Shoichet Brian K
Department of Pharmaceutical Chemistry, University of California-San Francisco, 1700 4th St., Byers Hall Room 508D, San Francisco, CA 94158, USA.
Drug Discov Today. 2006 Jul;11(13-14):607-15. doi: 10.1016/j.drudis.2006.05.014.
High-throughput screening (HTS) campaigns can be dominated by hits that ultimately turn out to be non-drug-like. These "nuisance" compounds often behave strangely, with steep dose-response curves, absence of clear structure-activity relationships, and high sensitivity to assay conditions. Several mechanisms contribute to these artifacts, including chemically reactive molecules, those that absorb light in assays and those that affect redox conditions. One of the most common mechanisms behind artifactual inhibition is discussed in this review: at micromolar concentrations organic molecules can aggregate to form particles in aqueous buffers, and these aggregates can sequester and thereby inhibit protein targets. Aggregation-based inhibition is baffling from a chemical perspective, but viewed biophysically such behavior is expected. The range of molecules that behave this way, their rapid detection in a screening environment and their possible biological implications will be considered here.
高通量筛选（HTS）活动可能会被最终证明是非药物样的活性物质所主导。这些“麻烦”化合物的行为往往很奇怪，具有陡峭的剂量反应曲线，缺乏明确的构效关系，并且对检测条件高度敏感。有几种机制会导致这些假象，包括化学反应性分子、在检测中吸收光的分子以及影响氧化还原条件的分子。本综述讨论了人为抑制背后最常见的机制之一：在微摩尔浓度下，有机分子可以在水性缓冲液中聚集形成颗粒，这些聚集体可以隔离并因此抑制蛋白质靶点。从化学角度来看，基于聚集的抑制令人困惑，但从生物物理角度来看，这种行为是可以预期的。这里将考虑以这种方式表现的分子范围、它们在筛选环境中的快速检测以及它们可能的生物学意义。
