Combinatorial computational method gives new picomolar ligands for a known enzyme

被引:64
作者
Grzybowski, BA
Ishchenko, AV
Kim, CY
Topalov, G
Chapman, R
Christianson, DW
Whitesides, GM
Shakhnovich, EI
机构
[1] Harvard Univ, Dept Chem & Biol Chem, Cambridge, MA 02138 USA
[2] Univ Penn, Dept Chem, Philadelphia, PA 19104 USA
关键词
D O I
10.1073/pnas.032673399
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Combinatorial small molecule growth algorithm was used to design inhibitors for human carbonic anhydrase II. Two enantiomeric candidate molecules were predicted to bind with high potency (with R isomer binding stronger than S), but in two distinct conformations. The experiments verified that computational predictions concerning the binding affinities and the binding modes were correct for both isomers. The designed R isomer is the best-known inhibitor (K-d similar to 30 pM) of human carbonic anhydrase II.
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收藏
页码:1270 / 1273
页数:4
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