Computational Evaluation of 2‐Phenyl‐4 H ‐chromen‐4‐one Analogues as Antihistamines: Potential Histamine N ‐Methyltransferase (HMT) Inhibitors

Abnormal release of histamine, which is present in relatively high concentration in the lungs, causes serious allergic vasoconstriction and anaphylactic manifestation in human beings. In mammals, a major pathway of histamine metabolism in the lungs is mediated by histamine N ‐methyl transferase (HMT) and diamine oxidase. The need to design a strategy of mechanistic computational evaluation of protein‐ligand affinity i.e . HMT‐ 2‐phenyl‐4 H ‐chromen‐4‐ones, protein complex binding energy has been established. A library of synthesized 2‐phenyl‐4 H ‐chromen‐4‐ones was docked into the active site cavity of target protein, HMT (Pdb: 2aot). The high‐resolution crystal structure of HMT complex with the competitive inhibitor N [2 (benzhydryloxy)ethyl] N N ‐Dimethylamine (Diphenhydramine) revealed a protein with a highly confined binding region that could be targeted in the design of specific anti‐histamines. The validation of docking programme by Potential Mean Force was compared with binding energy results of known ligands in the active sites of HMT, diphenhydramine / benadryl, promethazine, cyproheptadine, trimeton / avil etc . All the synthesized chromone derivatives showed comparable negative binding energies pointing towards the fact that these molecules could be potent antihistamines.