title: Comparative binding energy analysis considering multiple receptors: a step toward 3D-QSAR models for multiple targets.
abstract: Comparative binding energy analysis, a technique to derive receptor-based three-dimensional quantitative structure-activity relationships (3D-QSAR), is herein extended to consider both affinity and selectivity in the derivation of the QSAR model. The extension is based on allowing multiple structurally related receptors to enter the X-matrix employed in the derivation of the structure-activity model. As a result, a single model common to all of them is obtained that considers both intra- and inter-receptor affinity differences for a given congeneric series. We applied the technique to a series of 88 3-amidinophenylalanines, binding to thrombin, trypsin, and factor Xa (fXa). A single predictive regression model for the three receptors involving 202 complexes, with a leave-one out (LOO) cross-validated Q(2) of 0.689, was obtained, and selectivity requirements were investigated. We find that total or partial occupancy of any of the three main pockets in the binding site (D-site, P-site, and the rim of the S1-site) leads to higher affinity across the family. However, the fact that thrombin can make stronger interactions in the P-site, as a result of its exclusive 60-loop, makes of this site a specificity pocket for this thrombin. Occupancy of the D-site leads to more active inhibitors toward fXa for the same reason, but the model does not highlight strongly the D-box because inhibitors are too short to fully occupy it. Negative charge density in the neighborhood of position 88 (a Lys insertion in thrombin) is found to be a determinant for thrombin recognition. These results were consistent with previous studies on selectivity in the thrombin/trypsin/fXa system.
authors.affiliation: Department of Physiology and Biophysics, Mount Sinai School of Medicine, One Gustave L. Levy Place, P.O. Box 1218, New York, New York 10029, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Murcia
authors.forename: Antonio
authors.initials: A
authors.lastname: Morreale
authors.forename: Angel R
authors.initials: AR
authors.lastname: Ortiz
mesh_terms: D000595:Amino Acid Sequence; D001557:Benzenesulfonates / Q000737:chemistry; D001665:Binding Sites; D015951:Factor Xa / Q000737:chemistry*; D065427:Factor Xa Inhibitors; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009282:Naphthalenesulfonates / Q000737:chemistry; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000737:chemistry*; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D012044:Regression Analysis; D015842:Serine Proteinase Inhibitors / Q000737:chemistry*; D055672:Static Electricity; D013816:Thermodynamics; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000737:chemistry*; D014357:Trypsin / Q000737:chemistry*
chemical_list: D001557:Benzenesulfonates; D065427:Factor Xa Inhibitors; D008024:Ligands; D009282:Naphthalenesulfonates; D015842:Serine Proteinase Inhibitors; D010649:Phenylalanine; D014357:Trypsin; D013917:Thrombin; D015951:Factor Xa