Τίτλος:
Elucidation of the binding mechanism of renin using a wide array of computational techniques and biological assays
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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. © 2015 Elsevier Inc. All rights reserved.
Συγγραφείς:
Tzoupis, H.
Leonis, G.
Avramopoulos, A.
Reis, H.
Czyznikowska, Z.
Zerva, S.
Vergadou, N.
Peristeras, L.D.
Papavasileiou, K.D.
Alexis, M.N.
Mavromoustakos, T.
Papadopoulos, M.G.
Περιοδικό:
Journal of Molecular Graphics and Modelling
Εκδότης:
ELSEVIER SCIENCE INC 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA
Λέξεις-κλειδιά:
Assays; Bins; Calculations; Complex networks; Computation theory; Free energy; Hydrogen bonds; Lead compounds; Molecular dynamics; Perturbation techniques; Van der Waals forces, Ab initio calculations; Computational protocols; Effective fragment potentials; Energy decomposition analysis; Free-energy calculations; Renin; Van Der Waals interactions; Variational perturbation theory, Binding energy, enalkiren; remikiren; renin; zankiren; dipeptide; imidazole derivative; protein binding; proteinase inhibitor; renin, ab initio calculation; Article; bioassay; complex formation; conformational transition; crystal structure; hydrogen bond; ligand binding; molecular docking; molecular dynamics; priority journal; antagonists and inhibitors; chemistry; enzyme active site; enzyme assay; thermodynamics, Catalytic Domain; Dipeptides; Enzyme Assays; Hydrogen Bonding; Imidazoles; Molecular Dynamics Simulation; Protease Inhibitors; Protein Binding; Renin; Thermodynamics
DOI:
10.1016/j.jmgm.2015.09.015
