A prospective cross-screening study on G-protein-coupled receptors: lessons learned in virtual compound library design.
Fulltext:
103510.pdf
Embargo:
until further notice
Size:
3.656Mb
Format:
PDF
Description:
Publisher’s version
Publication year
2012Source
Journal of Medicinal Chemistry, 55, 11, (2012), pp. 5311-5325ISSN
Publication type
Article / Letter to editor
Display more detailsDisplay less details
Organization
CMBI
Former Organization
Physical Chemistry/Biophysical Chemistry
Journal title
Journal of Medicinal Chemistry
Volume
vol. 55
Issue
iss. 11
Page start
p. 5311
Page end
p. 5325
Subject
NCMLS 7: Chemical and physical biologyAbstract
We present the systematic prospective evaluation of a protein-based and a ligand-based virtual screening platform against a set of three G-protein-coupled receptors (GPCRs): the beta-2 adrenoreceptor (ADRB2), the adenosine A(2A) receptor (AA2AR), and the sphingosine 1-phosphate receptor (S1PR1). Novel bioactive compounds were identified using a consensus scoring procedure combining ligand-based (frequent substructure ranking) and structure-based (Snooker) tools, and all 900 selected compounds were screened against all three receptors. A striking number of ligands showed affinity/activity for GPCRs other than the intended target, which could be partly attributed to the fuzziness and overlap of protein-based pharmacophore models. Surprisingly, the phosphodiesterase 5 (PDE5) inhibitor sildenafil was found to possess submicromolar affinity for AA2AR. Overall, this is one of the first published prospective chemogenomics studies that demonstrate the identification of novel cross-pharmacology between unrelated protein targets. The lessons learned from this study can be used to guide future virtual ligand design efforts.
This item appears in the following Collection(s)
- Academic publications [238430]
- Electronic publications [122512]
- Faculty of Medical Sciences [90359]
Upload full text
Use your RU credentials (u/z-number and password) to log in with SURFconext to upload a file for processing by the repository team.