UFSRAT: Ultra-Fast Shape Recognition with Atom Types –The Discovery of Novel Bioactive Small Molecular Scaffolds for FKBP12 and 11βHSD1
UFSRAT: Ultra-Fast Shape Recognition with Atom Types –The Discovery of Novel Bioactive Small Molecular Scaffolds for FKBP12 and 11βHSD1
复制标题
UFSRAT：超快速原子类型形状识别 - FKBP12 和 11βHSD1 新型生物活性小分子支架的发现
作者：
S. Shave;E. Blackburn;Jillian Adie;D. Houston;M. Auer;S. Webster;P. Taylor;M. Walkinshaw
利用分子相似性来发现具有新型化学支架的生物活性小分子可能需要计算。我们描述了超快速形状识别与原子类型（UFSRAT），一个有效的算法，考虑了3D分布（形状）和静电的原子评分和检索分子能够使类似的相互作用的那些提供的查询。分子描述符的计算优化和预先计算使查询分子能够在包含380万个分子的数据库中运行，并在中等硬件上在10秒内返回结果。UFSRAT已在管道中用于鉴定两种临床相关药物靶点的生物活性分子; FK 506-结合蛋白12和11β-羟基类固醇脱氢酶1型。在FK 506-结合蛋白12的情况下，UFSRAT被用作基于结构的虚拟筛选管道的第一步，产生许多活性物质，其中最具活性的显示KD，app为281 µM，并且包含查询化合物中存在的子结构。单独运行UFSRAT技术也取得了成功，以鉴定11β-羟基类固醇脱氢酶1型的新活性物质，其中最具活性的活性物质在基于细胞的测定中显示出67 nM的IC 50，并且含有与查询完全不同的亚结构。这证明了UFSRAT算法执行支架跳的有价值的能力。可用性和实现该算法的基于Web的实现可在http://opus.bch.ed.ac.uk/ufsrat/上免费获得。
Motivation Using molecular similarity to discover bioactive small molecules with novel chemical scaffolds can be computationally demanding. We describe Ultra-fast Shape Recognition with Atom Types (UFSRAT), an efficient algorithm that considers both the 3D distribution (shape) and electrostatics of atoms to score and retrieve molecules capable of making similar interactions to those of the supplied query. Results Computational optimization and pre-calculation of molecular descriptors enables a query molecule to be run against a database containing 3.8 million molecules and results returned in under 10 seconds on modest hardware. UFSRAT has been used in pipelines to identify bioactive molecules for two clinically relevant drug targets; FK506-Binding Protein 12 and 11β-hydroxysteroid dehydrogenase type 1. In the case of FK506-Binding Protein 12, UFSRAT was used as the first step in a structure-based virtual screening pipeline, yielding many actives, of which the most active shows a KD, app of 281 µM and contains a substructure present in the query compound. Success was also achieved running solely the UFSRAT technique to identify new actives for 11β-hydroxysteroid dehydrogenase type 1, for which the most active displays an IC50 of 67 nM in a cell based assay and contains a substructure radically different to the query. This demonstrates the valuable ability of the UFSRAT algorithm to perform scaffold hops. Availability and Implementation A web-based implementation of the algorithm is freely available at http://opus.bch.ed.ac.uk/ufsrat/.
DOI：
10.1073/pnas.87.23.9231
发表时间：
1990-12-01
影响因子：
11.1
作者：
BIERER, BE;MATTILA, PS;SCHREIBER, SL
通讯作者：
SCHREIBER, SL