title: Structure-based prediction of free energy changes of binding of PTP1B inhibitors.
abstract: The goals were (1) to understand the driving forces in the binding of small molecule inhibitors to the active site of PTP1B and (2) to develop a molecular mechanics-based empirical free energy function for compound potency prediction. A set of compounds with known activities was docked onto the active site. The related energy components and molecular surface areas were calculated. The bridging water molecules were identified and their contributions were considered. Linear relationships were explored between the above terms and the binding free energies of compounds derived based on experimental inhibition constants. We found that minimally three terms are required to give rise to a good correlation (0.86) with predictive power in five-group cross-validation test (q2 = 0.70). The dominant terms are the electrostatic energy and non-electrostatic energy stemming from the intra- and intermolecular interactions of solutes and from those of bridging water molecules in complexes.
authors.affiliation: Structural Bioinformatics Inc., 10929 Technology Place, San Diego, CA 92127, USA. jing@strubix.com
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Shek Ling
authors.initials: SL
authors.lastname: Chan
authors.forename: Kal
authors.initials: K
authors.lastname: Ramnarayan
mesh_terms: D001665:Binding Sites; D002151:Calorimetry; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D008958:Models, Molecular; D008968:Molecular Conformation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D015203:Reproducibility of Results; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D004791:Enzyme Inhibitors; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases