Institute of Technical Biochemistry, Faculty of Biotechnology and Food Sciences, Lodz University of Technology , Stefanowskiego Street 4/10, 90-924 Łódź, Poland.
Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology , Żeromskiego Street 116, 90-924 Łódź, Poland.
J Med Chem. 2017 Nov 9;60(21):8781-8800. doi: 10.1021/acs.jmedchem.7b00811. Epub 2017 Oct 17.
Members of the Rab GTPase family are master regulators of vesicle trafficking. When disregulated, they are associated with a number of pathological states. The inhibition of RGGT, an enzyme responsible for post-translational geranylgeranylation of Rab GTPases represents one way to control the activity of these proteins. Because the number of molecules modulating RGGT is limited, we combined molecular modeling with biological assays to ascertain how modifications of phosphonocarboxylates, the first reported RGGT inhibitors, rationally improve understanding of their structure-activity relationship. We have identified the privileged position in the core scaffold of the imidazo[1,2-a]pyridine ring, which can be modified without compromising compounds' potency. Thus modified compounds are micromolar inhibitors of Rab11A prenylation, simultaneously being inactive against Rap1A/Rap1B modification, with the ability to inhibit proliferation of the HeLa cancer cell line. These findings were rationalized by molecular docking, which recognized interaction of phosphonic and carboxylic groups as decisive in phosphonocarboxylate localization in the RGGT binding site.
Rab GTPase 家族成员是囊泡运输的主要调节剂。当它们失调时，与许多病理状态有关。抑制 RGGT，一种负责 Rab GTPases 翻译后 geranylgeranylation 的酶，是控制这些蛋白质活性的一种方法。由于调节 RGGT 的分子数量有限，我们将分子建模与生物测定相结合，以确定膦羧酸酯的修饰（第一个报道的 RGGT 抑制剂）如何合理地提高对其结构-活性关系的理解。我们已经确定了咪唑并[1,2-a]吡啶环核心支架中的特权位置，在不影响化合物效力的情况下可以对其进行修饰。因此，修饰后的化合物是 Rab11A prenylation 的微摩尔抑制剂，同时对 Rap1A/Rap1B 修饰不活跃，具有抑制 HeLa 癌细胞系增殖的能力。这些发现通过分子对接得到了合理化，分子对接识别了膦酸和羧酸基团的相互作用，这对膦羧酸酯在 RGGT 结合位点中的定位是决定性的。
