Understanding Acute Hemolytic Anemia Severity Through Computational Analysis of G6PDChatham Variant: Designing a New Activator as a Potential Drug

Maysaa Alakbaree; Mustapha Suleiman; Abbas Hashim Abdulsalam; Ahmed Al-Hili; Mohd Shahir Shamsir Omar; Farah Hasan Ali; Nurriza Ab Latif; Muaawia Ahmed Hamza; Syazwani Itri  Amran

doi:10.11113/mjfas.v20n6.3876

Authors

Maysaa Alakbaree Department of Bioinformatics, College of Biomedical Informatics, University of Information Technology and Communications, Baghdad, Iraq
Mustapha Suleiman Department of Chemistry, Faculty of Science, Universiti Teknologi Malaysia, 81310 UTM Johor, Malaysia
Abbas Hashim Abdulsalam Department of Medical Laboratories Techniques, Al-Turath University College, Baghdad, Iraq
Ahmed Al-Hili Department of Anesthesia, Collage of Medical Technology, Al-Farahidi University, Baghdad, Iraq
Mohd Shahir Shamsir Omar Department of Biosciences, Faculty of Science, Universiti Teknologi Malaysia, 81310 UTM Johor, Malaysia
Farah Hasan Ali Department of Radiology and Ultrasound, Collage of Medical Technology, Al-Farahidi University, Baghdad, Iraq
Nurriza Ab Latif Department of Biosciences, Faculty of Science, Universiti Teknologi Malaysia, 81310 UTM Johor, Malaysia
Muaawia Ahmed Hamza Faculty of Medicine, King Fahad Medical City, Research Center, King Fahad Medical City, Riyadh, Saudi Arabia
Syazwani Itri Amran Department of Biosciences, Faculty of Science, Universiti Teknologi Malaysia, 81310 UTM Johor, Malaysia

DOI:

https://doi.org/10.11113/mjfas.v20n6.3876

Keywords:

C6PDChatham, molecular dynamic simulation, molecular docking, acute hemolytic anemia, computer-aided drug design.

Abstract

Glucose-6-phosphate dehydrogenase deficiency (G6PDD) is a major enzymatic disease affecting human red blood cells (RBCs), causing hemolytic anemia due to the diminish of the nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) synthesis and altered redox balance within erythrocytes. This study sought to correct the defect in G6PD^Chatham (Ala355Thr) caused by the loss of interactions (hydrogen bonds and salt bridges) by docking the AG1 molecule at the dimer interface, thus restoring these lost interactions. The enzyme conformation was then analyzed before and after AG1 binding using molecular dynamics simulation (MDS). The reasons behind the severity of acute hemolytic anemia (AHA) were explained using several parameters, such as root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), hydrogen bonds, salt bridges, radius of gyration (Rg), solvent accessible surface area (SASA), and covariance matrix analysis. Structural alterations in G6PD^Chatham, including the absence of interactions in a key region of the variant structure, can significantly impact protein stability and function, subsequently contributing to disease severity. Upon AG1 binding, these missing interactions were resorted to correct the structural defect of the variant. This restoration improves dimer stability and restores G6PD function. To develop new G6PD activators, several new analogues (SY7, SY8, SY9, and SY10) were rationally developed by substituting the linker region of the AG1 structure with other functional groups using the Avogadro software. These compounds were successfully synthesized and docked with G6PD^Chatham where the best binding affinity ranged between -8.0 and -9.1 kcal/mol. SY8, a promising G6PD activator, is predicted to be easily metabolized and excreted, making it less likely to cause toxicity. Its high drug score, drug-likeness, and favorable safety profile make it a strong candidate for synthesis and cellular testing. The toxicity risk assessment supported the overall drug score, increasing confidence in finding additional small-molecule activators for G6PDD disorder. Amidst the absence of effective treatments, such discovery hopes to improve the lives of those with AHA by assisting the development of appropriate pharmaceuticals for G6PDD.

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