3D pharmacophore based virtual screening of T-type calcium channel blockers.
Virtual screening of the commercial databases was done by using a three dimensional pharmacophore previously developed for T-type calcium channel blockers using CATALYSTtrade mark program. Biological evaluation of 25 selected virtual hits resulted in the discovery of a highly potent compound VH04 with IC(50) value of 0.10 microM, eight times as potent as the known selective T-type calcium channel blocker, mibefradil. Search for similar compounds yielded several hits with micro-molar IC(50) values and high T-type calcium channel selectivity. Based on the structure of the virtual hits, small molecule libraries with novel scaffolds were designed, synthesis and biological evaluation of which are currently in progress. This result shows a successful example of ligand based drug discovery of potent T-type calcium channel blockers.
Doddareddy
Munikumar Reddy
MR
Life Science Division, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea.
Choo
Hyunah
H
Cho
Yong Seo
YS
Rhim
Hyewhon
H
Koh
Hun Yeong
HY
Lee
Jung-Ha
JH
Jeong
Seong-Woo
SW
Pae
Ae Nim
AN
D000818:Animals; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000494:pharmacology*; D020864:Calcium Channels, N-Type / Q000187:drug effects / Q000235:genetics; D020747:Calcium Channels, T-Type / Q000187:drug effects* / Q000235:genetics; D002384:Catalysis; D002460:Cell Line; D003198:Computer Simulation; D016208:Databases, Factual; D004594:Electrophysiology; D006801:Humans; D020748:Mibefradil / Q000494:pharmacology; D008958:Models, Molecular; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D018075:RNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D014981:Xenopus
C479952:CACNA1H protein, human; D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; D020747:Calcium Channels, T-Type; D018075:RNA, Complementary; D020748:Mibefradil