title: Prediction of drug binding affinities by comparative binding energy analysis.
abstract: A new computational method for deducing quantitative structure-activity relationships (QSARs) using structural data from ligand-macromolecule complexes is presented. First, the ligand-macromolecule interaction energy is computed for a set of ligands using molecular mechanics calculations. Then, by selecting and scaling components of the ligand-macromolecule interaction energy that show good predictive ability, a regression equation is obtained in which activity is correlated with the interaction energies of parts of the ligands and key regions of the macromolecule. Application to the interaction of the human synovial fluid phospholipase A2 with 26 inhibitors indicates that the derived QSAR has good predictive ability and provides insight into the mechanism of enzyme inhibition. The method, which we term comparative binding energy (COMBINE) analysis, is expected to be applicable to ligand-receptor interactions in a range of contexts including rational drug design, host-guest systems, and protein engineering.
authors.affiliation: European Molecular Biology Laboratory, Heidelberg, Germany.
authors.forename: A R
authors.initials: AR
authors.lastname: Ortiz
authors.forename: M T
authors.initials: MT
authors.lastname: Pisabarro
authors.forename: F
authors.initials: F
authors.lastname: Gago
authors.forename: R C
authors.initials: RC
authors.lastname: Wade
mesh_terms: D001665:Binding Sites; D001667:Binding, Competitive; D004560:Electricity; D006801:Humans; D008958:Models, Molecular; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D010741:Phospholipases A / Q000037:antagonists & inhibitors* / Q000737:chemistry; D054467:Phospholipases A2; D013329:Structure-Activity Relationship; D013582:Synovial Fluid / Q000201:enzymology; D013816:Thermodynamics
chemical_list: D004364:Pharmaceutical Preparations; D010741:Phospholipases A; D054467:Phospholipases A2