Unveiling FragLites: Pioneering Precision in Drug Discovery

  • FragLites are a focused library of 31 halogenated fragments used to map protein binding sites with high sensitivity and specificity.
  • They enable identification of known and novel protein interaction hotspots, aiding drug discovery and protein biology.
  • Application on CDK2-cyclin A and bromodomain proteins (BRD4, ATAD2) validates their versatility in mapping ligand sites.
  • FragLite binding exploits halogen anomalous scattering for precise X-ray crystallographic detection.
  • The approach reduces resource needs compared to full fragment screening while maintaining comprehensive site mapping.
  • FragLites support development of chemical probes and inform mutation site selection for functional studies.
  1. Erlanson, D. A., Murray, C. W., & Davis, B. J. (2019). FragLites—Minimal, Halogenated Fragments Displaying Pharmacophore Doublets. Journal of Medicinal Chemistry:
    https://pubs.acs.org/doi/10.1021/acs.jmedchem.9b00304
  2. Wood, E. R., et al. (2024). Crystallographic fragment screening of CDK2-cyclin A: FragLites identify functional protein interaction hotspots. bioRxiv:
    https://www.biorxiv.org/content/10.1101/2024.06.03.596235v1.full.pdf
  3. Filippakopoulos, P., et al. (2022). Mapping ligand interactions of bromodomains BRD4 and ATAD2 reveals novel binding sites by fragment screening. Journal of Medicinal Chemistry:
    https://pubs.acs.org/doi/10.1021/acs.jmedchem.2c01357
  4. Keable, S. et al. (2025). Crystallographic Fragment Screening of CDK2-cyclin A: FragLites Rapidly Identify Multiple Binding Sites. European Journal of Medicinal Chemistry:
    https://www.sciencedirect.com/science/article/pii/S0969212625002655

FragLites have emerged as a groundbreaking tool in the realm of fragment-based drug discovery (FBDD), offering an innovative approach to identify and map protein interaction sites with unparalleled efficiency and precision. These small, halogenated molecular fragments leverage the powerful anomalous scattering property of halogens, enabling researchers to sensitively and unambiguously detect productive drug-like interactions through X-ray crystallography. Unlike traditional extensive fragment libraries, the FragLites set—a concise library of 31 halogenated fragments—can pinpoint key protein binding hotspots effectively, making it a resource-efficient method for understanding protein surfaces relevant for drug targeting.

Recent studies between 2024 and 2025 have validated the capabilities of FragLites across diverse protein systems. Notably, FragLites successfully mapped the protein-protein interaction (PPI) hotspots on cyclin-dependent kinase 2 (CDK2) and its complex with cyclin A, uncovering both known and previously uncharacterized binding sites. This chemically rich mapping serves as a foundational resource for designing chemical probes and selecting mutation sites that distinguish protein functions, thereby advancing both drug design and functional biology insights.

In addition to CDK2, FragLites have demonstrated their utility in mapping ligand binding sites of bromodomains such as BRD4 and ATAD2. The technology revealed that FragLites can recapitulate interactions identified by full fragment screening but with greater speed and reduced experimental resource input. This allows for early-stage assessment of protein tractability and informs hit-finding strategies. Furthermore, the FragLite framework extends to analogues termed PepLites that mimic peptide interactions, broadening their applicability.

The benefits of FragLites go beyond mere binding detection. Their selective binding profiles enable prioritization of functional hotspots over nonspecific or artefactual interactions, supported by corroborative mutational studies and structural analyses. This precision enriches the drug discovery pipeline by offering reliable starting points for rational design of lead-like molecules, greatly enhancing efficiency in early drug development stages. Overall, FragLites mark a significant advancement in fragment-based methodologies, illustrating a promising avenue for accelerating the discovery of novel therapeutics.