In-silico Analysis and Molecular Modeling of Tropomycin Receptor Kinase Inhibitors as an Anticancer agents

The aim of present study is to design a series of indazole-based derivatives using structure-based drug design and evaluated through molecular docking (Autodock Vina) and in-silico analysis via Swiss ADME and pharmacokinetics studies. Absorption, Distribution, Metabolism, Excretion, and Toxicity, which are key pharmacokinetic and safety properties evaluated during the drug discovery and development process. Eighteen compounds were designed by incorporating oxazole, thiazole, and imidazole rings. Among them, compound 9 (oxazole) demonstrated the highest binding affinity (–9.1 kcal/mol) towards the Tropomyosin receptor kinase A receptor. Halogen substitutions (Cl, Br) on the phenyl ring enhanced hydrophobic interactions with residues like PRO 600 and PHE 521. Both electron-donating (methyl) and electron-withdrawing (nitro) groups improved binding by altering electronic distribution. Oxygen atoms contributed significantly to hydrogen bonding with HIS 492 and HIS 493. The indazole core played a key role, forming stable interactions with ASP 668 and GLU 560. Oxazole and thiazole heterocycles further enhanced binding, with compound 18 (thiazole) showing strong affinity (–8.7 kcal/mol). Overall, these findings offer a solid foundation for developing potent, selective Tropomyosin receptor kinase A inhibitors based on the indazole scaffold.