CompassDock: Comprehensive Accurate Assessment Approach for Deep Learning-Based Molecular Docking in Inference and Fine-Tuning

TL;DR

This paper introduces Compass, a comprehensive assessment framework for molecular docking that evaluates physical, chemical, and bioactivity properties, and demonstrates how fine-tuning with Compass scores improves ligand conformation quality and favorability.

Contribution

The paper presents Compass, a novel assessment approach combining physical, chemical, and bioactivity evaluations, and integrates it with deep learning docking methods for improved accuracy and model fine-tuning.

Findings

Compass reveals substantial noise in PDBBind data.

Fine-tuning with Compass improves ligand favorability.

Compass-based fine-tuning enhances docking quality without sacrificing physical properties.

Abstract

Datasets used for molecular docking, such as PDBBind, contain technical variability - they are noisy. Although the origins of the noise have been discussed, a comprehensive analysis of the physical, chemical, and bioactivity characteristics of the datasets is still lacking. To address this gap, we introduce the Comprehensive Accurate Assessment (Compass). Compass integrates two key components: PoseCheck, which examines ligand strain energy, protein-ligand steric clashes, and interactions, and AA-Score, a new empirical scoring function for calculating binding affinity energy. Together, these form a unified workflow that assesses both the physical/chemical properties and bioactivity favorability of ligands and protein-ligand interactions. Our analysis of the PDBBind dataset using Compass reveals substantial noise in the ground truth data. Additionally, we propose CompassDock, which incorporates the Compass module with DiffDock, the state-of-the-art deep learning-based molecular docking method, to enable accurate assessment of docked ligands during inference. Finally, we present a new paradigm for enhancing molecular docking model performance by fine-tuning with Compass Scores, which encompass binding affinity energy, strain energy, and the number of steric clashes identified by Compass. Our results show that, while fine-tuning without Compass improves the percentage of docked poses with RMSD < 2{\AA}, it leads to a decrease in physical/chemical and bioactivity favorability. In contrast, fine-tuning with Compass shows a limited improvement in RMSD < 2{\AA} but enhances the physical/chemical and bioactivity favorability of the ligand conformation. The source code is available publicly at https://github.com/BIMSBbioinfo/CompassDock.