Drug Discovery and Design Center, Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai, 201203, China.
J Chem Inf Model. 2014 Jan 27;54(1):69-78. doi: 10.1021/ci400539q. Epub 2014 Jan 6.
Halogen bond has attracted a great deal of attention in the past years for hit-to-lead-to-candidate optimization aiming at improving drug-target binding affinity. In general, heavy organohalogens (i.e., organochlorines, organobromines, and organoiodines) are capable of forming halogen bonds while organofluorines are not. In order to explore the possible roles that halogen bonds could play beyond improving binding affinity, we performed a detailed database survey and quantum chemistry calculation with close attention paid to (1) the change of the ratio of heavy organohalogens to organofluorines along the drug discovery and development process and (2) the halogen bonds between organohalogens and nonbiopolymers or nontarget biopolymers. Our database survey revealed that (1) an obviously increasing trend of the ratio of heavy organohalogens to organofluorines was observed along the drug discovery and development process, illustrating that more organofluorines are worn and eliminated than heavy organohalogens during the process, suggesting that heavy halogens with the capability of forming halogen bonds should have priority for lead optimization; and (2) more than 16% of the halogen bonds in PDB are formed between organohalogens and water, and nearly 20% of the halogen bonds are formed with the proteins that are involved in the ADME/T process. Our QM/MM calculations validated the contribution of the halogen bond to the binding between organohalogens and plasma transport proteins. Thus, halogen bonds could play roles not only in improving drug-target binding affinity but also in tuning ADME/T property. Therefore, we suggest that albeit halogenation is a valuable approach for improving ligand bioactivity, more attention should be paid in the future to the application of the halogen bond for ligand ADME/T property optimization.
卤素键在过去几年中引起了广泛关注，因为它可以用于从先导化合物优化到候选化合物的优化，旨在提高药物靶标结合亲和力。一般来说，重有机卤素（即有机氯、有机溴和有机碘）能够形成卤素键，而有机氟则不能。为了探索卤素键除了提高结合亲和力之外可能发挥的作用，我们进行了详细的数据库调查和量子化学计算，特别关注：（1）在药物发现和开发过程中，重有机卤素与有机氟的比例的变化；（2）有机卤素与非生物聚合物或非靶标生物聚合物之间的卤素键。我们的数据库调查显示：（1）在药物发现和开发过程中，重有机卤素与有机氟的比例明显呈上升趋势，这表明在该过程中，有机氟比重有机卤素更容易磨损和消除，这表明具有形成卤素键能力的重卤素应该优先用于先导化合物优化；（2）PDB 中超过 16%的卤素键是在有机卤素和水之间形成的，近 20%的卤素键是与参与 ADME/T 过程的蛋白质形成的。我们的 QM/MM 计算验证了卤素键对有机卤素与血浆转运蛋白之间结合的贡献。因此，卤素键不仅可以提高药物靶标结合亲和力，还可以调节 ADME/T 性质。因此，我们建议，尽管卤化是提高配体生物活性的一种有价值的方法，但在未来应更加关注卤素键在配体 ADME/T 性质优化中的应用。
