Design of O-acetylserine sulfhydrylase inhibitors by mimicking nature.
Design of O-acetylserine sulfhydrylase inhibitors by mimicking nature.
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DOI：
10.1021/jm901325e
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发表时间：
2010-01-14
影响因子：
7.3
通讯作者：
Mozzarelli A
中科院分区：
文献类型：
--
作者：
Salsi E;Bayden AS;Spyrakis F;Amadasi A;Campanini B;Bettati S;Dodatko T;Cozzini P;Kellogg GE;Cook PF;Roderick SL;Mozzarelli A
抑制原核生物和原生动物中的半胱氨酸生物合成与抗生素的开发有关。流感嗜血杆菌O-乙酰丝氨酸硫化氢解酶（OASS）催化L-半胱氨酸的形成，通过将丝氨酸乙酰转移酶的C-末端五肽（MNLNI）插入活性位点而被抑制。产生400个MNXXI五肽，使用GOLD对接到OASS活性位点中并用HINT评分。末端P5 Ile约占结合能的50%。P4位的Glu或Asp以及P3位的Glu或Asp在较小程度上也显著促进结合相互作用。14个选定的五肽的预测亲和力与实验测定的解离常数相关。三个高亲和力的五肽-OASS复合物的X-射线结构与对接的姿势进行了比较。这些结果，结合GRID分析的活性位点，使我们能够定义一个pharmacophoric支架的拟肽抑制剂的设计。
The inhibition of cysteine biosynthesis in prokaryotes and protozoa has been proposed to be relevant for the development of antibiotics. Haemophilus influenzae O-acetylserine sulfhydrylase (OASS), catalyzing L-cysteine formation, is inhibited by the insertion of the C-terminal pentapeptide (MNLNI) of serine acetyltransferase into the active site. 400 MNXXI pentapeptides were generated, docked into OASS active site using GOLD and scored with HINT. The terminal P5 Ile accounts for about 50% of the binding energy. Glu or Asp at position P4, and to a lesser extent, at position P3, also significantly contribute to the binding interaction. The predicted affinity of 14 selected pentapeptides correlated well with the experimentally determined dissociation constants. The X-ray structure of three high affinity pentapeptides-OASS complexes were compared with the docked poses. These results, combined with a GRID analysis of the active site, allowed us to define a pharmacophoric scaffold for the design of peptidomimetic inhibitors.
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影响因子：
7.3
作者：
Cozzini, P;Fornabaio, M;Mozzarelli, A
通讯作者：
Mozzarelli, A
DOI：
10.1126/science.1176667
发表时间：
2009-08-28
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Fischbach MA;Walsh CT
通讯作者：
Walsh CT
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
7.3
作者：
Amadasi, Alessio;Surface, J. Andrew;Kellogg, Glen E.
通讯作者：
Kellogg, Glen E.
影响因子：
7.3
作者：
Fornabaio, M;Spyrakis, F;Kellogg, GE
通讯作者：
Kellogg, GE