Geometric Pocket-Centric Protein Encoding for Polypharmacology-Guided Multi-Target Drug Design

Abstract

Polypharmacology provides a powerful strategy for treating complex diseases, but identifying molecules that simultaneously satisfy coupled constraints across multiple biological targets remains difficult. Existing methods typically model protein pockets in isolation and struggle to jointly account for multiple heterogeneous binding sites when designing a single shared ligand. To address these limitations, we propose a pocket-structure-centric generative framework for polypharmacology. This framework introduces a novel protein topological representation that selectively masks ligand-irrelevant residues while explicitly modeling backbone folding geometry and inter-residue spatial proximity within binding pockets. In addition, structural representations are jointly fused with amino acid and nucleotide sequences to capture their complementary information across targets. Experiments on COVID-19, schizophrenia, and tumor targets show that this framework generates valid candidates with significantly improved binding affinities compared to state-of-the-art methods.