Abstract—Presently, we elucidate the mechanism of N¹- alkyltheobromine derivatives as histamine-H1 antagonist at a molecular level using computational method (in silico). The experiment was set up by docking those N¹- alkyltheobromines to the crystal structure of histamine-H1 receptor and the results showed that the ligands occupied the active pocket of histamine-H1 receptor by interacting with various amino acid residues such as Thr112, Tyr431, Ser111, Asp107 and Lys191 via hydrogen bonds as well as electrostatic interaction.