Active Biotech Research AB, Box 724, 220 07 Lund, Sweden.
ChemMedChem. 2010 Apr 6;5(4):608-17. doi: 10.1002/cmdc.200900454.
A strategy that combines virtual screening and structure-guided selection of fragments was used to identify three unexplored classes of human DHODH inhibitor compounds: 4-hydroxycoumarins, fenamic acids, and N-(alkylcarbonyl)anthranilic acids. Structure-guided selection of fragments targeting the inner subsite of the DHODH ubiquinone binding site made these findings possible with screening of fewer than 300 fragments in a DHODH assay. Fragments from the three inhibitor classes identified were subsequently chemically expanded to target an additional subsite of hydrophobic character. All three classes were found to exhibit distinct structure-activity relationships upon expansion. The novel N-(alkylcarbonyl)anthranilic acid class shows the most promising potency against human DHODH, with IC(50) values in the low nanomolar range. The structure of human DHODH in complex with an inhibitor of this class is presented.
采用虚拟筛选和基于结构的片段选择相结合的策略，鉴定了三种新颖的人二氢乳清酸脱氢酶（DHODH）抑制剂化合物类别：4-羟基香豆素、芬那酸和 N-（烷羰基）邻氨基苯甲酸。通过针对 DHODH 的泛醌结合位点内部亚位点的基于结构的片段选择，仅对少于 300 个片段进行筛选，从而实现了这一发现。鉴定出的三种抑制剂类别的片段随后被化学扩展，以针对疏水性更强的附加亚位点。在扩展后，所有三种类型的化合物均表现出明显的构效关系。新型 N-（烷羰基）邻氨基苯甲酸类化合物对人 DHODH 表现出最有前途的抑制活性，IC50 值处于纳摩尔低浓度范围。本文呈现了该类抑制剂与人 DHODH 复合物的结构。
