title: Investigating molecular dynamics-guided lead optimization of EGFR inhibitors.
abstract: 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.
authors.affiliation: Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA)-CONICET-Partner Institute of the Max Planck Society, Godoy Cruz 2390, C1425FQD Buenos Aires, Argentina.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Lavecchia
authors.affiliation: Grup d'Enginyeria Molecular (GEM), IQS School of Engineering, Universitat Ramon Llull, Via Augusta 390, Barcelona E-08017, Spain.
authors.forename: Raimon
authors.initials: R
authors.lastname: Puig de la Bellacasa
authors.affiliation: Grup d'Enginyeria Molecular (GEM), IQS School of Engineering, Universitat Ramon Llull, Via Augusta 390, Barcelona E-08017, Spain.
authors.forename: José I
authors.initials: JI
authors.lastname: Borrell
authors.affiliation: Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA)-CONICET-Partner Institute of the Max Planck Society, Godoy Cruz 2390, C1425FQD Buenos Aires, Argentina. Electronic address: cnc@cavasotto-lab.net.
authors.forename: Claudio N
authors.initials: CN
authors.lastname: Cavasotto
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D015195:Drug Design; D057075:Enzyme Assays; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000737:chemistry; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011994:Recombinant Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: EGFR; Hit-to-lead optimization; Ligand binding free energy calculation; MM/GBSA; Molecular docking; Molecular dynamics; Pyrido[2,3-d]pyrimidine; Small-molecule inhibitor