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Spring 2026 challenge: phase 2 contestant

Structure-Based Identification of Selective G4 Ligands for Oncogenic DNA targets

Alessio Maria Caramiello, University of Pavia, Pavia, Italy

During the first three months of the project, the molecular targets were successfully identified, curated from the Protein Data Bank (PDB), and prepared within the SeeSAR environment to establish a reliable docking workflow for G-quadruplex DNA structures. Two independent virtual screening campaigns were then performed using libraries of approximately 10,000 compounds each, generated from freely accessible databases including CartBlanche22, ZINC-20, and ZINC-22. The first library consisted of structurally diverse molecules randomly selected across major pharmacophoric families, while the second focused on derivatives and analogues of previously reported G4-binding ligands. Preliminary docking and scoring analyses enabled the generation of theoretical interaction profiles for broad classes of compounds, highlighting recurring binding patterns, stacking preferences, and potential hydrogen-bond interactions with different G-quadruplex topologies.
After 3 months, Alessio Maria has achieved the following milestones:
  1. The first project milestone was successfully achieved through the selection, curation, and preparation of four flagship G-quadruplex DNA targets, including oncogenic promoter G4s and the human telomeric G4, starting from experimentally resolved structures retrieved from the Protein Data Bank (PDB). All targets were imported, optimized, and organized within the SeeSAR environment to establish a consistent and reproducible docking workflow. In parallel, a dedicated ligand library was generated from publicly available chemical databases, combining structurally diverse compounds with derivatives inspired by previously reported G4 binders. Finally, the docking workflow was defined and standardized, including target preparation, pose generation, and HYDE-based scoring protocols, enabling the systematic evaluation of ligand binding modes, affinity trends, and selectivity profiles across multiple G4 topologies.
  2. Not justifiable, this milestone will be achieved by month 8
  3. Not justifiable, this milestone will be achieved by month 12