Structural identification of an HER2 receptor model binding pocket to optimize lead compounds: a combined experimental and computational approach.
The structural investigation of the ligand/target interactions represents a challenging task in the field of drug discovery or lead compound optimization. In the present study, a computational approach allowed the identification of the binding site of A9 peptide, within a synthetic model of HER2 receptor (HER2-DIVMP). To this aim, molecular docking calculations and molecular dynamics simulations were employed, taking into account experimental data obtained by fluorescence studies. The computational model was further validated by performing fluorescence binding studies between the ligand A9 and HER2-DIVMP mutants, prepared by replacing key amino acid residues. A new binding pocket of HER2-DIVMP was identified, which could be fruitfully exploited for future lead-optimization studies.
Institute of Biostructures and Bioimaging, National Research Council, Via Mezzocannone 16, 80134 Naples, Italy. stefania.deluca@cnr.it.
Emma
E
Langella
Institute of Biostructures and Bioimaging, National Research Council, Via Mezzocannone 16, 80134 Naples, Italy. stefania.deluca@cnr.it.
Enrica
E
Calce
Institute of Crystallography, National Research Council, Via Amendola 122/O, 70126 Bari, Italy. msaviano@unina.it.
Michele
M
Saviano
Institute of Biostructures and Bioimaging, National Research Council, Via Mezzocannone 16, 80134 Naples, Italy. stefania.deluca@cnr.it.
Stefania
S
De Luca
D000595:Amino Acid Sequence; D001665:Binding Sites; D003198:Computer Simulation; D055808:Drug Discovery; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009154:Mutation; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D013050:Spectrometry, Fluorescence
D008024:Ligands; D018719:Erb-b2 Receptor Tyrosine Kinases