CoMFA based de novo design of pyridazine analogs as PTP1B inhibitors

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. (C) 2006 Elsevier Inc. All rights reserved.