Discovery of Novel α-Amylase Inhibitors as Type Two Diabetes Mellitus Therapy through Fragment-Based Drug Design
Muhammad Fauzi Hidayat, Eka Gunarti Ningsih, Ahmad Husein Alkaff, Usman Sumo Friend Tambunan · Key engineering materials · 2020
Diabetes is one of the top causes of death in the world, with 425 million sufferers reported in 2017. About 90% of diabetics suffer from Type 2 Diabetes Mellitus (T2DM). Recent studies show that inhibiting the α-amylase enzyme can significantly decrease the postprandial blood glucose levels through blocking carbohydrate hydrolysis. Therefore, it can be a promising strategy for T2DM treatment. This research was aimed to find the new potential inhibitor for the α-amylase from lead-like compounds Molecular Operating Environment (MOE) database through fragment-based drug design, combining with structure-based pharmacophore design method to obtain new drug candidate for T2DM. There were 653,214 lead-like compounds which were obtained from MOE database and screened based on the Astex Rules of Three along with toxicity filter to gain lead-like fragments. The filtered fragments were docked into the binding site of the α-amylase utilizing MOE 2014.09 software. Potential lead-like fragments were grown to generate 25,600 new ligands by utilizing DataWarrior v5.0.0 software, based on the Lipinski’s Rule of Five and toxicity filter. Molecular docking simu-lation and pharmacological test was performed on the ligand libraries to acquire the best ligand, namely BGOJI which were chosen according to the lowest ΔG binding score, RMSD value < 2, good molecular interaction, ADME/T test result.