Discovery and Exploration of Small Molecule Binders for CT83: Computational Insights from Homology Modeling, Virtual Screening, MD Simulations, Interaction Fingerprint, and Network Communications.

Kita-Kyushu lung cancer antigen-1 (KK-LC-1), also known as CT83, is a member of the cancer/testis antigen (CTA) family and has emerged as an important target for cancer therapy. Its expression is typically restricted to certain cancers, including nonsmall cell lung cancer, gastric cancer, triple-negative breast cancer, and testicular tissues, making it an attractive candidate for targeted drug development against cancer cells. We identified several new small molecules using PubChem chemical property searches, Lipinski rule-based filtration, virtual screening, molecular docking, and molecular dynamics (MD) simulations, with reference to the compound Z839878730 reported in the literature. The selected molecules were CID24326943, CID24459131, CID46375999, CID46533890, and CID55836895. MD simulations (200 ns) revealed stable CT83-ligand complexes, with MMPBSA calculations showing that Z839878730, CID24459131, and CID46375999 exhibited the most favorable relative binding free energies. Among these, CID46375999 shared greater similarity with the reference compound, featuring a 1,3,4-thiadiazole-2-carboxamide scaffold, hydrophobic properties, and hydrogen bonding potential. In contrast, CID24459131, which features an imidazolidinone ring and relatively bulky substituents such as a diphenylethyl moiety, exhibits a more flexible and extended conformation. Although CID46375999 contains a piperidine ring, its overall structure is more conformationally constrained compared to CID24459131, likely due to fewer rotatable bonds and a more compact architecture. Overall, CID46375999 aligned more closely with the reference compound in terms of chemical properties. Interaction fingerprint analysis revealed frequent interactions with key residues Leu15, Ile16, Phe18, Trp19, Arg22, Leu38, Arg42, Pro43, Arg76, Gln77, and Ile80, including hydrophobic interactions, π-stacking (Phe18 and Trp19), and H-bonds (Arg22, Arg76, Gln77, and Ser44), and the communication network of these interactions provided insights into binding dynamics.