Investigating molecular dynamics-guided lead optimization of EGFR inhibitors

LAVECCHIA, M; PUIG DE LA BELLACASA R.; BORRELL, J.I.; CAVASOTTO, CLAUDIO N.

BIOORGANIC & MEDICINAL CHEMISTRY.

PERGAMON-ELSEVIER SCIENCE LTD

Lugar: Amsterdam; Año: 2016 vol. 24 p. 768 - 778

0968-0896

The Epidermal Growth Factor Receptor (EGFR) ispart 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 analogues 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 analogues, hydrogen bonding and van der Waals contributions, and water molecule bridging in the EGFR-analogue 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.