3D-QSAR Based Design of 3-Hydroxy-1,2,5-Oxadiazole Derivates as Stat3 Inhibitors and Their Docking Study

Abstract

Signal Transducer and Activator of Transcription 3 (STAT3) inhibitors hold immense promise in combating various cancers and inflammatory diseases. This work introduces an integrated approach to STAT3 inhibitors, employing an acid bioisosteric scaffold, 3-hydroxy-1,2,5-oxadiazole. Utilizing a combination of 3D Quantitative Structure-Activity Relationship (QSAR) modeling and molecular docking techniques, the designed molecules were meticulously analyzed for their binding interactions within the STAT3 binding pocket. Notably, the designed compounds exhibited a tripedal conformation, establishing crucial hydrogen bonds with key binding site residues, including Arg609, Ser613, Ser611, and Glu612. Moreover, comprehensive ADMET studies revealed the favorable drug likeness and safety profiles of the designed molecules, with minimal Lipinski violations and excellent absorption, metabolic, and safety properties observed across the compound library. The 3D-QSAR modeling employed in this study demonstrated high predictive accuracy, with an R2 value of 0.937 and Q2 value of 0.634, underscoring the robustness of the computational approach. Overall, this research provides valuable insights into the rational design of STAT3 inhibitors, offering promising avenues for the development of novel therapeutics targeting STAT3-mediated diseases such as cancer and inflammatory disorders.