Nurbo Johanna, Peterson Shane D, Dahl Göran, Helena Danielson U, Karlén Anders, Sandström Anja
Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala University, BMC, Box 574, SE-751 23 Uppsala, Sweden.
Bioorg Med Chem. 2008 May 15;16(10):5590-605. doi: 10.1016/j.bmc.2008.04.005. Epub 2008 Apr 6.
In an effort to develop a new type of HCV NS3 peptidomimetic inhibitor, a series of tripeptide inhibitors incorporating a mix of alpha- and beta-amino acids has been synthesized. To understand the structural implications of beta-amino acid substitution, the P(1), P(2), and P(3) positions of a potent tripeptide scaffold were scanned and combined with carboxylic acid and acyl sulfonamide C-terminal groups. Inhibition was evaluated and revealed that the structural changes resulted in a loss in potency compared with the alpha-peptide analogues. However, several compounds exhibited muM potency. Inhibition data were compared with modeled ligand-protein binding poses to understand how changes in ligand structure affected inhibition potency. The P(3) position seemed to be the least sensitive position for beta-amino acid substitution. Moreover, the importance of a proper oxyanion hole interaction for good potency was suggested by both inhibition data and molecular modeling. To gain further insight into the structural requirements for potent inhibitors, a three-dimensional quantitative structure-activity relationship (3D-QSAR) model has been constructed using comparative molecular field analysis (CoMFA). The most predictive CoMFA model has q(2)=0.48 and r(pred)(2)=0.68.
为了开发一种新型的丙型肝炎病毒（HCV）NS3拟肽抑制剂，已合成了一系列包含α-和β-氨基酸混合物的三肽抑制剂。为了理解β-氨基酸取代的结构影响，对一种有效的三肽支架的P(1)、P(2)和P(3)位置进行了扫描，并与羧酸和酰基磺酰胺C末端基团结合。对抑制作用进行了评估，结果表明与α-肽类似物相比，结构变化导致活性丧失。然而，几种化合物表现出微摩尔级别的活性。将抑制数据与模拟的配体-蛋白质结合构象进行比较，以了解配体结构的变化如何影响抑制活性。P(3)位置似乎是β-氨基酸取代最不敏感的位置。此外，抑制数据和分子建模均表明了适当的氧负离子空穴相互作用对良好活性的重要性。为了进一步深入了解有效抑制剂的结构要求，使用比较分子场分析（CoMFA）构建了三维定量构效关系（3D-QSAR）模型。预测性最强的CoMFA模型的q(2)=0.48，r(pred)(2)=0.68。
