Drug Promiscuity in PDB: Protein Binding Site Similarity Is Key
Drug Promiscuity in PDB: Protein Binding Site Similarity Is Key
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DOI：
10.1371/journal.pone.0059937
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发表时间：
2013-06-21
期刊：
影响因子：
3.7
通讯作者：
Schroeder, Michael
中科院分区：
文献类型：
--
作者：
Haupt, V. Joachim;Daminelli, Simone;Schroeder, Michael
药物重新定位将已有的药物应用于新的疾病适应症，越来越成功。药物再利用的先决条件是药物混杂(多元药理学)--一种药物与多个靶点结合的能力。关于毒品滥交的原因，存在着长期的争论。基于大型复合筛网，疏水性和分子量被认为是关键原因。然而，结果有时是相互矛盾的，并为进一步分析留下了空间。蛋白质结构提供了一个结构维度来解释混杂：一种药物可以结合多个靶点，因为药物是灵活的，或者因为这些靶点在结构上相似，甚至因为这些靶点具有相似的结合部位？我们基于一组164种药物的PDB靶蛋白的结构数据，对药物混杂进行了系统的研究。我们发现，混杂程度与配体的疏水性或分子质量等性质之间没有相关性，但与构象灵活性之间的相关性很弱。然而，我们确实发现了杂交性与蛋白质靶标的结构相似性和结合部位相似性之间的相关性。特别是，71%的药物至少有两个结合位点相似的靶点。为了克服在检测远程相似结合位点方面的问题，我们采用了结合位点相似性评分：LigandRMSD衡量排列的配体的相似性，并揭示蛋白质中远程局部相似性。它可以应用于任意结构结合位点的比对。详细讨论了抗癌药物甲氨蝶呤、天然产物栎素和抗糖尿病药物阿卡波糖三个有代表性的例子。我们的发现表明，全球结构和结合部位的相似性在解释PDB中观察到的药物混杂现象方面发挥了比疏水性或分子量等物理化学药物属性更重要的作用。此外，我们发现配基的灵活性有很小的影响。
Drug repositioning applies established drugs to new disease indications with increasing success. A pre-requisite for drug repurposing is drug promiscuity (polypharmacology) - a drug's ability to bind to several targets. There is a long standing debate on the reasons for drug promiscuity. Based on large compound screens, hydrophobicity and molecular weight have been suggested as key reasons. However, the results are sometimes contradictory and leave space for further analysis. Protein structures offer a structural dimension to explain promiscuity: Can a drug bind multiple targets because the drug is flexible or because the targets are structurally similar or even share similar binding sites? We present a systematic study of drug promiscuity based on structural data of PDB target proteins with a set of 164 promiscuous drugs. We show that there is no correlation between the degree of promiscuity and ligand properties such as hydrophobicity or molecular weight but a weak correlation to conformational flexibility. However, we do find a correlation between promiscuity and structural similarity as well as binding site similarity of protein targets. In particular, 71% of the drugs have at least two targets with similar binding sites. In order to overcome issues in detection of remotely similar binding sites, we employed a score for binding site similarity: LigandRMSD measures the similarity of the aligned ligands and uncovers remote local similarities in proteins. It can be applied to arbitrary structural binding site alignments. Three representative examples, namely the anticancer drug methotrexate, the natural product quercetin and the anti-diabetic drug acarbose are discussed in detail. Our findings suggest that global structural and binding site similarity play a more important role to explain the observed drug promiscuity in the PDB than physicochemical drug properties like hydrophobicity or molecular weight. Additionally, we find ligand flexibility to have a minor influence.