Pharmacophore-guided de novo drug design with diffusion bridge

Conghao Wang, Jagath C. Rajapakse

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 phamacophoreguided 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.