Di Li, Kerns Edward H
Wyeth Research, P.O. Box CN 8000, Princeton, NJ 08543-8000, USA.
Drug Discov Today. 2006 May;11(9-10):446-51. doi: 10.1016/j.drudis.2006.03.004.
Compound solubility in buffers and dimethyl sulfoxide (DMSO) has emerged as an important issue. Many discovery compounds have low solubility but are potentially valuable as leads. Unfortunately, low solubility affects bioassays by causing underestimated activity, reduced HTS-hit rates, variable data, inaccurate SAR, discrepancies between enzyme and cell assays and inaccurate in vitro ADME-Tox testing. Strategies for optimizing bioassays include: considering solubility in HTS-library design; early screening for solubility; improving storage and handling of DMSO stocks; optimizing dilution protocols; and ensuring that low-solubility compounds are fully solubilized in bioassays. These approaches allow for adequate assessments of valuable pharmacophores for which solubility can be chemically optimized at a later date.
化合物在缓冲液和二甲基亚砜（DMSO）中的溶解度已成为一个重要问题。许多用于药物研发的化合物溶解度较低，但作为先导化合物却具有潜在价值。不幸的是，低溶解度会影响生物测定，导致活性被低估、高通量筛选（HTS）命中率降低、数据不稳定、构效关系（SAR）不准确、酶法和细胞法测定结果存在差异以及体外药物代谢及毒性（ADME-Tox）测试不准确。优化生物测定的策略包括：在HTS文库设计中考虑溶解度；早期进行溶解度筛选；改进DMSO储备液的储存和处理；优化稀释方案；以及确保低溶解度化合物在生物测定中完全溶解。这些方法能够对有价值的药效基团进行充分评估，后续可对其溶解度进行化学优化。
