Are the physicochemical properties of antibacterial compounds really different from other drugs?
Are the physicochemical properties of antibacterial compounds really different from other drugs?
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DOI：
10.1186/s13321-016-0143-5
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发表时间：
2016
影响因子：
8.6
通讯作者：
Finn PW
中科院分区：
文献类型：
--
作者：
Ebejer JP;Charlton MH;Finn PW
现在人们普遍认识到，迫切需要具有新作用机制的新抗菌药物来对抗多重耐药细菌的增加。然而，很少有新的化合物进入市场。抗菌药物发现项目通常成功地在生物化学测定中鉴定有效分子，但一直受到难以获得抗菌活性的困扰。基于对市售抗菌化合物的分析，普遍持有的观点是抗菌药物具有与其他药物非常不同的物理化学性质，并且这种特性是抗菌活性所必需的。我们通过对ChEMBL数据库中的文献数据进行化学信息学分析，重新研究了这个问题。计算在抗菌试验中具有记录活性的化合物的理化性质，并与从ChEMBL提取的另外两个数据集、市售抗菌药物和市售用于其他治疗适应症的药物进行比较。还研究了化合物的化学类别和革兰氏阴性/革兰氏阳性谱。该分析表明，具有抗菌活性的化合物具有与其他药物类别非常相似的物理化学性质。目前许多抗菌药物的物理化学性质与传统的小分子治疗剂相差甚远，这一观察是正确的。然而，我们的分析不支持化合物必须位于这些“离群”区域之一以具有抗菌活性的推断。.本文的在线版本（doi：10.1186/s13321-016-0143-5）包含补充材料，可供授权用户使用。
It is now widely recognized that there is an urgent need for new antibacterial drugs, with novel mechanisms of action, to combat the rise of multi-drug resistant bacteria. However, few new compounds are reaching the market. Antibacterial drug discovery projects often succeed in identifying potent molecules in biochemical assays but have been beset by difficulties in obtaining antibacterial activity. A commonly held view, based on analysis of marketed antibacterial compounds, is that antibacterial drugs possess very different physicochemical properties to other drugs, and that this profile is required for antibacterial activity. We have re-examined this issue by performing a cheminformatics analysis of the literature data available in the ChEMBL database. The physicochemical properties of compounds with a recorded activity in an antibacterial assay were calculated and compared to two other datasets extracted from ChEMBL, marketed antibacterials and drugs marketed for other therapeutic indications. The chemical class of the compounds and Gram-negative/Gram-positive profile were also investigated. This analysis shows that compounds with antibacterial activity have physicochemical property profiles very similar to other drug classes. The observation that many current antibacterial drugs lie in regions of physicochemical property space far from conventional small molecule therapeutics is correct. However, the inference that a compound must lie in one of these “outlier” regions in order to possess antibacterial activity is not supported by our analysis. . The online version of this article (doi:10.1186/s13321-016-0143-5) contains supplementary material, which is available to authorized users.