What Ails Generative Structure-based Drug Design: Expressivity is Too Little or Too Much?

TL;DR

This paper investigates why current generative models for structure-based drug design underperform, analyzing their expressivity and proposing a simpler, more efficient model that achieves state-of-the-art results with fewer parameters.

Contribution

It provides the first theoretical analysis of GNN limitations in protein-ligand modeling and introduces a simple, parameter-efficient model that outperforms existing methods.

Findings

GNNs have representational limitations in protein-ligand complexes.

A simple metric-aware model achieves state-of-the-art results.

The proposed model is 100x smaller and 1000x faster than previous approaches.

Abstract

Several generative models with elaborate training and sampling procedures have been proposed to accelerate structure-based drug design (SBDD); however, their empirical performance turns out to be suboptimal. We seek to better understand this phenomenon from both theoretical and empirical perspectives. Since most of these models apply graph neural networks (GNNs), one may suspect that they inherit the representational limitations of GNNs. We analyze this aspect, establishing the first such results for protein-ligand complexes. A plausible counterview may attribute the underperformance of these models to their excessive parameterizations, inducing expressivity at the expense of generalization. We investigate this possibility with a simple metric-aware approach that learns an economical surrogate for affinity to infer an unlabelled molecular graph and optimizes for labels conditioned on this graph and molecular properties. The resulting model achieves state-of-the-art results using 100x fewer trainable parameters and affords up to 1000x speedup. Collectively, our findings underscore the need to reassess and redirect the existing paradigm and efforts for SBDD. Code is available at https://github.com/rafalkarczewski/SimpleSBDD.