In Silico Optimization of Epidermal Growth Factor Receptor Inhibitors Followed by Experimental Evaluation

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

Congreso; V Argentinian Conference on Bioinformatics and Computational Biology; 2014

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.  Starting from a dichlorobenzyl pyridopyrimidine scaffold, and following an in silico characterization of its binding mode, a combinatorial virtual library of analogs was built, and their binding free energy assessed by state-of-the-art computational methods.  Compounds with better and worse affinity were synthetized and their activity experimentally evaluated, obtaining a dibromobenzyl-substituted molecule with improved performance; experimental results were in excellent agreement with theoretical predictions.