Pharmacophore modeling, virtual screening and docking studies to identify novel HNMT inhibitors

被引:13
|
作者
Elumalai, Pavadai [1 ]
Liu, Hsuan-Liang [1 ,2 ]
Zhao, Jian-Hua [3 ]
Chen, Wilson [3 ]
Lin, Dar Shong [2 ,4 ,5 ,6 ]
Chuang, Chih-Kuang [2 ,7 ,8 ]
Tsai, Wei-Bor [9 ]
Ho, Yih [10 ]
机构
[1] Natl Taipei Univ Technol, Grad Inst Biotechnol, Taipei 10608, Taiwan
[2] Natl Taipei Univ Technol, Dept Chem Engn & Biotechnol, Taipei 10608, Taiwan
[3] Inst Nucl Energy Res, Chem Anal Div, Taoyuan Cty 32546, Taiwan
[4] Mackay Mem Hosp, Dept Pediat, Taipei 10449, Taiwan
[5] Mackay Mem Hosp, Dept Med Res, Taipei 10449, Taiwan
[6] Mackay Med Nursing & Management Coll, New Taipei City 25245, Taiwan
[7] Mackay Mem Hosp, Dept Med Res, Div Genet & Metab, Taipei 10449, Taiwan
[8] Fu Jen Catholic Univ, Coll Med, Taipei Cty 24205, Taiwan
[9] Natl Taiwan Univ, Dept Chem Engn, Taipei 106, Taiwan
[10] Taipei Med Univ, Sch Pharm, Taipei 110, Taiwan
关键词
Histamine N-methyltransferase; Pharmacophore model; Virtual screening; Molecular docking; Consensus score; HISTAMINE-N-METHYLTRANSFERASE; DIAMINE OXIDASE ACTIVITY; BRAIN; H-3; METABOLISM; MECHANISM; RELEASE; TACRINE; LIGANDS;
D O I
10.1016/j.jtice.2012.01.004
中图分类号
TQ [化学工业];
学科分类号
0817 ;
摘要
Histamine N-methyltransferase (HNMT) is the key enzyme responsible for inactivating histamine in bronchus, kidney, and the central nervous system of mammals. The inhibition of HNMT has therapeutically potential roles in neurodegenerative disease, memory and learning deficits and attention-deficit hyperactivity disorder. For better understanding the essential chemical features for HNMT inhibition and identifying novel inhibitors, a three-dimensional (3D) chemical-feature-based QSAR pharmacophore model for HNMT inhibitors was first time developed using Discovery Studio 2.5. The best model (Hypo1), which has the highest correlation coefficient (0.96), the highest cost difference (74.51) and the lowest RMS (0.73 angstrom), consists two hydrophobic, one hydrophobic aromatic, one hydrogen bond acceptor and one hydrogen bond acceptor lipid. The reliability of Hypo1 was further validated using external test set, cost analysis, Fischer's randomization method and decoy data set. The validated Hypo1 was then used as a 3D search query for virtual screening to retrieve potential inhibitors from NO database. Subsequently, the hit compounds were subjected to molecular docking studies with the crystal structure of HNMT. Finally, 10 hits were suggested as potential leads, which exhibited good estimated activities, favorable binding interactions, and high consensus scores. The obtained novel chemotype from this study may facilitate to discover a new scaffold for developing novel HNMT inhibitors. (C) 2012 Taiwan Institute of Chemical Engineers. Published by Elsevier B.V. All rights reserved.
引用
收藏
页码:493 / 503
页数:11
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