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  3. A Diffusion-based Framework For Designing Molecules In Flexible Protein Pockets.
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A diffusion-based framework for designing molecules in flexible protein pockets.

Jian Wang1, Dong Yan Zhang1, Shreshty Budakoti2

  • 1Department of Neurology and Neuroscience, University of Virginia, School of Medicine, Charlottesville, VA, USA.

Science Advances
|April 8, 2026

View abstract on PubMed

Summary
This summary is machine-generated.

YuelDesign, a new computational framework, generates drug molecules for flexible protein pockets by modeling dynamic protein-ligand interactions. This approach improves drug design for challenging targets, offering promising implications for pharmaceutical research.

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Area of Science:

  • Computational chemistry
  • Drug discovery
  • Structural biology

Background:

  • Designing molecules for flexible protein pockets is a major challenge in structure-based drug discovery.
  • Proteins undergo conformational changes upon ligand binding, complicating molecular design.
  • Current deep learning methods often treat protein pockets as rigid, failing to capture dynamic interactions.

Purpose of the Study:

  • To present YuelDesign, a novel diffusion-based framework for designing drug molecules targeting flexible protein pockets.
  • To enable joint modeling of protein pocket structures and ligand conformations in protein-ligand complexes.
  • To address the limitations of existing methods in capturing protein-ligand dynamics.

Main Methods:

  • YuelDesign employs a diffusion-based framework utilizing E3former for rotational and translational equivariance.
  • Dual diffusion processes are incorporated: an elucidated diffusion model (EDM) for coordinates and a discrete denoising diffusion probabilistic model (D3PM) for ligand atom types.
  • The framework iteratively refines both the geometry and chemical identity of generated molecules.

    • Main Results:

    • YuelDesign generates molecules with favorable drug-likeness and low synthetic complexity.
    • The generated molecules exhibit diverse chemical functional groups.
    • Docking energies of YuelDesign-generated molecules are comparable to those of native ligands.

    Conclusions:

    • YuelDesign offers a versatile framework for designing drugs targeting flexible protein pockets.
    • The joint modeling of pocket and ligand dynamics enhances drug design capabilities.
    • This approach holds significant promise for advancing drug discovery applications.