镰状细胞性贫血的量子化学背景和抗镰状细胞性药物开发的空白

Mohammad Suhail, Safwana Usmani, Mehmood Ahmad
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引用次数: 0

摘要

镰状细胞性贫血是目前世界面临的一大挑战。它只发生在具有Pro-Val-Glu (PVG)型突变的镰状血红蛋白(HbS)聚合,而在具有Pro-Val-Glu (PGG)残基的正常血红蛋白(HbA)中不会发生聚合。根据文献数据,Pro-Val-Glu的Val-beta6本质上是疏水的,它似乎适合相邻HbS的疏水口袋。将Pro-Val-Glu插入相邻HbS上的疏水口袋后,开始聚合。这是一个值得商榷的问题,即在HbS中用缬氨酸取代谷氨酸如何使其更容易进入相邻HbS上的疏水口袋进行聚合。文献中尚未发现HbS聚合反应性的数据。这是第一次在结构不同的HbA和HbS中进行理论计算。之后,在量子水平上对PVG和PGG进行了比较研究,以评估其在相邻HbS上的疏水口袋中的反应性。在量子水平上,发现Pro-Val-Glu的HOMO-LUMO间隙小于Pro-Glu-Glu。根据文献数据,较小的HOMO-LUMO间隙促进聚合反应的引发。在此基础上,还显示了HbS中的突变点(Pro-Val-Glu)对聚合的反应性更强,而HbA中的pro - gluu - glu则没有。这一首次开发的计算方法不仅对分子生物学家,而且对计算化学家和药物化学家都有很大的帮助。此外,本文还提出了基于抗镰状细胞病药物开发差距的必要修改。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
A quantum chemistry background of sickle cell anemia and gaps in antisickling drug development
Sickle cell anemia disease has been a great challenge for the world in the present situation. It occurs only due to the polymerization of sickle hemoglobin (HbS) having Pro-Val-Glu (PVG) typed mutation, while the polymerization does not occur in normal hemoglobin (HbA) having Pro-Glu-Glu (PGG) residues. According to data from the literature, Val-beta6 of Pro-Val-Glu is hydrophobic in nature, which appears to fit into a hydrophobic pocket in the adjacent HbS. After the insertion of Pro-Val-Glu into a hydrophobic pocket on the adjacent HbS, the polymerization is started. This is a questionable point on how the replacement of glutamic acid with valine in HbS makes it more reactive to fit into a hydrophobic pocket on adjacent HbS for polymerization. No data from the literature on the reactivity of HbS for polymerization was found yet. This is the first time that the theoretical calculation was done in both HbA and HbS where they were structurally different. After that, a comparative study between PVG and PGG was done at quantum level for the evaluation of the reactivity to fit into a hydrophobic pocket on adjacent HbS. At a quantum level, it was found that the HOMO-LUMO gap of Pro-Val-Glu was lower than that of Pro-Glu-Glu. According to the data from the literature, the lesser HOMO-LUMO gap promotes the initiation of the polymerization reaction. On the basis of the results, it was also shown how the mutation point (Pro-Val-Glu) in HbS becomes more reactive to polymerization, whereas Pro-Glu-Glu in HbA does not. The computational method developed for the first time will be very helpful not only for molecular biologists but also for computational and medicinal chemists. Additionally, the required modifications based on gaps in anti-sickling drug development are also suggested in the presented article.
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