Scaffold hopping, a technique used in drug discovery and development, aims to find new molecules with comparable biological activity by alteringthe core scaffold of a given molecule. Therefore, identifying privileged scaffolds is crucial for drug molecule design. Currently, the main methods for scaffold hopping include heterocycle replacements, ring opening or closure, topology-based hopping, and computational methods . Typically, these methods require validation of scaffold hopping rationality through binding free energy calculations. However, few computational methods take this into account largely owing to the high computational cost and challenges in achieving accuracy.