Abstract:
:In this work, we present a case study to explore the challenges associated with finding novel molecules for a receptor that has been studied in depth and has a wealth of chemical information available. Specifically, we apply a previously described protocol that incorporates explicit water molecules in the ligand binding site to prospectively screen over 2.5 million drug-like and lead-like compounds from the commercially available eMolecules database in search of novel binders to the adenosine A2A receptor (A2AAR). A total of seventy-one compounds were selected for purchase and biochemical assaying based on high ligand efficiency and high novelty (Tanimoto coefficient ≤0.25 to any A2AAR tested compound). These molecules were then tested for their affinity to the adenosine A2A receptor in a radioligand binding assay. We identified two hits that fulfilled the criterion of ~50 % radioligand displacement at a concentration of 10 μM. Next we selected an additional eight novel molecules that were predicted to make a bidentate interaction with Asn2536.55, a key interacting residue in the binding pocket of the A2AAR. None of these eight molecules were found to be active. Based on these results we discuss the advantages of structure-based methods and the challenges associated with finding chemically novel molecules for well-explored targets.
journal_name
J Comput Aided Mol Desjournal_title
Journal of computer-aided molecular designauthors
Lenselink EB,Beuming T,van Veen C,Massink A,Sherman W,van Vlijmen HW,IJzerman APdoi
10.1007/s10822-016-9963-7subject
Has Abstractpub_date
2016-10-01 00:00:00pages
863-874issue
10eissn
0920-654Xissn
1573-4951pii
10.1007/s10822-016-9963-7journal_volume
30pub_type
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journal_title:Journal of computer-aided molecular design
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