Halogens in Protein–Ligand Binding Mechanism: A Structural Perspective

Halogen atoms have been at the center of many rational medicinal chemistry applications in drug design. While fluorine and chlorine atoms are often added to enhance physicochemical properties, bromine and iodine elements are generally inserted to improve selectivity. Favorable halogen interactions such as halogen bond have been thoroughly studied through quantum mechanics and statistical analyses. Although most of the studies focus on halogen interaction through its σ-hole, hydrogen bonding also has a significant impact. Here, we present an analysis describing the interacting environment of halogen atoms in protein–ligand context. With consideration of structural redundancy in the PDB, tendencies toward specific molecular interactions consideration have been refined and implications for rational drug design with halogens further discussed. Finally, we highlight the moderate occurrence of halogen bonding and present the other roles of halogen in protein–ligand complexes, completing the medicinal chemistry guide to rational halogen interactions.卤素原子在药物设计领域的诸多合理药物化学应用中始终占据核心地位。氟与氯原子常被引入以改善化合物的理化性质，而溴、碘元素则多用于提升分子选择性。诸如卤键（halogen bond）这类有益的卤素相互作用，已通过量子力学与统计分析得到了全面研究。尽管多数研究聚焦于卤素通过σ空穴（σ-hole）介导的相互作用，但氢键同样具有显著影响。本研究针对蛋白质-配体环境中的卤素原子相互作用环境展开分析，结合蛋白质数据库（Protein Data Bank, PDB）中的结构冗余特性，优化了特定分子相互作用的倾向性分析，并进一步探讨了卤素在合理药物设计中的应用启示。最后，本文阐明了卤键的中等发生频率，梳理了卤素在蛋白质-配体复合物中的其他作用，完善了面向合理卤素相互作用的药物化学指南。