TY - JOUR
T1 - Pharmacophore modeling, virtual screening and docking studies to identify novel HNMT inhibitors
AU - Elumalai, Pavadai
AU - Liu, Hsuan Liang
AU - Zhao, Jian Hua
AU - Chen, Wilson
AU - Lin, Dar Shong
AU - Chuang, Chih Kuang
AU - Tsai, Wei Bor
AU - Ho, Yih
N1 - Funding Information:
The authors gratefully acknowledge the financial supports from the National Science Council of Taiwan (Project numbers: 99-2221-E-027-022-MY3 , 99-2221-E-027-037-MY2 , and 99-2622-E-027-003-CC3 ), the Institute of Nuclear Energy Research of Taiwan (Project number: 992001INER072 ), and National Taipei University of Technology and Taipei Medical University (Project number: NTUT-TMU-98-02 ).
PY - 2012/7
Y1 - 2012/7
N2 - 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. Å), 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 NCI 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.
AB - 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. Å), 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 NCI 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.
KW - Consensus score
KW - Histamine N-methyltransferase
KW - Molecular docking
KW - Pharmacophore model
KW - Virtual screening
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U2 - 10.1016/j.jtice.2012.01.004
DO - 10.1016/j.jtice.2012.01.004
M3 - Article
AN - SCOPUS:84862778272
SN - 1876-1070
VL - 43
SP - 493
EP - 503
JO - Journal of the Taiwan Institute of Chemical Engineers
JF - Journal of the Taiwan Institute of Chemical Engineers
IS - 4
ER -