Discovery Chemistry, F Hoffmann-La Roche AG, CH-4070 Basel, Switzerland.
J Med Chem. 2010 Mar 25;53(6):2601-11. doi: 10.1021/jm100087s.
The formation of intramolecular hydrogen bonds has a very pronounced effect on molecular structure and properties. We study both aspects in detail with the aim of enabling a more rational use of this class of interactions in medicinal chemistry. On the basis of exhaustive searches in crystal structure databases, we derive propensities for intramolecular hydrogen bond formation of five- to eight-membered ring systems of relevance in drug discovery. A number of motifs, several of which are clearly underutilized in drug discovery, are analyzed in more detail by comparing small molecule and protein-ligand X-ray structures. To investigate effects on physicochemical properties, sets of closely related structures with and without the ability to form intramolecular hydrogen bonds were designed, synthesized, and characterized with respect to membrane permeability, water solubility, and lipophilicity. We find that changes in these properties depend on a subtle balance between the strength of the hydrogen bond interaction, geometry of the newly formed ring system, and the relative energies of the open and closed conformations in polar and unpolar environments. A number of general guidelines for medicinal chemists emerge from this study.
分子内氢键的形成对分子结构和性质有非常显著的影响。我们详细研究了这两个方面，旨在使这类相互作用在药物化学中的应用更加合理。基于对晶体结构数据库的详尽搜索，我们得出了在药物发现中相关的五到八元环体系形成分子内氢键的倾向。通过比较小分子和蛋白质 - 配体 X 射线结构，对一些基序（其中有几个在药物发现中明显未被充分利用）进行了更详细的分析。为了研究对物理化学性质的影响，设计、合成并根据膜通透性、水溶性和脂溶性对具有和不具有形成分子内氢键能力的密切相关的结构进行了表征。我们发现，这些性质的变化取决于氢键相互作用的强度、新形成的环系统的几何形状以及在极性和非极性环境中开环和闭环构象的相对能量之间的微妙平衡。从这项研究中出现了一些一般性的药物化学指导原则。
