Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey 08854, United States.
Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey 08854, United States.
J Med Chem. 2023 May 11;66(9):6013-6024. doi: 10.1021/acs.jmedchem.2c01681. Epub 2023 Apr 28.
X-ray crystallographic fragment screening (XCFS) uses fragment-sized molecules (∼60 to 300 Da) to access binding sites on proteins that may be inaccessible to larger drug-like molecules (>300 Da). Previous studies have shown that fragments containing halogen atoms bind more often to proteins than non-halogenated fragments. Here, we designed the Halo Library containing 46 halogenated fragments (including the "universal fragment" 4-bromopyrazole), a majority of which have been reported to bind to or inhibit one or more targets. The library was screened against the crystals of HIV-1 reverse transcriptase with the drug rilpivirine, yielding an overall hit rate of 26%. Two new binding sites were discovered, and several hot spots were identified. This small library may thus provide a convenient tool for rapidly assessing the feasibility of a target for XCFS, mapping hot spots and cryptic sites, as well as finding fragment binders that can be useful for developing drug leads.
X 射线晶体学片段筛选 (XCFS) 使用片段大小的分子（约 60 至 300 道尔顿）来访问蛋白质上可能无法被较大的类药物分子（>300 道尔顿）访问的结合位点。先前的研究表明，含有卤素原子的片段比非卤化片段更频繁地与蛋白质结合。在这里，我们设计了包含 46 个卤化片段（包括“通用片段”4-溴吡唑）的 Halo 文库，其中大部分已被报道与一个或多个靶标结合或抑制。该文库与 HIV-1 逆转录酶的晶体一起进行了 rilpivirine 的筛选，总体命中率为 26%。发现了两个新的结合位点，并确定了几个热点。因此，这个小文库可以为快速评估 XCFS 的靶标可行性、绘制热点和隐匿位点以及寻找可用于开发药物先导物的片段结合物提供便利工具。
