Paper Citing NAMD - Abstract
Lavecchia, Martin J.; Puig de la Bellacasa, Raimon; Borrell, Jose I.; Cavasotto, Claudio N.
Investigating molecular dynamics-guided lead optimization of EGFR inhibitors
BIOORGANIC & MEDICINAL CHEMISTRY, 24:768-778, FEB 15 2016
The epidermal growth factor receptor (EGFR) is part of an extended family of proteins that together control aspects of cell growth and development, and thus a validated target for drug discovery. We explore in this work the suitability of a molecular dynamics-based end-point binding free energy protocol to estimate the relative affinities of a virtual combinatorial library designed around the EGFR model inhibitor 6{1} as a tool to guide chemical synthesis toward the most promising compounds. To investigate the validity of this approach, selected analogs including some with better and worse predicted affinities relative to 6{1} were synthesized, and their biological activity determined. To understand the binding determinants of the different analogs, hydrogen bonding and van der Waals contributions, and water molecule bridging in the EGFR-analog complexes were analyzed. The experimental validation was in good qualitative agreement with our theoretical calculations, while also a 6-dibromophenyl-substituted compound with enhanced inhibitory effect on EGFR compared to the reference ligand was obtained. (c) 2015 Elsevier Ltd. All rights reserved.
