Department of Biochemistry and Molecular Biology, University of Parma, Italy.
J Med Chem. 2010 Jan 14;53(1):345-56. doi: 10.1021/jm901325e.
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. Four-hundred MNXXI pentapeptides were generated in silico, 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 pentapeptide-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.
已提出抑制原核生物和原生动物的半胱氨酸生物合成与抗生素的发展有关。流感嗜血杆菌 O-乙酰丝氨酸硫醇酶（OASS）催化 l-半胱氨酸的形成，其活性位点被丝氨酸乙酰转移酶的 C 末端五肽（MNLNI）插入所抑制。通过计算机生成了 400 个 MNXXI 五肽，使用 GOLD 将其对接至 OASS 的活性位点，并使用 HINT 进行评分。末端 P5 异亮氨酸约占结合能的 50%。位置 P4 的 Glu 或 Asp 以及在较小程度上位置 P3 也对结合相互作用有重要贡献。预测的 14 种选择五肽的亲和力与实验测定的解离常数很好地相关。与对接构象相比，比较了三个高亲和力五肽-OASS 复合物的 X 射线结构。这些结果与活性位点的 GRID 分析相结合，使我们能够为设计肽模拟抑制剂定义药效团支架。
