A study of Amentoflavone and its derivatives towards human lysosomal Acid-Alpha-Glucosidase (GAA) - pompe disease on its binding affinity and molecular interactions / Amar Hakimin Rosman

Human lysosomal acid alpha glucosidase is the protein that contains the enzyme responsible for breaking down glycogen into glucose in the lysosomes. As glucose is the body’s primary source of energy, especially for the muscles, the role of the human lysosomal acid alpha glucosidase is important as it breaks down the huge amount of glycogen consumed by humans. However, problems arise when there is a mutation in the acid alpha glucosidase gene (4). This mutation prevents the production of the needed amount of acid alpha glucosidase enzyme that is needed to break down the glycogen (4). This causes buildup of glycogen in human cells, which causes damage to organs and tissues. The main issue with Pompe disease is that it does not have a cure and due to the small number of cases it is not often placed as a priority (7). There are many proposed treatment methods, but for this research, the method used will be ligand-targeting therapy. The way it works is that by specifically attaching a ligand to the human lysosomal acid alpha glucosidase by molecular docking, we can enhance its binding affinity so that it can create more amounts of enzymes in the human lysosomes which will lead to more efficient and higher rate of glycogen breakdown. To find the appropriate ligand for this method, six different ligands were used for this simulation which are Amentoflavone, Bilobetin, Heveaflavone, Isoginkgetin, Putraflavone and Sequoiaflavone. To measure the effectiveness of each ligand, they are subjected to a binding affinity test to find the ligand with the lowest binding affinity and molecular interactions test to find out their interactions when bound to the human lysosomal acid alpha glucosidase. Using AMDock to find the appropriate value of binding affinity, while there wasn’t a significant difference between each of the ligands, Amentoflavone has the lowest binding affinity at-9.3 and the best molecular interactions as they pose the most amounts of conventional hydrogen bond and pi-alkyl bond at three of each bond. The low value of binding affinity and the specific molecular interactions mentioned made it the most stable and effective ligand of all six that were researched. However, as this is only an online simulation, it is recommended to conduct physical research and testing to truly provide the most usable results.