Insights into docking and scoring neuronal alpha4beta2 nicotinic receptor agonists using molecular dynamics simulations and QM/MM calculations.
A combined quantum mechanical (QM)-polarized docking and molecular dynamics approach to study the binding mode and to predict the binding affinity of ligands acting at the alpha4beta2-nAChR is presented. The results obtained in this study indicate that the quantum mechanical/molecular mechanics docking protocol well describes the charge-driven interactions occurring in the binding of nicotinic agonists, and it is able to represent the polarization effects on the ligand exerted by the surrounding atoms of the receptor at the binding site. This makes it possible to properly score agonists of alpha4beta2-nAChR and to reproduce the experimental binding affinity data with good accuracy, within a mean error of 2.2 kcal/mol. Moreover, applying the QM-polarized docking to an ensemble of nAChR conformations obtained from MD simulations enabled us to accurately capture nAChR-ligand induced-fit effects.
Laboratorio di Molecular Modeling, Cheminformatics and QSAR, Dipartimento di Scienze Farmaceutiche, Laboratorio di Progettazione, Sintesi e Studio di Eterocicli Biologicamente Attivi, Polo Scientifico, Università degli Studi di Firenze, Via Ugo Schiff, 6, 50019 Sesto Fiorentino (FI), Italy.
Jacopo
J
Sgrignani
Claudia
C
Bonaccini
Giovanni
G
Grazioso
Matteo
M
Chioccioli
Andrea
A
Cavalli
Paola
P
Gratteri
D001665:Binding Sites; D003198:Computer Simulation; D008024:Ligands; D008956:Models, Chemical; D018722:Nicotinic Agonists / Q000737:chemistry* / Q000494:pharmacology; D011789:Quantum Theory; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000187:drug effects; D013329:Structure-Activity Relationship
D008024:Ligands; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2