Discovery of Novel Human HNMT Inhibitors through Ligand and Structure-Based Drug Design

• Main Authors: Pavadai Elumalai, P.Elumalai
• Other Authors: 劉宣良
• Format: Others
• Language: en_US
• Published: 2012
• Online Access: http://ndltd.ncl.edu.tw/handle/ex8g23

博士 === 國立臺北科技大學 === 工程科技研究所 === 100 === Histamine, a biogenic amine, plays many important pathophysiological roles in human tissues such as mediator in allergic responses, a regulator of gastric acid secretion, a messenger in bronchial asthma, and a neurotransmitter in the central nervous system. The histamine is inactivated by histamine-metabolizing major enzyme histamine N-methyltransferase (EC 2.1.1.8; HNMT) in various tissues for example bronchus, kidney and the central nervous system. Importantly, it has been shown that HNMT is the only pathway for termination of the neurotransmitter action of histamine in the brain. Recently, the inhibition of HNMT has been demonstrated to play therapeutic roles in the treatment of neurodegenerative disease, memory and learning deficits and attention-deficit hyperactivity disorder. Thus, to better understand the essential chemical features for HNMT inhibition and discover novel HNMT inhibitors, common feature, ligand-based and structure-based pharmacophore models were, in this study, developed based on the most active inhibitors, structurally divers inhibitors and the highest resolution crystal structure of HNMT using Hip-Hop, HypoGen and Ludi algorithms of Discovery Studio 2.5 software, respectively. The best models were selected and the goodness-of-hit validation scores of three models showed more than 0.7, indicating that the pharmacophore models are efficient to identify novel hits using virtual screening techniques. The pharmacophore models were then employed as 3D-search query for virtual screening to retrieve potential hits from NCI, Chembridge and Maybridge databases. Subsequently, the hit compounds were subjected to molecular docking studies with the crystal structure of human HNMT. Finally, total of 20 hits were suggested as potential leads, which exhibited good estimated activities, favorable binding interactions, high pharmacophore fit values and high consensus scores. The obtained novel chemotype from these studies could facilitate to discover new scaffold in the development of novel HNMT inhibitors.