A Physically-Informed Subgraph Isomorphism Approach to Molecular Docking Using Quantum Annealers

2026-04-10

AI Summary

This work addresses the limited accuracy of traditional molecular docking approaches, which rely predominantly on geometric complementarity while neglecting essential physicochemical interactions. To overcome this limitation, the authors propose a quantum annealing–based docking method that integrates multiscale interaction modeling. In this framework, the ligand is represented as a geometric graph and mapped onto a three-dimensional discrete grid of the protein binding pocket; candidate binding poses are generated via subgraph isomorphism. Crucially, the formulation encodes key physicochemical terms—including Coulombic forces, van der Waals interactions, hydrogen bonding, and hydrophobic effects—into a unified QUBO (Quadratic Unconstrained Binary Optimization) representation for the first time. Experimental results on a D-Wave quantum annealer demonstrate that this approach significantly outperforms purely geometric docking strategies, yielding markedly improved prediction accuracy.

Technology Category

• Machine Learning: Quantum Machine Learning
• Search and Optimization: Mixed Discrete/Continuous Search
• Constraint Satisfaction and Optimization: Satisfiability

Application Category

• Graph Algorithms and Modeling for the Web: Graph embeddings and representation learning for Web-related graphs
• Search and Retrieval-Augmented AI: Web query analysis, representation and understanding
• Semantics and Knowledge: Methods to enhance, augment, integrate or synergize semantic models such as knowledge graphs and LLMs

Abstract

Molecular docking is a crucial step in the development of new drugs as it guides the positioning of a small molecule (ligand) within the pocket of a target protein. In the literature, a feasibility study explored the potential of D-Wave quantum annealers for purely geometric molecular docking, neglecting physicochemical interactions between the protein and the ligand and focusing solely on their simplified geometries. To achieve this, the ligands were represented as graphs incorporating their geometric properties and then mapped onto a grid that discretized the three-dimensional space of the protein pocket. The quality of the ligand pose on the protein pocket was evaluated through the isomorphism between the ligand graph and the spatial grid. This paper builds on the previous study by introducing physicochemical interactions between the protein-ligand pair into the QUBO problem to improve the accuracy of the docking results. This paper presents a novel QUBO formulation that includes Coulomb and van der Waals forces, together with components representing H-bond and hydrophobic interactions. We integrate these physical interactions as corrective terms to the previous purely geometric QUBO formulation, and provide experimental results using the D-Wave quantum annealers to demonstrate their impact on the accuracy of the docking results.

Problem

• molecular docking
• physicochemical interactions
• quantum annealing
• QUBO
• subgraph isomorphism

Innovation

• physically-informed
• quantum annealing
• molecular docking
• QUBO formulation
• subgraph isomorphism