Pharmacophore-guided de novo drug design with diffusion bridge

TL;DR

PharmacoBridge is a novel diffusion-based method that uses pharmacophore guidance to generate bioactive drug molecules with high target affinity, offering precise control over molecular features in 3D space.

Contribution

It introduces a pharmacophore-guided diffusion approach with SE(3)-equivariance for de novo drug design, improving control over molecular feature arrangements.

Findings

Generated molecules show high binding affinity.

Effective conversion of pharmacophore arrangements into molecules.

Provides sophisticated control over biochemical features.

Abstract

De novo design of bioactive drug molecules with potential to treat desired biological targets is a profound task in the drug discovery process. Existing approaches tend to leverage the pocket structure of the target protein to condition the molecule generation. However, even the pocket area of the target protein may contain redundant information since not all atoms in the pocket is responsible for the interaction with the ligand. In this work, we propose PharmacoBridge, a phamacophore-guided de novo design approach to generate drug candidates inducing desired bioactivity via diffusion bridge. Our method adapts the diffusion bridge to effectively convert pharmacophore arrangements in the spatial space into molecular structures under the manner of SE(3)-equivariant transformation, providing sophisticated control over optimal biochemical feature arrangements on the generated molecules. PharmacoBridge is demonstrated to generate hit candidates that exhibit high binding affinity with potential protein targets.