title: Prediction of enzyme inhibition and mode of inhibitory action based on calculation of distances between hydrogen bond donor/acceptor groups of the molecule and docking analysis: An application on the discovery of novel effective PTP1B inhibitors.
abstract: PTP1B is a protein tyrosine phosphatase involved in insulin receptor desensitization. PTP1B inhibition prolongs the activated state of the receptor, practically enhancing the effect of insulin. Thus PTP1B has become a drug target for the treatment of type II diabetes. PTP1b is an enzyme with multiple binding sites for competitive and allosteric inhibitors. Prediction of inhibitory action using docking analysis has limited success in case of enzymes with multiple binding sites, since the selection of the right crystal structure depends on the kind of inhibitor. In the present study, a two-step strategy for the prediction of PTP1b inhibitory action was applied to 12 compounds. Based on the study of known inhibitors, we isolated the structural characteristics required for binding to each binding site. As a first step, 3D-structures of the molecules were produced and their structural parameters were measured and used for prediction of the binding site of the compound. These results were used for the selection of the appropriate crystal structure for docking analysis of each compound, and the final prediction was based on the estimated binding energies. This strategy effectively predicted the activity of all compounds. A linear correlation was found between estimated binding energy and inhibition measured in vitro (r = -0.894).
authors: a Department of Medical Laboratory Studies, School of Health and Medical Care , Alexander Technological Educational Institute of Thessaloniki , Greece.
authors: P
authors: P
authors: Eleftheriou
authors: b Department of Medicinal Chemistry, School of Medicine , Aristotle University of Thessaloniki , Greece.
authors: A
authors: A
authors: Petrou
authors: b Department of Medicinal Chemistry, School of Medicine , Aristotle University of Thessaloniki , Greece.
authors: A
authors: A
authors: Geronikaki
authors: b Department of Medicinal Chemistry, School of Medicine , Aristotle University of Thessaloniki , Greece.
authors: K
authors: K
authors: Liaras
authors: a Department of Medical Laboratory Studies, School of Health and Medical Care , Alexander Technological Educational Institute of Thessaloniki , Greece.
authors: S
authors: S
authors: Dirnali
authors: a Department of Medical Laboratory Studies, School of Health and Medical Care , Alexander Technological Educational Institute of Thessaloniki , Greece.
authors: M
authors: M
authors: Anna
mesh_terms: D001665:Binding Sites; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011487:Protein Conformation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D004791:Enzyme Inhibitors; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1
keywords: PTP1b inhibitors; active centre; allosteric centre; competitive inhibitors; diabetes; docking analysis; structural characteristics; thiazols; uncompetitive inhibitors