title: CoMFA based de novo design of pyridazine analogs as PTP1B inhibitors.
abstract: PTP1B plays an important role as a negative regulator in insulin and leptin signaling pathways. Potent and orally active PTP1B inhibitors can act as potential agents for the treatment of Type 2 diabetes and obesity. CoMFA (Comparative Molecular Field Analysis) and de novo ligand design using LeapFrog (LF) studies were performed on pyridazine analogs, reported to be selective and non-competitive inhibitors of PTP1B. A robust model was developed which produced statistically significant results with cross-validated and conventional correlation coefficients of 0.619 and 0.990, respectively. Further, the robustness of the model was verified by bootstrapping analysis. LeapFrog (LF) program is a de novo drug discovery tool, which uses CoMFA maps to generate hypothetical cavity and ligands. As the crystal structure of PTP1B-pyridazine complex is not yet known, the contours of CoMFA model was used to serve as a pharmacophoric model to generate hypothetical cavity for LeapFrog calculations. Ligands were optimized using this concept.
authors.affiliation: Centre for Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Punjab 160062, India.
authors.forename: Pramod C
authors.initials: PC
authors.lastname: Nair
authors.forename: M Elizabeth
authors.initials: ME
authors.lastname: Sobhia
mesh_terms: D000818:Animals; D003198:Computer Simulation; D017076:Computer-Aided Design; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000201:enzymology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008958:Models, Molecular; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D011724:Pyridazines / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D055672:Static Electricity; D013816:Thermodynamics
chemical_list: D004791:Enzyme Inhibitors; D011724:Pyridazines; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; C516609:Ptpn1 protein, mouse