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Effect of hydrophobic and hydrogen bonding interactions on the potency of ß-alanine analogs of G-protein coupled glucagon receptor inhibitors.
Proteins: Structure, Function, and Bioinformatics ( IF 2.9 ) Pub Date : 2019-09-10 , DOI: 10.1002/prot.25807
Pushyaraga P Venugopal 1 , Bratin K Das 1 , E Soorya 1 , Debashree Chakraborty 1
Affiliation  

G-protein coupled glucagon receptors (GCGRs) play an important role in glucose homeostasis and pathophysiology of Type-II Diabetes Mellitus (T2DM). The allosteric pocket located at the trans-membrane domain of GCGR consists of hydrophobic (TM5) and hydrophilic (TM7) units. Hydrophobic interactions with the amino acid residues present at TM5, found to facilitate the favorable orientation of antagonist at GCGR allosteric pocket. A statistically robust and highly predictive 3D-QSAR model was developed using 58 β-alanine based GCGR antagonists with significant variation in structure and potency profile. The correlation coefficient (R2 ) and cross-validation coefficient (Q2 ) of the developed model were found to be 0.9981 and 0.8253, respectively at the PLS factor of 8. The analysis of the favorable and unfavorable contribution of different structural features on the glucagon receptor antagonists was done by 3D-QSAR contour plots. Hydrophobic and hydrogen bonding interactions are found to be main dominating non-bonding interactions in docking studies. Presence of highest occupied molecular orbital (HOMO) in the polar part and lowest unoccupied molecular orbital (LUMO) in the hydrophobic part of antagonists leads to favorable protein-ligand interactions. Molecular mechanics/generalized born surface area (MM/GBSA) calculations showed that van der Waals and nonpolar solvation energy terms are crucial components for thermodynamically stable binding of the inhibitors. The binding free energy of highly potent compound was found to be -63.475 kcal/mol; whereas the least active compound exhibited binding energy of -41.097 kcal/mol. Further, five 100 ns molecular dynamics simulation (MD) simulations were done to confirm the stability of the inhibitor-receptor complex. Outcomes of the present study can serve as the basis for designing improved GCGR antagonists.

中文翻译:

疏水和氢键相互作用对G蛋白偶联胰高血糖素受体抑制剂的ß-丙氨酸类似物效力的影响。

G蛋白偶联的胰高血糖素受体(GCGRs)在II型糖尿病(T2DM)的葡萄糖稳态和病理生理中起着重要作用。位于GCGR跨膜结构域的变构口袋由疏水(TM5)和亲水(TM7)单元组成。与存在于TM5的氨基酸残基的疏水相互作用可促进拮抗剂在GCGR变构口袋中的有利取向。使用58种基于β-丙氨酸的GCGR拮抗剂开发了统计上可靠且具有高度预测性的3D-QSAR模型,该拮抗剂在结构和效能方面存在显着变化。在PLS因子为8时,开发模型的相关系数(R2)和交叉验证系数(Q2)分别为0.9981和0.8253。通过3D-QSAR等高线图分析了不同结构特征对胰高血糖素受体拮抗剂的有利和不利贡献。在对接研究中,发现疏水键和氢键相互作用是主要的非键相互作用。拮抗剂的极性部分中最高占据分子轨道(HOMO)的存在和拮抗剂的疏水部分中最低未占据分子轨道的(LUMO)导致有利的蛋白质-配体相互作用。分子力学/广义生表面积(MM / GBSA)计算表明,范德华力和非极性溶剂化能量项是抑制剂热力学稳定结合的关键组成部分。发现高效化合物的结合自由能为-63.475 kcal / mol;而活性最低的化合物的结合能为-41。097大卡/摩尔 此外,进行了五次100 ns的分子动力学模拟(MD)模拟,以确认抑制剂-受体复合物的稳定性。本研究的结果可作为设计改进的GCGR拮抗剂的基础。
更新日期:2020-01-04
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