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Biophysical chemistry behind sickle cell anemia and the mechanism of voxelotor action.

Scientific Reports 2024 January 23
Sickle cell anemia disease has been a great challenge to the world in the present situation. It occurs only due to the polymerization of sickle hemoglobin (HbS) having Pro-Val-Glu typed mutation, while the polymerization does not occur in normal hemoglobin (HbA) having Pro-Glu-Glu peptides. It is also well confirmed that the oxygenated HbS (OHbS) does not participate in the polymerization, while the deoxygenated HbS (dHbS) does, which causes the shape of red blood cells sickled. After polymerization, the blood has a low oxygen affinity. Keeping this fact into consideration, only those drugs are being synthesized that stabilize the OHbS structure so that the polymerization of HbS can be stopped. The literature data showed no systematic description of the changes occurring during the OHbS conversion to dHbS before polymerization. Hence, an innovative reasonable study between HbA and HbS, when they convert into their deoxygenated forms, was done computationally. In this evaluation, physiochemical parameters in HbA/HbS before and after deoxygenation were studied and compared deeply. The computationally collected data was used to understand the abnormal behaviour of dHbS arising due to the replacement of Glu6 with Val6. Consequently, during the presented computational study, the changes occurring in HbS were found opposite/abnormal as compared to HbA after the deoxygenation of both. The mechanism of Voxelotor (GBT-440) action to stop the HbS polymerization was also explained with the help of computationally collected data. Besides, a comparative study between GBT-440 and another suggested drug was also done to know their antisickling strength. Additionally, the effect of pH, CO, CO2 , and 2,3-diphosphoglycerate (2,3-DPG) on HbS structure was also studied computationally.

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