H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
Curr Top Med Chem. 2011;11(7):760-70. doi: 10.2174/156802611795165098.
Proteins are often enantioselective towards their binding partners. When designing small molecules to interact with these targets, one should consider stereoselectivity. As considerations for exploring structure space evolve, chirality is increasingly important. Binding affinity for a chiral drug can differ for diastereomers and between enantiomers. For the virtual screening and computational design stage of drug development, this problem can be compounded by incomplete stereochemical information in structure libraries leading to a "coin toss" as to whether or not the "ideal" chiral structure is present. Creating every stereoisomer for each chiral compound in a structure library leads to an exponential increase in the number of structures resulting in potentially unmanageable file sizes and screening times. Therefore, only key chiral structures, enantiomeric pairs based on relative stereochemistry need be included, and lead to a compromise between exploration of chemical space and maintaining manageable libraries. In clinical environments, enantiomers of chiral drugs can have reduced, no, or even deleterious effects. This underscores the need to avoid mixtures of compounds and focus on chiral synthesis. Governmental regulations emphasizing the need to monitor chirality in drug development have increased. The United States Food and Drug Administration issued guidelines and policies in 1992 concerning the development of chiral compounds. These guidelines require that absolute stereochemistry be known for compounds with chiral centers and that this information should be established early in drug development in order that the analysis can be considered valid. From exploration of structure space to governmental regulations it is clear that the question of chirality in drug design is of vital importance.
蛋白质通常对其结合伙伴具有对映体选择性。在设计与这些靶标相互作用的小分子时，应考虑立体选择性。随着探索结构空间的考虑因素的发展，手性变得越来越重要。手性药物与非对映异构体和对映异构体的结合亲和力可能不同。对于药物开发的虚拟筛选和计算设计阶段，由于结构库中立体化学信息不完整，可能会导致“掷硬币”，从而无法确定“理想”手性结构是否存在，这会使这个问题更加复杂。在结构库中为每个手性化合物创建每个立体异构体都会导致结构数量呈指数级增加，从而导致潜在的不可管理的文件大小和筛选时间。因此，只需包含基于相对立体化学的关键手性结构和对映体对，就需要在探索化学空间和保持可管理的库之间进行折衷。在临床环境中，手性药物的对映异构体可能具有降低、没有甚至有害的作用。这强调了避免化合物混合物和专注于手性合成的必要性。强调在药物开发中监测手性的政府法规有所增加。美国食品和药物管理局在 1992 年发布了有关手性化合物开发的指南和政策。这些指南要求具有手性中心的化合物的绝对立体化学结构必须已知，并且应该在药物开发的早期阶段确定该信息，以便可以认为该分析是有效的。从结构空间的探索到政府法规，很明显，药物设计中的手性问题至关重要。
