AbstractIn the present study, the identification of potential α‐amylase inhibitors is explored as a potential strategy for treating type‐2 diabetes mellitus. A computationally driven approach using molecular docking was employed to search for new α‐amylase inhibitors. The interactions of potential drugs with the enzyme's active site were investigated and compared with the contacts established by acarbose (a reference drug for α‐amylase inhibition) in the crystallographic structure 1B2Y. For this active site characterization, both molecular docking and molecular dynamics simulations were performed, and the residues involved in the α‐amylase–acarbose complex were considered to analyse the potential drug's interaction with the enzyme. Two potential α‐amylase inhibitors (AN‐153I105594 and AN‐153I104845) have been selected following this computational strategy. Both compounds established a large number of interactions with key binding site α‐amylase amino acids and obtained a comparable docking score concerning the reference drug (acarbose). Aiming to further analyse candidates' properties, their ADME (absorption, distribution, metabolism, excretion) parameters, druglikeness, organ toxicity, toxicological endpoints and median lethal dose (LD50) were estimated. Overall estimations are promising for both candidates, and in silico toxicity predictions suggest that a low toxicity should be expected.