Diabetes mellitus is a metabolic disorder leading to hyperglycemia and organ damage. In 2017, the International Diabetes Federation (IDF) reported that about 425 million people living with diabetes, most of which suffer from type 2 diabetes mellitus. The drug development for controlling glucose level is crucial to treat people with type 2 diabetes mellitus. Alpha-amylase plays an imperative role in carbohydrate hydrolysis. Hence, the inhibition of alpha-amylase, which halt the glucose absorption, can be a promising pathway for developing type 2 diabetes mellitus drugs. Natural product has been known as the lead drugs for various diseases. In this research, the fragment merging drug design was performed by employing both the existing drug, voglibose, as the template and the natural product compounds to generate newly constructed ligands. The fragments were acquired from ZINC15 natural product database and then were screened according to Astex’s Rules of Three, pharmacophore properties, and molecular docking simulation. The 482 selected fragments were evaluated under Lipinski’s Rule of Five and toxicity effects using DataWarrior software. The ligands underwent molecular flexible docking simulation followed by the ADME-Tox prediction by using Toxtree, AdmetSAR, and SwissADME software. In the end, two lead compounds showed the best properties as an alpha-amylase inhibitor based on their low ΔG
, acceptable RMSD score, favorable pharmacological properties, and molecular interaction.