title: In search of novel ligands using a structure-based approach: a case study on the adenosine A2Areceptor.
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 A2Areceptor (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 A2Areceptor 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.
authors.affiliation: Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands.
authors.forename: Eelke B
authors.initials: EB
authors.lastname: Lenselink
authors.affiliation: Schrödinger, Inc., 120 West 45th Street, New York, NY, 10036, USA.
authors.forename: Thijs
authors.initials: T
authors.lastname: Beuming
authors.affiliation: Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands.
authors.forename: Corine
authors.initials: C
authors.lastname: van Veen
authors.affiliation: Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands.
authors.forename: Arnault
authors.initials: A
authors.lastname: Massink
authors.affiliation: Schrödinger, Inc., 120 West 45th Street, New York, NY, 10036, USA.
authors.forename: Woody
authors.initials: W
authors.lastname: Sherman
authors.affiliation: Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands.
authors.forename: Herman W T
authors.initials: HW
authors.lastname: van Vlijmen
authors.affiliation: Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands. ijzerman@lacdr.leidenuniv.nl.
authors.forename: Adriaan P
authors.initials: AP
authors.lastname: IJzerman
mesh_terms: D058908:Adenosine A2 Receptor Agonists / Q000737:chemistry; D058917:Adenosine A2 Receptor Antagonists / Q000737:chemistry; D001665:Binding Sites; D003198:Computer Simulation; D016208:Databases, Factual; D004353:Drug Evaluation, Preclinical; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011869:Radioligand Assay; D043705:Receptor, Adenosine A2A / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014867:Water
chemical_list: D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D008024:Ligands; D043705:Receptor, Adenosine A2A; D014867:Water
keywords: Adenosine A2A receptor; Diverse chemical space; Explicit water; Novel ligand; Virtual screening