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Insight into binding mode of inhibitor 8CA to A-FABP based on molecular dynamics simulation

- , 2016,
Abstract: 脂肪细胞脂肪酸结合蛋白A-FABP(Adipocyte fatty-acid binding protein)是治疗脂质调节生物过程相关疾病的重要靶标. 分子动力学模拟和MM-PBSA方法被采用研究抑制剂8CA与A-FABP结合模式. 研究结果表明静电相互作用和范德华作用驱动了抑制剂8CA与A-FABP的结合。基于残基的能量分解表明抑制剂8CA与R126间的极性相互作用为抑制剂与A-FABP的结合提供了重要贡献. 该残基与8CA的相互作用较好地稳定了抑制剂与A-FABP复合物的稳定性. 我们期望这个研究能为治疗炎症、动脉硬化和代谢病药物设计提供一定的理论指导。
Adipocyte fatty-acid binding protein (A-FABP) is an important target of drug designs treating some diseases related to lipid-mediated biology. Molecular dynamics (MD) simulations coupled with molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) calculation were carried out to study the binding mode of 8CA to A-FABP. The results show that electrostatics and van der Waals interactions drive the binding of 8CA to A-FABP. The calculation from residue-based free energy decomposition suggests that the polar interaction of 8CA with the residue R126 provides an important contribution to the 8CA binding. This polar interaction plays a key role in the stabilization of 8CA/A-FABP complex. We expect that this study can contribute some theoretical guidance for design of potent inhibitors within the fields of metabolic disease, inflammation and atherosclerosis.
清远麻鸡h-fabp和a-fabp基因mrna的差异表达研究  [PDF]
西北农林科技大学学报(自然科学版) , 2010,
Abstract: 【目的】分析心脏脂肪酸结合蛋白(h-fabp)和脂肪细胞型脂肪酸结合蛋白(a-fabp)基因mrna在不同日龄清远麻鸡不同组织中的差异表达量,为进一步阐明h-fabp、a-fabp在鸡imf含量和腹脂沉积中的作用机制奠定基础。【方法】依据鸡h-fabp和a-fabp基因及参照基因gapdh序列设计引物,以鸡心肌、胸肌、腿肌、肝脏和腹脂mrna逆转录合成的cdna为模版,应用sybrgreenⅰ实时荧光定量pcr,检测56和120日龄清远麻鸡a-fabp、h-fabp基因mrna的差异表达量。【结果】h-fabp、a-fabp和gapdh的基因融解曲线均为单峰,无杂峰及二聚体,定量准确。120d时清远麻鸡的胸肌和腿肌的肌内脂肪(imf)含量显著高于56d;h-fabp基因mrna120d时在心肌、胸肌和腿肌的差异表达量显著高于56d,且同一日龄时在心肌的差异表达量显著高于胸肌和腿肌(p<0.05)。120d时清远麻鸡a-fabp基因mrna在腹脂和肝脏的差异表达量显著高于56d;同一日龄时,a-fabp基因mrna在腹脂的差异表达量显著高于肝脏,a-fabp基因在心肌、胸肌和腿肌中不表达。相关分析表明,h-fabp基因mrna差异表达量与胸肌、腿肌imf含量分别呈显著和极显著正相关,a-fabp基因mrna差异表达量与腹脂率呈极显著负相关。【结论】h-fabp基因主要在鸡肌肉组织的肌内脂肪中表达,而且在心肌中高度表达,与imf含量呈显著或极显著的正相关,其是imf含量的下调基因;a-fabp基因主要在腹脂与肝脏中表达,且在腹脂中高度表达,与腹脂率呈极显著负相关,是脂肪细胞的上调基因,且为正调控。
Targeting Fatty Acid Binding Protein (FABP) Anandamide Transporters – A Novel Strategy for Development of Anti-Inflammatory and Anti-Nociceptive Drugs  [PDF]
William T. Berger, Brian P. Ralph, Martin Kaczocha, Jing Sun, Trent E. Balius, Robert C. Rizzo, Samir Haj-Dahmane, Iwao Ojima, Dale G. Deutsch
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0050968
Abstract: Fatty acid binding proteins (FABPs), in particular FABP5 and FABP7, have recently been identified by us as intracellular transporters for the endocannabinoid anandamide (AEA). Furthermore, animal studies by others have shown that elevated levels of endocannabinoids resulted in beneficial pharmacological effects on stress, pain and inflammation and also ameliorate the effects of drug withdrawal. Based on these observations, we hypothesized that FABP5 and FABP7 would provide excellent pharmacological targets. Thus, we performed a virtual screening of over one million compounds using DOCK and employed a novel footprint similarity scoring function to identify lead compounds with binding profiles similar to oleic acid, a natural FABP substrate. Forty-eight compounds were purchased based on their footprint similarity scores (FPS) and assayed for biological activity against purified human FABP5 employing a fluorescent displacement-binding assay. Four compounds were found to exhibit approximately 50% inhibition or greater at 10 μM, as good as or better inhibitors of FABP5 than BMS309403, a commercially available inhibitor. The most potent inhibitor, γ-truxillic acid 1-naphthyl ester (ChemDiv 8009-2334), was determined to have Ki value of 1.19±0.01 μM. Accordingly a novel α-truxillic acid 1-naphthyl mono-ester (SB-FI-26) was synthesized and assayed for its inhibitory activity against FABP5, wherein SB-FI-26 exhibited strong binding (Ki 0.93±0.08 μM). Additionally, we found SB-FI-26 to act as a potent anti-nociceptive agent with mild anti-inflammatory activity in mice, which strongly supports our hypothesis that the inhibition of FABPs and subsequent elevation of anandamide is a promising new approach to drug discovery. Truxillic acids and their derivatives were also shown by others to have anti-inflammatory and anti-nociceptive effects in mice and to be the active component of Chinese a herbal medicine (Incarvillea sinensis) used to treat rheumatism and pain in humans. Our results provide a likely mechanism by which these compounds exert their effects.
Fatty Acid Binding Proteins FABP9 and FABP10 Participate in Antibacterial Responses in Chinese Mitten Crab, Eriocheir sinensis  [PDF]
Lin Cheng, Xing-Kun Jin, Wei-Wei Li, Shuang Li, Xiao-Nv Guo, Juan Wang, Ya-Nan Gong, Lin He, Qun Wang
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0054053
Abstract: Invertebrates rely solely on the innate immune system for defense against pathogens and other stimuli. Fatty acid binding proteins (FABP), members of the lipid binding proteins superfamily, play a crucial role in fatty acid transport and lipid metabolism and are also involved in gene expression induced by fatty acids. In the vertebrate immune system, FABP is involved in inflammation regulated by fatty acids through its interaction with peroxidase proliferator activate receptors (PPARs). However, the immune functions of FABP in invertebrates are not well characterized. For this reason, we investigated the immune functionality of two fatty acid binding proteins, Es-FABP9 and Es-FABP10, following lipopolysaccharide (LPS) challenge in the Chinese mitten crab (Eriocheir sinensis). An obvious variation in the expression of Es-FABP9 and Es-FABP10 mRNA in E. sinensis was observed in hepatopancreas, gills, and hemocytes post-LPS challenge. Recombinant proteins rEs-FABP9 and rEs-FABP10 exhibited distinct bacterial binding activity and bacterial agglutination activity against Escherichia coli and Staphylococcus aureus. Furthermore, bacterial growth inhibition assays demonstrated that rEs-FABP9 responds positively to the growth inhibition of Vibrio parahaemolyticuss and S. aureus, while rEs-FABP10 responds positively to the growth inhibition of Aeromonas hydrophila and Bacillus subtilis. Coating of agarose beads with recombinant rEs-FABP9 and rEs-FABP10 dramatically enhanced encapsulation of the beads by crab hemocytes in vitro. In conclusion, the data presented here demonstrate the participation of these two lipid metabolism-related proteins in the innate immune system of E. sinensis.
Developmental Changes of the H-FABP mRNA Expression in Hainan Black Goat
S. Guan,H.L. Zhou,G.Y. Hou,D.J. Wang,T.S. Xu,D.F. Wang,L.G. Shi,G. Rong,M. Li
Agricultural Journal , 2013, DOI: 10.3923/aj.2012.370.373
Abstract: This study investigated the H-FABP mRNA expression levels in Hainan Black goats. Males from 1-4 months of age beyond adult animals were selected. Three animals of each age were slaughtered to collect samples from heart skeletal muscle (Longissimus dorsi muscle, psoas major muscle, biceps femoris muscle) adipose tissue liver and kidney. The total RNA was obtained to investigate the H-FABP mRNA expression levels by real-time PCR. The results showed that the H-FABP mRNA expression levels in heart and skeletal muscle have the same basic trends at different growth periods. The highest H-FABP mRNA expression in heart and skeletal muscle appeared at 2 months of age and it was extreme higher than those at other ages (p<0.01). The lowest H-FABP mRNA expression level in these tissues were at 1 month old. H-FABP mRNA expression level in adipose tissue was different from those in heart and skeletal muscle. The highest H-FABP mRNA expression in adipose tissue appeared at adult age and its expression was extreme higher than those in younger ages (p<0.01). In addition, the H-FABP mRNA expression pattern in liver was different from the other tissues. The expression in the liver at 1 month of age was significantly higher than those at 2-4 months of age. However, the highest level occurred at adult age. The differences in H-FABP mRNA expression level at 3 and 4 months old were not significant in liver, heart, skeletal muscle and adipose tissue. On the other hand, H-FABP mRNA expression level in heart was the highest and significantly higher than other tissues at all ages. But, H-FABP mRNA expression level in liver was extreme higher than those in skeletal muscle and adipose tissue at 1 month old age (p<0.01). Besides, H-FABP mRNA expression in adipose tissue appears to increase as the age increase.
细粒棘球蚴FABP基因的原核表达及蛋白鉴定  [PDF]
生物技术通报 , 2010,
Abstract: 构建原核表达载体pET-FABP,优化表达条件,采用免疫学方法鉴定纯化的FABP融合蛋白。载体pMD19-T-FABP和pET-44a(+)经EcoRⅠ和HindⅢ双酶切,将回收的FABP片段与pET-44a(+)连接,构建原核表达载体pET-FABP并在大肠杆菌BL21(DE3)中表达,优化表达条件,纯化FABP融合蛋白,Westernblotting鉴定。成功构建了原核表达载体pET-FABP并在大肠杆菌中高效表达。纯化后的蛋白经SDS-PAGE和Westernblotting鉴定正确。构建的表达载体pET-FABP可以在大肠杆菌中大量表达Nus-FABP融合蛋白,为进一步研制FABP亚单位疫苗奠定了基础。
h-fabpa-fabp基因表达与肌内脂肪含量相关研究  [PDF]
牲畜兽医学报 , 2006,
Abstract: ?选用h-fabp和a-fabp基因作为影响鸡肌内脂肪沉积的候选基因,以北京油鸡、矮脚鸡、白莱航鸡和aa肉鸡为研究群体,利用rt-pcr和实时荧光定量pcr技术,分别对56、90、120日龄h-fabp和a-fabp基因mrna进行定量分析,结合imf含量及屠体性状测定,分析h-fabp及a-fabp基因表达水平对imf含量等的影响。结果表明:h-fabp基因mrna随日龄的增长表达量显著降低,而a-fabp基因mrna随日龄的增长表达量显著升高,并表现出显著的品种效应(p<0.01),性别因素对a-fabp基因表达影响显著。北京油鸡、白莱航鸡和aa鸡群体的h-fabp基因mrna表达水平与imf含量及屠体重呈现显著的负相关,而a-fabp基因mrna表达水平与屠体重显著相关,与imf含量没有显著的相关性。矮脚鸡a-fabp基因mrna水平与imf含量呈现显著的负相关,其h-fabp基因mrna水平对屠体重影响显著,表现出显著的品种差异。
FABP4 Dynamics in Obesity: Discrepancies in Adipose Tissue and Liver Expression Regarding Circulating Plasma Levels  [PDF]
María Isabel Queipo-Ortu?o, Xavier Escoté, Victoria Ceperuelo-Mallafré, Lourdes Garrido-Sanchez, Merce Miranda, Mercedes Clemente-Postigo, Rafael Pérez-Pérez, Belen Peral, Fernando Cardona, Jose Manuel Fernández-Real, Francisco J. Tinahones, Joan Vendrell
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0048605
Abstract: Background FABP4 is predominantly expressed in adipose tissue, and its circulating levels are linked with obesity and a poor atherogenic profile. Objective In patients with a wide BMI range, we analyze FABP4 expression in adipose and hepatic tissues in the settings of obesity and insulin resistance. Associations between FABP4 expression in adipose tissue and the FABP4 plasma level as well as the main adipogenic and lipolytic genes expressed in adipose tissue were also analyzed. Methods The expression of several lipogenic, lipolytic, PPAR family and FABP family genes was analyzed by real time PCR. FABP4 protein expression in total adipose tissues and its fractions were determined by western blot. Results In obesity FABP4 expression was down-regulated (at both mRNA and protein levels), with its levels mainly predicted by ATGL and inversely by the HOMA-IR index. The BMI appeared as the only determinant of the FABP4 variation in both adipose tissue depots. FABP4 plasma levels showed a significant progressive increase according to BMI but no association was detected between FABP4 circulating levels and SAT or VAT FABP4 gene expression. The gene expression of FABP1, FABP4 and FABP5 in hepatic tissue was significantly higher in tissue from the obese IR patients compared to the non-IR group. Conclusion The inverse pattern in FABP4 expression between adipose and hepatic tissue observed in morbid obese patients, regarding the IR context, suggests that both tissues may act in a balanced manner. These differences may help us to understand the discrepancies between circulating plasma levels and adipose tissue expression in obesity.
鸭a-fabp基因的克隆及其组织表达  [PDF]
牲畜兽医学报 , 2008,
Abstract: ?本文采用rt-pcr方法从35周龄母鸭脂肪组织中克隆了a-fabp基因的cdna序列,其长度为422bp,包含了1个399bp的完整cds,编码132个氨基酸。该序列与家禽(鹅、鸡)和哺乳动物(人、小鼠、猪、牛)的afabp基因序列约有94%和73.4%~75.7%的同源性,而相应氨基酸序列的同源性为92.4%和72.0%~77.3%。半定量rt-pcr研究结果为a-fabp基因在间脑、肺和肾组织中不表达,在脂肪组织中的表达明显高于其他组织(p<0.5)。表明a-fabp基因在动物进化中具有高度保守性,该基因的表达具有组织特异性。
ORIGINAL PAPER: Exercise h-FABP plasma concentration in healthy subjects
?ukasz A. Ma?ek,Marcin Grabowski,Monika Szpotańska,Mateusz ?piewak
Archives of Medical Science , 2005,
Abstract: Introduction: Heart fatty acid binding protein (h-FABP) is considered a heart specific marker of necrosis, but it is also present in the skeletal muscles. The aim of the study is to check whether h-FABP plasma concentration increases in healthy subjects after exercise. Material and methods: Plasma h-FABP concentrations were measured in 16 healthy men and 3 healthy women (mean age 24) before and after their participation in the 11 kilometer-long marathon – XVI Independent Race in Warsaw by means of a point-of-care semi-quantitative test. Results: All 19 runners had a negative result of the pre-run h-FABP test (<7 μg/l). Out of eighteen runners who finished the race: 9 (50%) presented with a positive result of the point-of-care test, 7 runners (39%) had a negative result and in 2 participants the test showed invalid results. All studied subjects were free of cardiologic risk factors, recent infections and were not on any medication. All positive results were found among the male subjects. Discussion: Plasma h-FABP can increase after moderate exercise probably due to skeletal muscle injury. The concentrations observed after moderate exercise are generally lower than those reported for the acute myocardial infarction. Conclusion: The point-of-care h-FABP test might be therefore useful in the diagnosis of myocardial necrosis in subjects with angina pectoris and exercise induced chest pain
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