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Structure‐Based Design of a Monosaccharide Ligand Targeting Galectin‐8
ChemMedChem ( IF 3.6 ) Pub Date : 2018-07-10 , DOI: 10.1002/cmdc.201800224 Mohammad H. Bohari 1 , Xing Yu 1 , Chandan Kishor 1 , Brijesh Patel 1 , Rob Marc Go 1 , Hadieh A. Eslampanah Seyedi 1 , Yaron Vinik 2 , I. Darren Grice 1, 3 , Yehiel Zick 2 , Helen Blanchard 1
ChemMedChem ( IF 3.6 ) Pub Date : 2018-07-10 , DOI: 10.1002/cmdc.201800224 Mohammad H. Bohari 1 , Xing Yu 1 , Chandan Kishor 1 , Brijesh Patel 1 , Rob Marc Go 1 , Hadieh A. Eslampanah Seyedi 1 , Yaron Vinik 2 , I. Darren Grice 1, 3 , Yehiel Zick 2 , Helen Blanchard 1
Affiliation
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Galectin‐8 is a β‐galactoside‐recognising protein that has a role in the regulation of bone remodelling and is an emerging new target for tackling diseases with associated bone loss. We have designed and synthesised methyl 3‐O‐[1‐carboxyethyl]‐β‐d‐galactopyranoside (compound 6) as a ligand to target the N‐terminal domain of galectin‐8 (galectin‐8N). Our design involved molecular dynamics (MD) simulations that predicted 6 to mimic the interactions made by the galactose ring as well as the carboxylic acid group of 3′‐O‐sialylated lactose (3′‐SiaLac), with galectin‐8N. Isothermal titration calorimetry (ITC) determined that the binding affinity of galectin‐8N for 6 was 32.8 μm, whereas no significant affinity was detected for the C‐terminal domain of galectin‐8 (galectin‐8C). The crystal structure of the galectin‐8N–6 complex validated the predicted binding conformation and revealed the exact protein–ligand interactions that involve evolutionarily conserved amino acids of galectin and also those unique to galectin‐8N for recognition. Overall, we have initiated and demonstrated a rational ligand design campaign to develop a monosaccharide‐based scaffold as a binder of galectin‐8.
中文翻译：
针对半乳糖凝集素8的单糖配体的基于结构的设计
Galectin-8是一种β-半乳糖苷识别蛋白，在调节骨骼重塑中发挥作用，并且是解决与骨丢失相关疾病的新兴靶标。我们已经设计并合成了甲基3 - O- [1-羧乙基]-β- d-吡喃半乳糖苷（化合物6）作为靶向半乳糖凝集素8（N半乳糖凝集素8 N）的N端结构域的配体。我们的设计涉及分子动力学（MD）模拟，该模拟预测6可以模拟半乳糖环以及3'- O-唾液酸化乳糖（3'-SiaLac）的羧酸基团与半乳糖凝集素8 N的相互作用。等温滴定热法（ITC）确定了Galectin-8的结合亲和力Ñ为6为32.8μ米，而对于半乳凝素8（半乳凝素8的C末端结构域没有检测到显著亲和力Ç）。galectin-8 N – 6复合物的晶体结构验证了预测的结合构象，并揭示了涉及Galectin进化上保守的氨基酸以及galectin-8 N独特的蛋白质-配体相互作用，以进行识别。总体而言，我们已经启动并证明了合理的配体设计方案，以开发基于单糖的支架作为半乳凝素8的结合剂。
更新日期：2018-07-10
中文翻译：
针对半乳糖凝集素8的单糖配体的基于结构的设计
Galectin-8是一种β-半乳糖苷识别蛋白，在调节骨骼重塑中发挥作用，并且是解决与骨丢失相关疾病的新兴靶标。我们已经设计并合成了甲基3 - O- [1-羧乙基]-β- d-吡喃半乳糖苷（化合物6）作为靶向半乳糖凝集素8（N半乳糖凝集素8 N）的N端结构域的配体。我们的设计涉及分子动力学（MD）模拟，该模拟预测6可以模拟半乳糖环以及3'- O-唾液酸化乳糖（3'-SiaLac）的羧酸基团与半乳糖凝集素8 N的相互作用。等温滴定热法（ITC）确定了Galectin-8的结合亲和力Ñ为6为32.8μ米，而对于半乳凝素8（半乳凝素8的C末端结构域没有检测到显著亲和力Ç）。galectin-8 N – 6复合物的晶体结构验证了预测的结合构象，并揭示了涉及Galectin进化上保守的氨基酸以及galectin-8 N独特的蛋白质-配体相互作用，以进行识别。总体而言，我们已经启动并证明了合理的配体设计方案，以开发基于单糖的支架作为半乳凝素8的结合剂。
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