Autoregressive fragment-based diffusion for pocket-aware ligand design

Mahdi Ghorbani, Leo Gendelev, Paul Beroza, Michael Keiser

Keywords: Diffusion model, Drug design, Protein pocket, binding, Autoregressive, fragments

TL;DR: Diffusion model for fragment based drug design conditioned on protein pocket

Abstract: In this work, we introduce AutoFragDiff, a fragment-based autoregressive diffusion model for generating 3D molecular structures conditioned on target protein structures. We employ geometric vector perceptrons to predict atom types and spatial coordinates of new molecular fragments conditioned on molecular scaffolds and protein pockets. Our approach improves the local geometry of the resulting 3D molecules while maintaining high predicted binding affinity to protein targets. The model can also perform scaffold extension from user-provided starting molecular scaffold.

Submission Number: 71