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Assessing Protein Kinase Selectivity with Molecular Dynamics and MM‐PBSA Binding Free Energy Calculations
Author(s) -
Muzzioli Elena,
Del Rio Alberto,
Rastelli Giulio
Publication year - 2011
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2011.01140.x
Subject(s) - molecular dynamics , chemistry , selectivity , biophysics , computational biology , computational chemistry , biochemistry , biology , catalysis
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.