3DLinker: An E(3) Equivariant Variational Autoencoder for Molecular Linker Design

TL;DR

This paper introduces 3DLinker, a novel E(3) equivariant variational autoencoder that generates molecular linkers conditioned on two molecules, accurately predicting their 3D structures and anchor points for drug design.

Contribution

The paper presents the first model capable of generating 3D molecular linkers conditioned on two molecules, predicting anchor atoms, and considering 3D orientations with E(3) equivariance.

Findings

Higher molecular graph recovery rate

More accurate 3D coordinate prediction

Effective in linker generation tasks

Abstract

Deep learning has achieved tremendous success in designing novel chemical compounds with desirable pharmaceutical properties. In this work, we focus on a new type of drug design problem -- generating a small "linker" to physically attach two independent molecules with their distinct functions. The main computational challenges include: 1) the generation of linkers is conditional on the two given molecules, in contrast to generating full molecules from scratch in previous works; 2) linkers heavily depend on the anchor atoms of the two molecules to be connected, which are not known beforehand; 3) 3D structures and orientations of the molecules need to be considered to avoid atom clashes, for which equivariance to E(3) group are necessary. To address these problems, we propose a conditional generative model, named 3DLinker, which is able to predict anchor atoms and jointly generate linker graphs and their 3D structures based on an E(3) equivariant graph variational autoencoder. So far as we know, there are no previous models that could achieve this task. We compare our model with multiple conditional generative models modified from other molecular design tasks and find that our model has a significantly higher rate in recovering molecular graphs, and more importantly, accurately predicting the 3D coordinates of all the atoms.