Precision Medicine Unit, Department of Biotechnology, Faculty of Natural Sciences, University of the Western Cape, Robert Sobukwe Road, Bellville, 7535, South Africa.
Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg, Cape Town, 7505, South Africa.
Sci Rep. 2022 Oct 8;12(1):16936. doi: 10.1038/s41598-022-21291-4.
Single nucleotide polymorphisms detected in the solute carrier member family-22 has been shown to result in a variable response in the treatment of type 2 diabetes mellitus with Metformin. This study predicted a three-dimensional protein structure for the SLC22A2 protein sequence using AlphaFold 2 and modelled five haplotypes within SLC22A2 protein structure observed in the Xhosa population of South Africa. The protein models were used to determine the effect(s) of haplotype variations on the transport function of Metformin and 10 other drugs by the SLC22A2 protein. Molecular dynamic simulation studies, molecular docking and interaction analysis of the five SLC22A2 haplotypes were performed in complex with the ligand 5RE in a POPC lipid bilayer to understand the mechanism of drug binding. Weakest binding free energy was found between 5RE and haplotype 1. Molecular docking studies indicated the top binding ligands as well as Metformin to bind inside the transport channel in all haplotypes increasing the probability of Metformin inhibition during co-administration of drugs. Metformin showed reduced binding affinity and number of interactions compared to the top four binding molecules. Molecular dynamic simulation analysis indicated that haplotypes 1, 3 and 4 were less stable than 2 and 5. The findings suggest haplotypes 4 and 5 having stronger preference for large inhibitor molecule binding in the active site and this could result in haplotypes 4 and 5 demonstrating reduced Metformin clearance via the SLC22A2 transporter during co-administration of drugs. The current study is the first to investigate the potential effect(s) of haplotype variation on the protein structure of SLC22A2 to assess its ability to transport Metformin in an indigenous South African population.
在溶质载体家族 22 中检测到的单核苷酸多态性已被证明会导致二甲双胍治疗 2 型糖尿病的治疗反应出现差异。本研究使用 AlphaFold 2 预测了 SLC22A2 蛋白序列的三维蛋白结构，并对南非科萨人群中观察到的 SLC22A2 蛋白结构中的五个单倍型进行了建模。使用蛋白模型来确定单倍型变异对 SLC22A2 蛋白对二甲双胍和其他 10 种药物的转运功能的影响。在 POPC 脂质双层中，对五个 SLC22A2 单倍型与配体 5RE 的复合物进行了分子动力学模拟研究、分子对接和相互作用分析，以了解药物结合的机制。在与 5RE 结合方面，发现单倍型 1 的结合自由能最弱。分子对接研究表明，在所有单倍型中，前四个结合配体以及二甲双胍都可以进入转运通道结合，从而增加了药物联合使用时二甲双胍抑制的可能性。与前四个结合分子相比，二甲双胍的结合亲和力和相互作用数量都减少了。分子动力学模拟分析表明，单倍型 1、3 和 4 比 2 和 5 更不稳定。研究结果表明，单倍型 4 和 5 对活性部位中较大抑制剂分子的结合具有更强的偏好，这可能导致单倍型 4 和 5 在药物联合使用期间通过 SLC22A2 转运体降低二甲双胍的清除率。本研究首次调查了单倍型变异对 SLC22A2 蛋白结构的潜在影响，以评估其在南非本土人群中转运二甲双胍的能力。
