodistrian University of Athens, Panepistimioupolis Zographou 15771, Greece. Electronic address: haralambostz@gmail.com.
authors.forename: Haralambos
authors.initials: H
authors.lastname: Tzoupis
authors.affiliation: Institute of Biology, Pharmaceutical Chemistry and Biotechnology, National Hellenic Research Foundation, 48 Vas. Constantinou Ave., Athens 11635, Greece. Electronic address: georgios.leonis@gmail.com.
authors.forename: Georgios
authors.initials: G
authors.lastname: Leonis
authors.affiliation: Institute of Biology, Pharmaceutical Chemistry and Biotechnology, National Hellenic Research Foundation, 48 Vas. Constantinou Ave., Athens 11635, Greece.
authors.forename: Aggelos
authors.initials: A
authors.lastname: Avramopoulos
authors.affiliation: Institute of Biology, Pharmaceutical Chemistry and Biotechnology, National Hellenic Research Foundation, 48 Vas. Constantinou Ave., Athens 11635, Greece.
authors.forename: Heribert
authors.initials: H
authors.lastname: Reis
authors.affiliation: Department of Inorganic Chemistry, Faculty of Pharmacy, Wrocław Medical University, Szewska 38 PL-50139 Wrocław, Poland.
authors.forename: Żaneta
authors.initials: Ż
authors.lastname: Czyżnikowska
authors.affiliation: Institute of Biology, Pharmaceutical Chemistry and Biotechnology, National Hellenic Research Foundation, 48 Vas. Constantinou Ave., Athens 11635, Greece.
authors.forename: Sofia
authors.initials: S
authors.lastname: Zerva
authors.affiliation: National Center for Scientific Research "Demokritos", Institute of Advanced Materials, Physicochemical Processes, Nanotechnology and Microsystems, Molecular Thermodynamics and Modelling of Materials Laboratory, GR-153 10, Aghia Paraskevi Attikis, Greece.
authors.forename: Niki
authors.initials: N
authors.lastname: Vergadou
authors.affiliation: Scienomics Sarl, 17 square Edouard VII, 75009 Paris, France.
authors.forename: Loukas D
authors.initials: LD
authors.lastname: Peristeras
authors.affiliation: Institute of Biology, Pharmaceutical Chemistry and Biotechnology, National Hellenic Research Foundation, 48 Vas. Constantinou Ave., Athens 11635, Greece.
authors.forename: Konstantinos D
authors.initials: KD
authors.lastname: Papavasileiou
authors.affiliation: Institute of Biology, Pharmaceutical Chemistry and Biotechnology, National Hellenic Research Foundation, 48 Vas. Constantinou Ave., Athens 11635, Greece.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Alexis
authors.affiliation: Department of Chemistry, National and Kapodistrian University of Athens, Panepistimioupolis Zographou 15771, Greece.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mavromoustakos
authors.affiliation: Institute of Biology, Pharmaceutical Chemistry and Biotechnology, National Hellenic Research Foundation, 48 Vas. Constantinou Ave., Athens 11635, Greece. Electronic address: mpapad@eie.gr.
authors.forename: Manthos G
authors.initials: MG
authors.lastname: Papadopoulos
mesh_terms: D020134:Catalytic Domain; D004151:Dipeptides / Q000737:chemistry; D057075:Enzyme Assays; D006860:Hydrogen Bonding; D007093:Imidazoles / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D011480:Protease Inhibitors / Q000737:chemistry; D011485:Protein Binding; D012083:Renin / Q000737:chemistry*; D013816:Thermodynamics; D000092502:Renin Inhibitors
chemical_list: D004151:Dipeptides; D007093:Imidazoles; D011480:Protease Inhibitors; D012083:Renin; D000092502:Renin Inhibitors; C056622:enalkiren; C065581:remikiren
keywords: Ab initio calculations; Free energy calculations; Molecular dynamics; Renin