Investigating molecular dynamics-guided lead optimization of EGFR inhibitors

Martin J. Lavecchia, Raimon Puig De La Bellacasa, José I. Borrell, Claudio N. Cavasotto

Research output: Indexed journal article Articlepeer-review

11 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)768-778
Number of pages11
JournalBioorganic and Medicinal Chemistry
Issue number4
Publication statusPublished - 15 Feb 2016


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