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Updated: May 22, 2026

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Structural Hotspot Conditioning for Diffusion-Based Molecular Design.

Diego Masone1,2, Marcelo Caparotta1,2

  • 1Instituto de Histología y Embriología de Mendoza (IHEM) Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional de Cuyo (UNCuyo), Mendoza 5500, Argentina.

Journal of Chemical Information and Modeling
|May 21, 2026
PubMed
Summary
This summary is machine-generated.

Structural hotspot conditioning enhances diffusion models for molecular design by guiding generative processes with interaction-relevant chemical knowledge. This approach enables controllable trade-offs between affinity, feasibility, and diversity for drug discovery.

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Area of Science:

  • Computational chemistry
  • Drug discovery
  • Artificial intelligence in chemistry

Background:

  • Diffusion models are powerful for molecular design but require effective integration of protein-ligand interaction data.
  • Incorporating prior chemical knowledge is crucial for guiding generative models toward high-quality molecular solutions.

Purpose of the Study:

  • To investigate structural hotspot conditioning for injecting interaction-relevant chemical knowledge into pocket-conditioned diffusion models.
  • To evaluate different strategies for defining atom-level reference points for hotspot conditioning.
  • To benchmark the performance of hotspot-conditioned diffusion models against established methods.

Main Methods:

  • Developed and evaluated three strategies for defining structural hotspots: docking score-based selection, pharmacophore localization, and hydrogen-bonding site prediction.
  • Utilized MolSnapper, a unified diffusion-based generative model, for molecular generation.
  • Benchmarked performance on the CrossDocked2020 dataset, assessing affinity, quality, plausibility, and diversity.

Main Results:

  • Explicit hotspot conditioning systematically altered generative behavior compared to baselines.
  • Achieved controllable trade-offs between ligand affinity, chemical feasibility, and diversity.
  • Demonstrated effectiveness in an iterative case study on the Ube2T allosteric pocket.

Conclusions:

  • Structural hotspot conditioning is a flexible and tunable variable for diffusion-based molecular generation.
  • This approach guides the generation of chemically meaningful solutions for drug discovery.
  • Hotspot conditioning offers a promising avenue for designing ligands against challenging targets.