Institute of Pharmaceutical Chemistry, Philipps-University Marburg, Germany.
Proteins. 2009 Aug 1;76(2):317-30. doi: 10.1002/prot.22345.
Structure-based drug design tries to mutually map pharmacological space populated by putative target proteins onto chemical space comprising possible small molecule drug candidates. Both spaces are connected where proteins and ligands recognize each other: in the binding pockets. Therefore, it is highly relevant to study the properties of the space composed by all possible binding cavities. In the present contribution, a global mapping of protein cavity space is presented by extracting consensus cavities from individual members of protein families and clustering them in terms of their shape and exposed physicochemical properties. Discovered similarities indicate common binding epitopes in binding pockets independent of any possibly given similarity in sequence and fold space. Unexpected links between remote targets indicate possible cross-reactivity of ligands and suggest putative side effects. The global clustering of cavity space is compared to a similar clustering of sequence and fold space and compared to chemical ligand space spanned by the chemical properties of small molecules found in binding pockets of crystalline complexes. The overall similarity architecture of sequence, fold, and cavity space differs significantly. Similarities in cavity space can be mapped best to similarities in ligand binding space indicating possible cross-reactivities. Most cross-reactivities affect co-factor and other endogenous ligand binding sites.
基于结构的药物设计试图将假定靶蛋白的药理学空间相互映射到包含可能的小分子药物候选物的化学空间上。这两个空间在蛋白质和配体相互识别的结合口袋中相互连接。因此，研究由所有可能的结合腔组成的空间的特性是非常相关的。在本研究中，通过从蛋白质家族的各个成员中提取共识腔，并根据其形状和暴露的物理化学性质对它们进行聚类，来呈现蛋白质腔空间的全局映射。发现的相似性表明，结合口袋中的结合表位是共同的，与序列和折叠空间中可能存在的任何相似性无关。远程靶标之间的意外联系表明配体可能具有交叉反应性，并提示可能的副作用。腔空间的全局聚类与序列和折叠空间的类似聚类进行了比较，并与晶体复合物结合口袋中小分子的化学性质所跨越的化学配体空间进行了比较。序列、折叠和腔空间的整体相似性结构有很大的不同。腔空间的相似性可以最好地映射到配体结合空间的相似性上，表明可能存在交叉反应性。大多数交叉反应性会影响辅因子和其他内源性配体结合位点。
