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Discovery and Exploration of Small Molecule Binders for CT83: Computational Insights from Homology Modeling, Virtual

Varun Dewaker1, Sung Taek Park1,2,3, Jae Jun Lee1,4

  • 1Institute of New Frontier Research, College of Medicine, Hallym University, Chuncheon-Si, Gangwon-Do 24252, Republic of Korea.

ACS Omega
|June 16, 2025
PubMed

Insights

New small molecules targeting Kita-Kyushu lung cancer antigen-1 (KK-LC-1) were identified. CID46375999 showed promising binding affinity and interactions, making it a potential candidate for cancer therapy development.

Area of Science:

  • Oncology
  • Computational Chemistry
  • Drug Discovery

Background:

  • Kita-Kyushu lung cancer antigen-1 (KK-LC-1), or CT83, is a cancer/testis antigen (CTA) family member.
  • Restricted expression in cancers like lung, gastric, and breast cancers makes CT83 a promising therapeutic target.

Purpose of the Study:

  • To identify novel small molecules targeting CT83 for cancer therapy.
  • To evaluate the binding affinity and interaction profiles of candidate molecules with CT83.

Main Methods:

  • Utilized PubChem searches, Lipinski's rule filtration, virtual screening, molecular docking, and molecular dynamics (MD) simulations.
  • Performed 200 ns MD simulations and Molecular Mechanics with the Poisson-Boltzmann Surface Area (MMPBSA) calculations.
  • Analyzed interaction fingerprints to understand binding dynamics and key residue interactions.

Main Results:

  • Identified five candidate molecules: CID24326943, CID24459131, CID46375999, CID46533890, and CID55836895.
  • MD simulations confirmed stable CT83-ligand complexes; Z839878730, CID24459131, and CID46375999 showed favorable binding energies.
  • CID46375999 demonstrated strong similarity to the reference compound, featuring a 1,3,4-thiadiazole-2-carboxamide scaffold and stable interactions with key residues like Leu15, Phe18, and Arg76.

Conclusions:

  • CID46375999 emerged as a highly promising candidate due to its structural similarity to the reference compound and favorable binding characteristics.
  • The identified interactions, including hydrophobic, π-stacking, and hydrogen bonds, provide crucial insights into the binding mechanism of CT83 inhibitors.
  • These findings support the development of CT83-targeted therapies for cancers expressing this antigen.

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