Optimization of Adenosine 5′-Carboxamide Derivatives as Adenosine Receptor Agonists Using Structure-Based Ligand Design and Fragment Screening

Tosh, Dilip K.; Phan, Khai; Gao, Zhan‐Guo; Gakh, Andrei A.; Xu, Fei; Deflorian, Francesca; Abagyan, Ruben; Stevens, Raymond C.; Katritch, Vsevolod

doi:10.1021/jm300095s

Cited by 54 publications

(52 citation statements)

References 66 publications

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“…141 By this approach, a library of 2000 compounds was enumerated in silico, by linking fragments (MW < 150) to adenosine-5′-carboxamide and then docking the resulting adducts. From this set, 16 compounds were synthesized and tested in biological assays and 15 of them were found to have submicromolar affinity for the adenosine A 2A receptor, including 23, which was the highest affinity compound identified (A 2A pK i 7.5; Figure 4).…”

Section: Virtual Screening At the Adenosine A 2a Receptormentioning

confidence: 99%

Structurally Enabled Discovery of Adenosine A_2A Receptor Antagonists

2016

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Over the past decade there has been a revolution in the field of G protein-coupled receptor (GPCR) structural biology. Many years of innovative research from different areas have come together to fuel this significant change in the fortunes of this field, which for many years was characterized by the paucity of high-resolution structures. The determination to succeed has been in part due to the recognized importance of these proteins as drug targets, and although the pharmaceutical industry has been focusing on these receptors, it can be justifiably argued and demonstrated that many of the approved and commercially successful GPCR drugs can be significantly improved to increase efficacy and/or reduce undesired side effects. In addition, many validated targets in this class remain to be drugged. It is widely recognized that application of structure-based drug design approaches can help medicinal chemists a long way toward discovering better drugs. The achievement of structural biologists in providing high-resolution insight is beginning to transform drug discovery efforts, and there are a number of GPCR drugs that have been discovered by use of structural information that are in clinical development. This review aims to highlight the key developments that have brought success to GPCR structure resolution efforts and exemplify the practical application of structural information for the discovery of adenosine A receptor antagonists that have potential to treat multiple conditions.

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Section: Virtual Screening At the Adenosine A 2a Receptormentioning

confidence: 99%

Structurally Enabled Discovery of Adenosine A_2A Receptor Antagonists

2016

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“…In this context, in recent studies, the structure of a known GPCR agonist was systematically varied using the ICM software (Internal Coordinate Mechanics; Molsoft LLC, San Diego, CA). A library of 2000 small fragments was screened in silico for fit within a small pocket, to successfully predict those favoring adenosine receptor affinity when linked to the 5Ј-carbonyl group of modified adenosine (Tosh et al, 2012).…”

Section: Structure-based Discovery Of Gpcr Ligands Is Increasingly Momentioning

confidence: 99%

New Insights for Drug Design from the X-Ray Crystallographic Structures of G-Protein-Coupled Receptors

Jacobson

Costanzi

2012

Molecular Pharmacology

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Methodological advances in X-ray crystallography have made possible the recent solution of X-ray structures of pharmaceutically important G protein-coupled receptors (GPCRs), including receptors for biogenic amines, peptides, a nucleoside, and a sphingolipid. These high-resolution structures have greatly increased our understanding of ligand recognition and receptor activation. Conformational changes associated with activation common to several receptors entail outward movements of the intracellular side of transmembrane helix 6 (TM6) and movements of TM5 toward TM6. Movements associated with specific agonists or receptors have also been described [e.g., extracellular loop (EL) 3 in the A 2A adenosine receptor]. The binding sites of different receptors partly overlap but differ significantly in ligand orientation, depth, and breadth of contact areas in TM regions and the involvement of the ELs. A current challenge is how to use this structural information for the rational design of novel potent and selective ligands. For example, new chemotypes were discovered as antagonists of various GPCRs by subjecting chemical libraries to in silico docking in the X-ray structures. The vast majority of GPCR structures and their ligand complexes are still unsolved, and no structures are known outside of family A GPCRs. Molecular modeling, informed by supporting information from site-directed mutagenesis and structure-activity relationships, has been validated as a useful tool to extend structural insights to related GPCRs and to analyze docking of other ligands in already crystallized GPCRs.

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“…The utility of GPCR structures in the identification of novel antagonists and inverse agonist chemotypes has been demonstrated by structure-based virtual screening campaigns, where hit rates as high as 20 to 70% have been observed (Kolb et al, 2009;Carlsson et al, 2010Carlsson et al, , 2011Katritch et al, 2010;de Graaf et al, 2011a;Jacobson and Costanzi, 2012;Mysinger et al, 2012). Active state structures of GPCRs have also been successfully used in virtual screening and structure-based rational design of agonists (Vilar et al, 2011;Shoichet and Kobilka, 2012;Tosh et al, 2012;Weiss et al, 2013). However, the utility of crystal structures in the discovery of new allosteric and bitopic (hybrid allosteric-orthosteric) GPCR ligands has yet to be established.…”

Section: Introductionmentioning

confidence: 99%

Structure-Based Ligand Discovery Targeting Orthosteric and Allosteric Pockets of Dopamine Receptors

Lane

Chubukov²,

Liu³

et al. 2013

Molecular Pharmacology

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Small molecules targeting allosteric pockets of G proteincoupled receptors (GPCRs) have a great therapeutic potential for the treatment of neurologic and other chronic disorders. Here we performed virtual screening for orthosteric and putative allosteric ligands of the human dopamine D 3 receptor (D3R) using two optimized crystal-structure-based models: the receptor with an empty binding pocket (D3R APO ), and the receptor complex with dopamine (D3R Dopa ). Subsequent biochemical and functional characterization revealed 14 novel ligands with a binding affinity of better than 10 mM in the D3R APO candidate list (56% hit rate), and 8 novel ligands in the D3R Dopa list (32% hit rate). Most ligands in the D3R APO model span both orthosteric and extended pockets and behave as antagonists at D3R, with compound 7 showing the highest potency of dopamine inhibition (IC 50 5 7 nM). In contrast, compounds identified by the D3R Dopa model are predicted to occupy an allosteric site at the extracellular extension of the pocket, and they all lack the anchoring amino group. Compounds targeting the allosteric site display a variety of functional activity profiles, where behavior of at least two compounds (23 and 26) is consistent with noncompetitive allosteric modulation of dopamine signaling in the extracellular signal-regulated kinase 1 and 2 phosphorylation and b-arrestin recruitment assays. The high affinity and ligand efficiency of the chemically diverse hits identified in this study suggest utility of structure-based screening targeting allosteric sites of GPCRs.

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Optimization of Adenosine 5′-Carboxamide Derivatives as Adenosine Receptor Agonists Using Structure-Based Ligand Design and Fragment Screening

Cited by 54 publications

References 66 publications

Structurally Enabled Discovery of Adenosine A_2A Receptor Antagonists

Structurally Enabled Discovery of Adenosine A_2A Receptor Antagonists

New Insights for Drug Design from the X-Ray Crystallographic Structures of G-Protein-Coupled Receptors

Structure-Based Ligand Discovery Targeting Orthosteric and Allosteric Pockets of Dopamine Receptors

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Optimization of Adenosine 5′-Carboxamide Derivatives as Adenosine Receptor Agonists Using Structure-Based Ligand Design and Fragment Screening

Cited by 54 publications

References 66 publications

Structurally Enabled Discovery of Adenosine A2A Receptor Antagonists

Structurally Enabled Discovery of Adenosine A2A Receptor Antagonists

New Insights for Drug Design from the X-Ray Crystallographic Structures of G-Protein-Coupled Receptors

Structure-Based Ligand Discovery Targeting Orthosteric and Allosteric Pockets of Dopamine Receptors

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Structurally Enabled Discovery of Adenosine A_2A Receptor Antagonists

Structurally Enabled Discovery of Adenosine A_2A Receptor Antagonists