Taeung Song  Jin Hyuk Kim  Hyeon Jun Park  Jonghwan Choi

10.5626/JOK.2025.52.6.539

Machine Learning Large Language Model Drug Discovery binding affinity prediction mutant protein

Drug development is a costly and time-consuming process. Accurately predicting the impact of protein mutations on drug-target binding affinity remains a major challenge. Previous studies have utilized long short-term memory (LSTM) and transformer models for amino acid sequence processing. However, LSTMs suffer from long-sequence dependency issues, while transformers face high computational costs. In contrast, pretrained large language models (pLLMs) excel in handling long sequences, yet prompt-based approaches alone are insufficient for accurate binding affinity prediction. This study proposed a method that could leverage pLLMs to analyze protein structural data, transform it into embedding vectors, and use a separate machine learning model for numerical binding affinity prediction. Experimental results demonstrated that the proposed approach outperformed conventional LSTM and prompt-based methods, achieving lower root mean square error (RMSE) and higher Pearson correlation coefficient (PCC), particularly in mutation-specific predictions. Additionally, performance analysis of pLLM quantization confirmed that the method maintained sufficient accuracy with reduced computational cost.