A Selectivity Study of FFAR4/FFAR1 Agonists by Molecular Modeling.
A Selectivity Study of FFAR4/FFAR1 Agonists by Molecular Modeling.
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通过分子模型研究 FFAR4/FFAR1 激动剂的选择性。
DOI：
10.1021/acs.jcim.9b00735
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发表时间：
2019
影响因子：
5.6
通讯作者：
Yuan Haoliang
中科院分区：
文献类型：
--
作者：
Zhang Xiangying;Sun Hongbin;Wen Xiaoan;Yuan Haoliang
FFAR 4已被认为是代谢疾病（包括糖尿病）的潜在靶标。以本课题组报道的化合物SR 13为代表的具有联苯骨架的化合物表现出明显的FFAR 4选择性。然而，其选择性的分子基础尚未明确公开。本研究通过分子模拟的方法，对FFAR 4/FFAR 1与受体激动剂之间的蛋白质-配体相互作用进行了研究。确定的重要残留物与实验研究中发现的残留物一致。此外，研究结果还表明，SR 13在FFAR 4和FFAR 1之间的选择性取决于它能否通过其优先构象从入口区进入配体结合位点。SR 13的优先构象和狭窄的入口区域之间的巨大差异决定了其对FFAR 1的弱激动剂活性。这些发现将促进选择性FFAR 4激动剂的进一步开发。
FFAR4 has been considered as a potential target for metabolic diseases, including diabetes. Some compounds with biphenyl scaffold, represented by compoundSR13reported by our group, showed significant FFAR4 selectivity. However, the molecular basis for their selectivity has not been definitely disclosed. This study provided insights into the protein–ligand interactions between agonists and FFAR4/FFAR1 by molecular modeling. The important residues identified were consistent with those found in experimental studies. Moreover, the results proposed that the selectivity ofSR13between FFAR4 and FFAR1 depended on whether it can enter the ligand-binding site through the entrance region by adopting its preferential conformation. The big difference between the preferential conformation ofSR13and the narrow entrance region determined its poor agonist activity against FFAR1. These findings will facilitate the further development of selective FFAR4 agonists.