New serotonin 5-HT(6) ligands from common feature pharmacophore hypotheses.
Serotonin 5-HT6 receptor antagonists are thought to play an important role in the treatment of psychiatry, Alzheimer's disease, and probably obesity. To find novel and potent 5-HT6 antagonists and to provide a new idea for drug design, we used a ligand-based pharmacophore to perform the virtual screening of a commercially available database. A three-dimensional common feature pharmacophore model was developed by using the HipHop program provided in Catalyst software and was used as a query for screening the database. A recursive partitioning (RP) model which can separate active and inactive compounds was used as a filtering system. Finally a sequential virtual screening procedure (SQSP) was conducted, wherein both the common feature pharmacophore and the RP model were used in succession to improve the results. Some of the hits were selected based on druglikeness, ADME properties, structural diversity, and synthetic accessibility for real biological evaluation. The best hit compound showed a significant IC50 value of 9.6 nM and can be used as a lead for further drug development.
Life Science Division, Korea Institute of Science and Technology, P.O. Box 131, Cheongryang, Seoul 130-650, South Korea.
Hye-Jung
HJ
Kim
Munikumar Reddy
MR
Doddareddy
Hyunah
H
Choo
Yong Seo
YS
Cho
Kyoung Tai
KT
No
Woo-Kyu
WK
Park
Ae Nim
AN
Pae
D001185:Artificial Intelligence; D016208:Databases, Factual; D015195:Drug Design; D008024:Ligands; D008956:Models, Chemical; D011985:Receptors, Serotonin / Q000378:metabolism*; D012984:Software
D008024:Ligands; D011985:Receptors, Serotonin; C097216:serotonin 6 receptor