Baell Jonathan B, Harvey Andrew J, Norton Raymond S
Biomolecular Research Institute, Parkville, Victoria, Australia.
J Comput Aided Mol Des. 2002 Apr;16(4):245-62. doi: 10.1023/a:1020214720560.
ShK toxin is a structurally defined, 35-residue polypeptide which blocks the voltage-gated Kv1.3 potassium channel in T-lymphocytes and has been identified as a possible immunosuppressant. Our interest lies in the rational design and synthesis of type-III mimetics of protein and polypeptide structure and function. ShK toxin is a challenging target for mimetic design as its binding epitope consists of relatively weakly binding residues, some of which are discontinuous. We discuss here our investigations into the design and synthesis of 1st generation, small molecule mimetics of ShK toxin and highlight any principles relevant to the generic design of type-III mimetics of continuous and discontinuous binding epitopes. We complement our approach with attempted pharmacophore-based database mining.
ShK毒素是一种结构明确的35个氨基酸残基的多肽，它可阻断T淋巴细胞中的电压门控Kv1.3钾通道，并已被确定为一种可能的免疫抑制剂。我们的兴趣在于蛋白质和多肽结构与功能的III型模拟物的合理设计与合成。ShK毒素是模拟设计的一个具有挑战性的目标，因为其结合表位由结合相对较弱的残基组成，其中一些是不连续的。我们在此讨论对第一代ShK毒素小分子模拟物的设计与合成的研究，并强调与连续和不连续结合表位的III型模拟物的通用设计相关的任何原则。我们通过基于药效团的数据库挖掘来补充我们的方法。
