Computational studies on structural aspects of pyrazolo[3,4-b]pyridine derivatives as TRKA inhibitors in cancer therapy.

Tropomyosin receptor kinases (TRKs) play a crucial role in nerve development, and their dysregulation due to genetic alterations, such as NTRK fusions, has been linked to various cancers. Recently, TRKs have emerged as effective therapeutic targets. However, resistance to these therapies presents significant challenges. In this study, a series of pyrazolo[3,4-b]pyridine derivatives were analyzed to generate pharmacophore-based models, conduct molecular docking, perform molecular dynamics (MD) simulations, and evaluate absorption, distribution, metabolism, excretion, and toxicity (ADMET). The generated pharmacophore hypothesis, ADRR_1, identified essential characteristics required for biological activity. Molecular docking was carried out on 37 ligands, yielding docking scores ranging from -12.672 to -14.169 kcal/mol. The best fit was observed for ligand L5, which formed five conventional hydrogen bonds with residues Glu546, Met620, Lys627, and Lys572. Additionally, three carbon-hydrogen bonds were established between the pyrazolo[3,4-b]pyridine moiety and residues Gly623, Glu618, and Asp703. MD simulations further confirmed the stability of the TRKA-L5 complex, underscoring the robust interactions between L5 and the target protein. The virtual screening study used 453 ligands from the ZINC database and identified the hit ligand ZINC000013331109, which exhibited a docking score of -10.775 kcal/mol and demonstrated good binding affinity with key amino acids. All screened ZINC hits adhered to the Lipinski Rule of Five (Ro5), and notably, ZINC000013331109 did not exhibit hepatotoxicity, unlike the top-scoring ligands and entrectinib, which were associated with liver toxicity. This study highlights the potential of ZINC000013331109 as a promising candidate for TRKA inhibition. Further research is warranted to explore the efficacy and safety of this ligand in clinical settings.