Docking Based De novo Design of Few Tolcapone Derivatives as Catechol-o-Methyl Transferase (Comt) Inhibitors

[摘要] Catechol-O-methyl tranferase (COMT; E.C.2.1.1.6) is widely distributed enzyme in nature that plays an essential role in the metabolism of catechol neurotransmitters and catechol linked foreign entities. As L-DOPA, a key medicine in Parkinsonism is being catabolised by COMT, this justified the interest in developing improved COMT inhibitors as significant adjunct to L-DOPA therapy. Although tolcapone have gained considerable attention in bringing therapeutic benefit, yet owing to its fatal hepatotoxic potential entacapone and certain other drug came into existence. The scope for further betterment prompted us to design a series of 48 compounds based on the molecular skeleton of tolcapone have been developed conventionally. In the process of ensuring their drug ability, computational ligand docking methodology, AutoDock 4.0, based on genetic algorithm was employed. Binding mode analysis between docked compounds and the protein were analyzed using ADT (version 1.5.4). The best docking result can be considered to be the conformation which is in the close proximity to the active site along with low (docked) energy. Compounds SB10, SB11, SB31 and SB33 have been found to meet both the stated criteria, thereby chosen to be potent.

[学科分类] 药理学