Structure-Based Discovery of A(2A) Adenosine Receptor Ligands

Department of Pharmaceutical Chemistry, University of California, 1700 4th Street, Box 2550, San Francisco, California 94158, USA.
Journal of Medicinal Chemistry (Impact Factor: 5.45). 05/2010; 53(9):3748-55. DOI: 10.1021/jm100240h
Source: PubMed


The recent determination of X-ray structures of pharmacologically relevant GPCRs has made these targets accessible to structure-based ligand discovery. Here we explore whether novel chemotypes may be discovered for the A(2A) adenosine receptor, based on complementarity to its recently determined structure. The A(2A) adenosine receptor signals in the periphery and the CNS, with agonists explored as anti-inflammatory drugs and antagonists explored for neurodegenerative diseases. We used molecular docking to screen a 1.4 million compound database against the X-ray structure computationally and tested 20 high-ranking, previously unknown molecules experimentally. Of these 35% showed substantial activity with affinities between 200 nM and 9 microM. For the most potent of these new inhibitors, over 50-fold specificity was observed for the A(2A) versus the related A(1) and A(3) subtypes. These high hit rates and affinities at least partly reflect the bias of commercial libraries toward GPCR-like chemotypes, an issue that we attempt to investigate quantitatively. Despite this bias, many of the most potent new ligands were novel, dissimilar from known ligands, providing new lead structures for modulation of this medically important target.

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    • "The energy contributions were extracted from precalculated grids (Irwin et al., 2009). Additionally, the side chain dipole moments of several residues in the orthosteric site (5-HT 1B receptor: Thr134 3.37 , Thr209 5.39 , Ser211 5.42 , Thr212 5.43 , and Ser334 6.55 ; 5-HT 2B receptor: Thr140 3.37 , Ser222 5.43 , and Asn344 6.55 ) were increased as previously described (Carlsson et al., 2010; Weiss et al., 2013). The desolvation penalty for a ligand conformation was estimated from a precalculated grid of the transfer free energy of each docked molecule from aqueous solution to a low-dielectric medium (Mysinger and Shoichet, 2010). "
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    ABSTRACT: The development of safe and effective drugs relies on the discovery of selective ligands. Serotonin (5-hydroxytryptamine [5-HT]) G protein-coupled receptors are therapeutic targets for CNS disorders but are also associated with adverse drug effects. The determination of crystal structures for the 5-HT1B and 5-HT2B receptors provided an opportunity to identify subtype selective ligands using structure-based methods. From docking screens of 1.3 million compounds, 22 molecules were predicted to be selective for the 5-HT1B receptor over the 5-HT2B subtype, a requirement for safe serotonergic drugs. Nine compounds were experimentally verified as 5-HT1B-selective ligands, with up to 300-fold higher affinities for this subtype. Three of the ligands were agonists of the G protein pathway. Analysis of state-of-the-art homology models of the two 5-HT receptors revealed that the crystal structures were critical for predicting selective ligands. Our results demonstrate that structure-based screening can guide the discovery of ligands with specific selectivity profiles.
    Structure 07/2014; 22(8):1140–1151. DOI:10.1016/j.str.2014.05.017 · 5.62 Impact Factor
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    • "An inactive state structure of the A 2A AR was applied to in silico searches of diverse chemical libraries to identify antagonists of several AR subtypes. This approach has been useful for discovery of antagonists at both the A 2A AR (Katritch et al. 2010; Carlsson et al. 2010; van der Horst et al. 2011; Congreve et al. 2012; Langmead et al. 2012) and the closely related A 1 and A 3 ARs, by homology. Four separate homology models of the human A 1 AR were built based on optimization with different bound (known) ligands of that subtype, and 2.2 million lead-like compounds were docked in all four models (Kolb et al. 2012). "
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    ABSTRACT: New insights into drug design are derived from the X-ray crystallographic structures of G protein-coupled receptors (GPCRs), and the adenosine receptors (ARs) are at the forefront of this effort. The 3D knowledge of receptor binding and activation promises to enable drug discovery for GPCRs in general, and specifically for the ARs. The predictability of modeling based on the X-ray structures of the A2AAR has been well demonstrated in the identification, design and modification of both known and novel AR agonists and antagonists. It is expected that structure-based design of drugs acting through ARs will provide new avenues to clinically useful agents.
    12/2013; 1:22. DOI:10.1186/2193-9616-1-22
    • "An error in the alignment of extracellular loop 2 (EL2) is shown in Figure S3. EL2 plays a key role in receptor activation and ligand binding (Barwell et al., 2013; Ivanov, Barak, & Jacobson, 2009) and errors in EL2 have been shown to limit the development and use of GPCR homology models (Ivanov et al., 2009), which can otherwise be useful in both the study of receptor activation and in docking studies to identify novel ligands (Carlsson et al., 2010; Katritch et al., 2010; Taddese , Simpson, Wall, Blaney, & Reynolds, 2013). "
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