Machine learning methods for pK_a prediction of small molecules: Advances and challenges

The acid-base dissociation constant (pK_a) is a fundamental property influencing many ADMET properties of small molecules. However, rapid and accurate pK_a prediction remains a great challenge. In this review, we outline the current advances in machine-learning-based QSAR models for pK_a prediction, including descriptor-based and graph-based approaches, and summarize their pros and cons. Moreover, we highlight the current challenges and future directions regarding experimental data, crucial factors influencing pK_a and in silico prediction tools. We hope that this review can provide a practical guidance for the follow-up studies.