Definition of fatty acid transport protein-2 (FATP2) structure facilitates identification of small molecule inhibitors for the treatment of diabetic complications.
Definition of fatty acid transport protein-2 (FATP2) structure facilitates identification of small molecule inhibitors for the treatment of diabetic complications.
复制标题
脂肪酸转运蛋白 2 (FATP2) 结构的定义有助于识别用于治疗糖尿病并发症的小分子抑制剂。
DOI：
10.1016/j.ijbiomac.2023.125328
复制
发表时间：
2023
影响因子：
8.2
通讯作者：
Schelling,JeffreyR
中科院分区：
文献类型：
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作者：
Kumar,Mukesh;Gaivin,RobertJ;Khan,Shenaz;Fedorov,Yuriy;Adams,DrewJ;Zhao,Weiyang;Lee,Hsueh-Yun;Dai,Xinghong;Dealwis,ChrisG;Schelling,JeffreyR
由于与终末器官并发症相关的发病率和死亡率，糖尿病是一个主要的公共卫生问题。脂肪酸转运蛋白-2（FATP 2）对脂肪酸的摄取有助于高血糖症、糖尿病肾病和肝病的发病机制。由于FATP 2结构未知，因此构建了同源模型，通过AlphaFold 2预测和定点突变进行验证，然后用于进行虚拟药物发现筛选。对两种低微摩尔IC 50 FATP 2抑制剂进行计算机相似性搜索，然后进行对接和药代动力学预测，将80万种不同化合物库缩小到23种。进一步评价这些候选物对细胞中FATP 2依赖性脂肪酸摄取和细胞凋亡的抑制。两种化合物表现出纳摩尔IC 50，并通过分子动力学模拟进一步表征。结果突出了将同源模型与计算机模拟和体外筛选相结合的可行性，以经济地鉴定FATP 2的高亲和力抑制剂，作为糖尿病及其并发症的潜在治疗。
Diabetes is a major public health problem due to morbidity and mortality associated with end organ complications. Uptake of fatty acids by Fatty Acid Transport Protein-2 (FATP2) contributes to hyperglycemia, diabetic kidney and liver disease pathogenesis. Because FATP2 structure is unknown, a homology model was constructed, validated by AlphaFold2 prediction and site-directed mutagenesis, and then used to conduct a virtual drug discovery screen. In silico similarity searches to two low-micromolar IC50FATP2 inhibitors, followed by docking and pharmacokinetics predictions, narrowed a diverse 800,000 compound library to 23 hits. These candidates were further evaluated for inhibition of FATP2-dependent fatty acid uptake and apoptosis in cells. Two compounds demonstrated nanomolar IC50, and were further characterized by molecular dynamic simulations. The results highlight the feasibility of combining a homology model with in silico and in vitro screening, to economically identify high affinity inhibitors of FATP2, as potential treatment for diabetes and its complications.