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Workshop: Machine Learning in Structural Biology Workshop

Structure-based Drug Design with Equivariant Diffusion Models

Arne Schneuing · Yuanqi Du · Charles Harris · Arian Jamasb · Ilia Igashov · weitao Du · Tom Blundell · Pietro LiĆ³ · Carla Gomes · Max Welling · Michael Bronstein · Bruno Correia


Structure-based drug design (SBDD) aims to design small-molecule ligands that bind with high affinity and specificity to pre-determined protein targets. Traditional SBDD pipelines start with large-scale docking of compound libraries from public databases, thus limiting the exploration of chemical space to existent previously studied regions. Recent machine learning methods approached this problem using an atom-by-atom generation approach, which is computationally expensive. In this paper, we formulate SBDD as a 3D-conditional generation problem and present DiffSBDD, an E(3)-equivariant 3D-conditional diffusion model that generates novel ligands conditioned on protein pockets. Furthermore, we curate a new dataset of experimentally determined binding complex data from Binding MOAD to provide a realistic binding scenario that complements the synthetic CrossDocked dataset. Comprehensive in silico experiments demonstrate the efficiency of DiffSBDD in generating novel and diverse drug-like ligands that engage protein pockets with high binding energies as predicted by in silico docking.

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