Department of Chemistry, Punjabi University, Patiala, India.
SAR QSAR Environ Res. 2013;24(9):733-52. doi: 10.1080/1062936X.2013.797493. Epub 2013 Jun 14.
Glutamine: fructose-6-phosphate amidotransferase (GFAT), also termed GFPT1 and GFAT1, catalyzes the first committed step of the hexosamine biosynthesis pathway in mammals and consequently plays an important role in type 2 diabetes. In the present study, a combination of pharmacophore modelling, homology modelling, and molecular docking analysis was performed to design new glutamine competitive inhibitors of human GFAT, and to investigate important interaction details of inhibitor molecules. A pharmacophore model of GFAT inhibitors was developed, subsequently validated, and utilized for the screening by the PHASE database to identify new molecules. Afterwards, homology modelling was performed to construct the glutamine-binding site of the GFAT protein. The modelled active site was utilized to dock the studied molecules to investigate important receptor-ligand interactions and to scrutinize database-screened molecules on the basis of essential interactions. This systematic in silico protocol helped us to identify new molecules that would be explored for the treatment of type 2 diabetes and its complications.
果糖-6-磷酸氨基转移酶（GFAT），也称为 GFPT1 和 GFAT1，在哺乳动物中催化己糖胺生物合成途径的第一步，因此在 2 型糖尿病中发挥重要作用。在本研究中，结合药效团建模、同源建模和分子对接分析，设计了新型人 GFAT 谷氨酰胺竞争抑制剂，并研究了抑制剂分子的重要相互作用细节。开发了 GFAT 抑制剂的药效团模型，随后进行了验证，并利用 PHASE 数据库进行筛选，以鉴定新的分子。然后，进行同源建模以构建 GFAT 蛋白的谷氨酰胺结合位点。利用模拟的活性位点将研究的分子对接，以研究重要的受体-配体相互作用，并根据必需相互作用对数据库筛选的分子进行仔细检查。这种系统的计算方法有助于我们识别新的分子，这些分子将被探索用于治疗 2 型糖尿病及其并发症。
