Structure-based design of alicyclic fused pyrazole derivatives for targeting TGF-β receptor I kinase: molecular docking and dynamics insights

Abstract

TGF-β receptor I kinase plays a significant role in cancer biology and is a well-established target for cancer drug development, as evidenced by active molecules like Galunisertib (LY2157229). Computational studies were conducted to analyse the catalytic site of TGF-β receptor I kinase, identifying key amino acid residues essential for binding. Based on these findings, Alicyclic fused pyrazole derivatives were designed. The target molecules were synthesized through a multi-step process, with an important intermediate obtained via Suzuki coupling, followed by various ligand and catalyst optimizations. A total of thirteen molecules were synthesized by optimizing temperature, solvent, and base. After characterization, the synthesized, Alicyclic fused pyrazole derivatives were screened for TGF-β receptor I kinase inhibition and in vitro cytotoxic activity. To further elucidate their binding mechanism, molecular docking and molecular dynamics studies were performed. The most active compound 16c, was subjected to in silico ADME screening, which revealed a favorable pharmacokinetic profile. Molecular Dynamics simulation study indicated that specific aminoacid residue interaction with TGF-β receptor I kinase. Additionally, DFT calculations were conducted on the active molecules to gain deeper insights into their electronic properties, supporting their potential as effective anticancer agents.