Polarizable Water Molecules in Ligand−Macromolecule Recognition. Impact on the Relative Affinities of Competing Pyrrolopyrimidine Inhibitors for FAK Kinase

• Published in: Journal of the American Chemical Society Vol. 132; no. 10; pp. 3312 - 3320
• Main Authors: de Courcy, Benoit, Piquemal, Jean-Philip, Garbay, Christiane, Gresh, Nohad
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 17.03.2010
• Subjects: Binding Sites; Chemical Sciences; Focal Adhesion Protein-Tyrosine Kinases - antagonists & inhibitors; Focal Adhesion Protein-Tyrosine Kinases - chemistry; Focal Adhesion Protein-Tyrosine Kinases - metabolism; Ligands; Macromolecular Substances; Models, Molecular; or physical chemistry; Pyrimidines - chemistry; Pyrimidines - pharmacology; Pyrroles - chemistry; Pyrroles - pharmacology; Theoretical and; Thermodynamics; Water - chemistry; Water - metabolism

Using polarizable molecular mechanics (PMM), we have compared the complexation energies of the focal adhesion kinase (FAK) kinase by five inhibitors in the pyrrolopyrimidine series. These inhibitors only differ by the substitution position of a carboxylate group on their benzene or pyridine rings, a...