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Discovery of high affinity ligands for beta(2)-adrenergic receptor through pharmacophore-based high-throughput virtual screening and docking

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Discovery of high affinity ligands for beta(2)-adrenergic receptor through pharmacophore-based high-throughput virtual screening and docking.pdf (3.392Mb)
Date
2014
Author
Yakar, Rüya
Akten, Ebru Demet
Abstract
Novel high affinity compounds for human beta(2)-adrenergic receptor (beta(2)-AR) were searched among the clean drug-like subset of ZINC database consisting of 9928465 molecules that satisfy the Lipinski's rule of five. The screening protocol consisted of a high-throughput pharmacophore screening followed by an extensive amount of docking and rescoring. The pharmacophore model was composed of key features shared by all five inactive states of beta(2)-AR in complex with inverse agonists and antagonists. To test the discriminatory power of the pharmacophore model a small-scale screening was initially performed on a database consisting of 117 compounds of which 53 antagonists were taken as active inhibitors and 64 agonists as inactive inhibitors. Accordingly 7.3% of the ZINC database subset (729413 compounds) satisfied the pharmacophore requirements along with 44 antagonists and 17 agonists. Afterwards all these hit compounds were docked to the inactive apo form of the receptor using various docking and scoring protocols. Following each docking experiment the best pose was further evaluated based on the existence of key residues for antagonist binding in its vicinity. After final evaluations based on the human intestinal absorption (HIA) and the blood brain barrier (BBB) penetration properties 62 hit compounds have been clustered based on their structural similarity and as a result four scaffolds were revealed. Two of these scaffolds were also observed in three high affinity compounds with experimentally known K-i values. Moreover novel chemical compounds with distinct structures have been determined as potential beta(2)-AR drug candidates. (C) 2014 Elsevier Inc. All rights reserved.

Source

Journal of Molecular Graphics and Modelling

Volume

53

Pages

148-160

URI

https://hdl.handle.net/20.500.12469/690
https://doi.org/10.1016/j.jmgm.2014.07.007

Collections

  • Araştırma Çıktıları / PubMed [194]
  • Araştırma Çıktıları / Scopus [1482]
  • Araştırma Çıktıları / WOS [1415]
  • Biyoinformatik ve Genetik / Bioinformatics and Genetics [211]

Keywords

Virtual screening
Pharmacophore modeling
Beta(2)-Adrenergic receptor
Docking
Scoring

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