Zhao Hongtao, Caflisch Amedeo
Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
Bioorg Med Chem Lett. 2015 Jun 1;25(11):2372-6. doi: 10.1016/j.bmcl.2015.04.005. Epub 2015 Apr 10.
We analyze the chemical space coverage of kinase inhibitors in the public domain from a fragment point of view. A set of 26,668 kinase inhibitors from the ChEMBL database of bioactive molecules were decomposed automatically by fragmentation at rotatable bonds. Remarkably, about half of the resulting 10,302 fragments originate from inaccessible libraries, as they are not present in commercially available compounds. By mapping to the established kinase pharmacophore models, privileged fragments in sub-pockets are identified, for example, the 5681 ring-containing fragments capable of forming bi-dentate hydrogen bonds with the hinge region in the ATP binding site. Surprisingly, hinge-binding fragments in current kinase inhibitors cover only 1% of the potential hinge-binders obtained by decomposing a library of nearly 7.5 million commercially available compounds, which indicates that a large fraction of chemical space is unexplored.
我们从片段的角度分析了公共领域中激酶抑制剂的化学空间覆盖情况。来自生物活性分子ChEMBL数据库的一组26668种激酶抑制剂通过在可旋转键处进行碎片化自动分解。值得注意的是，所得的10302个片段中约有一半源自无法获取的文库，因为它们不存在于市售化合物中。通过映射到已建立的激酶药效团模型，可识别亚口袋中的优势片段，例如，能够与ATP结合位点的铰链区形成双齿氢键的含5681环片段。令人惊讶的是，当前激酶抑制剂中的铰链结合片段仅覆盖通过分解近750万种市售化合物文库获得的潜在铰链结合剂的1%，这表明很大一部分化学空间尚未被探索。
