title: Assessing protein kinase selectivity with molecular dynamics and mm-pbsa binding free energy calculations.
abstract: An application of molecular dynamics and molecular mechanics Poisson-Boltzmann surface area techniques to the prediction of protein kinase inhibitor selectivity is presented. A highly active and selective ERK2 inhibitor was placed in equivalent orientations in five different protein kinases (SRC, LCK, GSK3, JNK3 and Aurora-A). Binding free energies were then computed with the molecular mechanics Poisson-Boltzmann surface area approach using 15 nanosecond fully solvated molecular dynamics trajectories of the corresponding protein-ligand complexes. The results show correlation with experimentally determined selectivities and provide useful insights into the underlying structural determinants for selectivity.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Modena e Reggio Emilia, Via Campi 183, 41125 Modena, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Muzzioli
authors.forename: Alberto
authors.initials: A
authors.lastname: Del Rio
authors.forename: Giulio
authors.initials: G
authors.lastname: Rastelli
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011494:Protein Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D012997:Solvents / Q000737:chemistry; D013499:Surface Properties; D013816:Thermodynamics
chemical_list: D004791:Enzyme Inhibitors; D012997:Solvents; D011494:Protein Kinases