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Artificial intelligence-guided discovery of a lead compound with antifolate-like activity against bacterial and human

Yi-Lin Chen1, Yi-Min Chen2, Yan Zou1

  • 1Department of Medical Oncology, Quzhou People's Hospital, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou, China.

Frontiers in Cellular and Infection Microbiology
|July 24, 2026
PubMed

Insights

This study explores Compound 8 as a potential antifolate drug targeting thymidylate synthase (TYMS) in colorectal cancer (CRC) and bacteria. AI-driven modeling and assays show its promise as an early lead, though further optimization is needed.

Area of Science:

  • Biochemistry
  • Computational Biology
  • Drug Discovery

Background:

  • Thymidylate synthase (TYMS) is a validated target for colorectal cancer (CRC) therapy.
  • Conserved active-site architecture between human TYMS and bacterial homologs offers potential for cross-species drug discovery.
  • Antifolates are a key class of drugs targeting the TYMS pathway.

Purpose of the Study:

  • To evaluate the conserved active-site architecture of human TYMS and bacterial TYSY KLEP7 for early lead discovery.
  • To investigate Compound 8 as an antifolate-like lead targeting the TYMS-axis.
  • To establish an AI-enabled structure-to-phenotype framework for drug discovery.

Main Methods:

  • Integrated computational methods including AlphaFold3, molecular modeling, docking, and molecular dynamics (MD).
  • Cross-validation using crystal structures and biochemical assays.
  • Phenotypic assays for cell viability and antibacterial activity.
  • Target-axis engagement assays using siRNAs and antisense oligonucleotides.

Main Results:

  • Compound 8 demonstrated dose-dependent inhibition of CRC cell viability with preliminary selectivity.
  • Antibacterial activity against *K. pneumoniae* was modest, requiring higher concentrations for bactericidal effects.
  • Compound 8 engaged both human TYMS and bacterial *thyA* (the gene encoding TYSY), inhibiting enzyme activity.
  • AI-driven modeling predicted Compound 8's ability to maintain key interactions within the folate-binding groove.

Conclusions:

  • An AI-enabled structure-to-phenotype framework was established for TYMS-axis drug discovery.
  • Compound 8 represents an early-stage antifolate-like lead for TYMS-axis targeting.
  • Further studies are required for purified-enzyme validation, ADME profiling, safety assessment, and antibacterial optimization.
Keywords:
AI-driven drug discoveryAlphaFold3candidate cross-species ligandcolorectal cancerphenotypic evaluationtarget validationthymidylate synthase (TYMS)

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