PILOT: Equivariant diffusion for pocket conditioned de novo ligand generation with multi-objective guidance via importance sampling

TL;DR

PILOT is an equivariant diffusion model that generates protein pocket-specific ligands with desired properties using multi-objective guidance, outperforming existing methods and demonstrating potential for drug discovery.

Contribution

The paper introduces PILOT, a novel equivariant diffusion approach with importance sampling for multi-objective ligand generation conditioned on protein pockets.

Findings

Outperforms existing methods on CrossDocked2020 benchmark.

Generates potent ligands with predicted $IC_{50}$ values for unseen pockets.

Maintains high synthetic accessibility in generated molecules.

Abstract

The generation of ligands that both are tailored to a given protein pocket and exhibit a range of desired chemical properties is a major challenge in structure-based drug design. Here, we propose an in-silico approach for the $\textit{de novo}$ generation of 3D ligand structures using the equivariant diffusion model PILOT, combining pocket conditioning with a large-scale pre-training and property guidance. Its multi-objective trajectory-based importance sampling strategy is designed to direct the model towards molecules that not only exhibit desired characteristics such as increased binding affinity for a given protein pocket but also maintains high synthetic accessibility. This ensures the practicality of sampled molecules, thus maximizing their potential for the drug discovery pipeline. PILOT significantly outperforms existing methods across various metrics on the common benchmark dataset CrossDocked2020. Moreover, we employ PILOT to generate novel ligands for unseen protein pockets from the Kinodata-3D dataset, which encompasses a substantial portion of the human kinome. The generated structures exhibit predicted $IC_{50}$ values indicative of potent biological activity, which highlights the potential of PILOT as a powerful tool for structure-based drug design.