Pocket-specific 3D Molecule Generation by Fragment-based Autoregressive Diffusion Models
Keywords: 3D molecule generation, drug design, protein binding pocket, generative model, diffusion model
TL;DR: Using fragment-based autoregressive diffusion model to generate 3D molecules for protein binding pockets
Abstract: Autoregressive model is widely adopted to generate 3D molecules which can fit any protein binding pocket. Current autoregressive model suffers from two major drawbacks. First, it is hard to capture local geometric patterns as only one atom is generated at each step. Second, most of the autoregressive models generate atoms and chemical bonds in two separate processes, which causes a number of problems such as incorrect counts of rings, a bias distribution of bond lengths, and inaccurate 3D molecular structures. To tackle this problem, we designed a model, named FragDiff, to generate 3D molecules fragment-by-fragment for pockets. In each generation step, FragDiff places a molecular fragment around the pocket by using E(3)-equivariant diffusion generative models to simultaneously predict the atom types, atom coordinates and the chemical bonds of the fragment. Extensive experimental results confirm our assumption that unifying the atoms and bonds generations could significantly improve the quality of the sampled 3D molecules in terms of more accurate distributions of 2D subgraphs and 3D substructures.
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