Leveraging Large Language Models for Literature-Driven Prioritization of Protein Binding Pockets

Motivation Accurately identifying and prioritizing protein binding pockets is a foundational element of small-molecule drug discovery. Defining these known pockets currently relies on a laborious manual process of extracting key residue data from selected publications, reconciling inconsistent terminology, and independently computing volumetric representations. This manual curation to ensure biological relevance is time-consuming, error-prone, and represents a major bottleneck for efficient, high-throughput drug discovery. Results We present a novel approach for the identification and prioritization of protein binding pockets for small molecules by combining geometric pocket detection with Large Language Models (LLMs). Our method leverages Fpocket to generate candidate pockets, which are then validated against published experimental data extracted from research articles using LLM with a series of prompts fine-tuned to identify and extract residue-level information associated with experimentally confirmed binding sites. We developed a curated benchmark dataset of diverse proteins and associated literature to train and evaluate the LLM's performance in paper relevance assessment and pocket extraction. Availability and Implementation The developed benchmark dataset and methodology are freely available at the GitHub repository (https://github.com/receptor-ai/LLM-benchmark-dataset) and Zenodo (DOI: 10.5281/zenodo.15798647). Supplementary information Supplementary data are available at Bioinformatics online.