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.