Forskning ved Københavns Universitet - Københavns Universitet


Identification of novel α7 nicotinic receptor ligands by in silico screening against the crystal structure of a chimeric α7 receptor ligand binding domain

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • Atilla Akdemir
  • Ewald Edink
  • Andrew J. Thompson
  • Sarah C.R. Lummis
  • Kooistra, Albert Jelke
  • Chris De Graaf
  • Iwan J.P. De Esch

A hierarchical in silico screening procedure using the crystal structure of an agonist bound chimeric α7/Ls-AChBP protein was successfully applied to both proprietary and commercial databases containing drug-like molecules. An overall hit rate of 26% (pKi ≥5.0) was obtained, with an even better hit rate of 35% for the commercial compound collection. Structurally novel and diverse ligands were identified. Binding studies with [ 3H]epibatidine on chimeric α7/5-HT3 receptors yielded submicromolar inhibition constants for identified hits. Compared to a previous screening procedure that utilized the wild type Ls-AChBP crystal structure, the current study shows that the recently obtained α7/Ls-AChBP chimeric protein crystal structure is a better template for the identification of novel α7 receptor ligands.

TidsskriftBioorganic and Medicinal Chemistry
Udgave nummer19
Sider (fra-til)5992-6002
Antal sider11
StatusUdgivet - 1 okt. 2012
Eksternt udgivetJa

ID: 199376408