a Department of Biochemistry, Protein Research Chair, College of Sciences , King Saud University , Riyadh 11451 , Saudi Arabia.
b King Fahd Medical Research Center , King Abdulaziz University , Jeddah 21589 , Saudi Arabia.
J Biomol Struct Dyn. 2018 Oct;36(13):3453-3462. doi: 10.1080/07391102.2017.1389661. Epub 2017 Oct 30.
The transport of more than 90% of the drugs viz. anticoagulants, analgesics, and general anesthetics in the blood takes place by albumin. Hence, albumin is the prime protein needs to be investigated to find out the nature of drug binding. Serum albumin molecules are prone to glycation at elevated blood glucose levels as observed in diabetics. In this piece of work, glycation of bovine serum albumin (BSA) was carried out with glyceraldehyde and characterized by molecular docking and fluorometry techniques. Glycation of BSA showed 25% loss of free amino groups and decreased protein fluorescence (60%) with blue shift of 6 nm. The present study was also designed to evaluate the binding of colchicine (an anti-inflammatory drug) to native and glycated BSA and its ability to displace 8-analino-1-nephthalene sulfonic acid (ANS), from the BSA-ANS complex. Binding of ANS to BSA showed strong binding (K = 4.4 μM) with native conformation in comparison to glycated state (K = 8.4 μM). On the other hand, colchicine was able to quench the fluorescence of native BSA better than glycated BSA and also showed weaker affinity (K = 23 μM) for glycated albumin compared with native state (K = 16 μM). Molecular docking study showed that both glyceraldehyde and colchicine bind to common residues located near Sudlow's site I that explain the lower binding of colchicine in the glycated BSA. Based on our results, we believe that reduced drugs-binding affinity to glycated albumin may lead to drugs accumulation and precipitation in diabetic patients.
血液中超过 90%的药物（如抗凝剂、镇痛药和全身麻醉药）的转运都是通过白蛋白进行的。因此，白蛋白是需要研究的主要蛋白质，以了解药物结合的性质。正如糖尿病患者所观察到的那样，血清白蛋白分子在高血糖水平下容易发生糖基化。在这项工作中，用甘油醛对牛血清白蛋白（BSA）进行了糖基化，并通过分子对接和荧光技术进行了表征。BSA 的糖基化导致 25%的游离氨基基团损失和 60%的蛋白质荧光（60%）减少，同时蓝移 6nm。本研究还旨在评估秋水仙碱（一种抗炎药物）与天然和糖基化 BSA 的结合及其从 BSA-ANS 复合物中置换 8-氨基-1-萘磺酸（ANS）的能力。与糖基化状态（K=8.4μM）相比，ANS 与 BSA 的结合显示出较强的结合（K=4.4μM），具有天然构象。另一方面，秋水仙碱能够更好地猝灭天然 BSA 的荧光，而与天然状态相比，它对糖基化白蛋白的亲和力也较弱（K=23μM）（K=16μM）。分子对接研究表明，甘油醛和秋水仙碱都结合到位于 Sudlow 位点 I 附近的常见残基上，这解释了秋水仙碱在糖基化 BSA 中结合较弱的原因。基于我们的结果，我们认为糖基化白蛋白与药物结合亲和力的降低可能导致药物在糖尿病患者中的积累和沉淀。
