Comparative Assessment of Protein Kinase Inhibitors in Public Databases and in PKIDB
Comparative Assessment of Protein Kinase Inhibitors in Public Databases and in PKIDB
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DOI：
10.3390/molecules25143226
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发表时间：
2020-07-01
期刊：
影响因子：
4.6
通讯作者：
Bonnet, Pascal
中科院分区：
文献类型：
--
作者：
Bournez, Colin;Carles, Fabrice;Bonnet, Pascal
自2001年美国食品和药物管理局（FDA）首次批准蛋白激酶抑制剂（PKI）以来，已有55种新的PKIs进入市场，许多抑制剂目前正在临床试验中进行评估。这清楚地表明蛋白激酶仍然是制药工业的主要药物靶标。在以前的工作中，我们已经介绍了PKIDB，一个公开的数据库，收集已经批准的PKI（第4阶段），以及目前正在进行临床试验的PKI（第0至3阶段）。该数据库经常更新，并在此对新数据进行分析。此外，我们比较了PKIDB中存在的一组PKI与ChEMBL（最大的公开化学数据库）中发现的早期临床前研究中的PKI。对于每个数据集，列出了与药物相似性相关的理化描述符的分布。根据这些结果，提出了更新的指导方针，以优先考虑靶向蛋白激酶的化合物。主成分分析的结果表明，公共基础设施数据库数据集完全包含在公共数据库中的所有公共基础设施中。所有分子的主惯性矩（PMI）分析加强了这一观察。有趣的是，我们注意到临床试验中的PKI倾向于探索新的3D化学空间。虽然绝大多数的PKIs位于“平地”的区域，我们发现很少化合物探索的三维结构空间。最后，基于频率计数对两个数据集进行支架多样性分析。这些结果使人们深入了解PKIs的化学空间，并可以指导研究人员探索新的未探索领域。PKIDB可从以下网站免费访问：http://www.icoa.fr/pkidb。
Since the first approval of a protein kinase inhibitor (PKI) by the Food and Drug Administration (FDA) in 2001, 55 new PKIs have reached the market, and many inhibitors are currently being evaluated in clinical trials. This is a clear indication that protein kinases still represent major drug targets for the pharmaceutical industry. In a previous work, we have introduced PKIDB, a publicly available database, gathering PKIs that have already been approved (Phase 4), as well as those currently in clinical trials (Phases 0 to 3). This database is updated frequently, and an analysis of the new data is presented here. In addition, we compared the set of PKIs present in PKIDB with the PKIs in early preclinical studies found in ChEMBL, the largest publicly available chemical database. For each dataset, the distribution of physicochemical descriptors related to drug-likeness is presented. From these results, updated guidelines to prioritize compounds for targeting protein kinases are proposed. The results of a principal component analysis (PCA) show that the PKIDB dataset is fully encompassed within all PKIs found in the public database. This observation is reinforced by a principal moments of inertia (PMI) analysis of all molecules. Interestingly, we notice that PKIs in clinical trials tend to explore new 3D chemical space. While a great majority of PKIs is located on the area of "flatland", we find few compounds exploring the 3D structural space. Finally, a scaffold diversity analysis of the two datasets, based on frequency counts was performed. The results give insight into the chemical space of PKIs, and can guide researchers to reach out new unexplored areas. PKIDB is freely accessible from the following website:http://www.icoa.fr/pkidb.