3D Pharmacophore Based Virtual Screening of A2A Adenosine Receptor Antagonists

Wei, Jing; Qu, Wanlu; Ye, Yingda; Gao, Qingzhi

doi:10.2174/092986610790780260

Cited by 8 publications

(8 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Prior to this, homology models were constructed from the structures of other GPCRs, 125 for example, the X-ray structure of the β2 adrenergic receptor, 126 and other methods were also used, such as ligandbased approaches that built on the prior knowledge of A 2A receptor ligands. 127 Furthermore, homology models of all four adenosine receptor subtypes (A 1 , A 2A , A 2B , and A 3 ) have been used to perform in silico predictions of selectivity, 128,129 but such examples of pan-selectivity predictions and optimizations are relatively rare and may be improved by the availability of X-ray structures of the other subtypes.…”

Section: Virtual Screening At the Adenosine A 2a Receptormentioning

confidence: 99%

Structurally Enabled Discovery of Adenosine A_2A Receptor Antagonists

2016

View full text Add to dashboard Cite

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.

show abstract

Section: Virtual Screening At the Adenosine A 2a Receptormentioning

confidence: 99%

Structurally Enabled Discovery of Adenosine A_2A Receptor Antagonists

2016

View full text Add to dashboard Cite

show abstract

“…Mounting evidence indicates the advantage of incorporating protein-ligand interactions over the analysis with conventional ligand information alone. Here, we have used the inhibitor library for each protein to probe the pharmacophoric features that are necessary for the selective inhibition of Gsk3β [47][48][49][50]. This method has the advantage of combining pharmacophore perception with protein-ligand energetic terms to rank the importance of pharmacophore features.…”

Section: Resultsmentioning

confidence: 99%

“…Pharmacophore-based methods have been widely used in virtual screening [48,[50][51][52][53][54]. Application of structure-based pharmacophore in VS provides an advantage over the ligandbased pharmacophore approach as it uses the spatial information of the target protein for topological description of ligand-receptor interactions.…”

Section: Virtual Screeningmentioning

confidence: 99%

A rational approach to selective pharmacophore designing: an innovative strategy for specific recognition of Gsk3β

Pradeep

Rajanikant

2012

Mol Divers

View full text Add to dashboard Cite

We propose a novel cheminformatics approach that combines structure and ligand-based design to identify target-specific pharmacophores with well-defined exclusion ability. Our strategy includes the prediction of selective interactions, developing structure, and knowledge-based selective pharmacophore models, followed by database screening and molecular docking. This unique strategy was employed in addressing the off-target toxicity of Gsk3β and CDKs. The connections of Gsk3β in eukaryotic cell apoptosis and the extensive potency of Gsk3β inhibitors to block cell death have made it a potential drug-discovery target for many grievous human disorders. Gsk3β is phylogenetically very closely related to the CDKs, such as CDK1 and CDK2, which are suggested to be the off-target proteins of Gsk3β inhibitors. Here, we have employed novel computational approaches in designing the ligand candidates that are potentially inhibitory against Gsk3β, with well-defined the exclusion ability to CDKs. A structure-ligand -based selective pharmacophore was modeled. This model was used to retrieve molecules from the zinc database. The hits retrieved were further screened by molecular docking and protein-ligand interaction fingerprints. Based on these results, four molecules were predicted as selective Gsk3β antagonists. It is anticipated that this unique approach can be extended to investigate any protein-ligand specificity.

show abstract

“…The surprise of that structure was the orientation of the ligand in the binding pocket, which was very different from that of the biogenic amine receptors. These structures have allowed comformational dynamic, docking and virtual screening studies and have contributed to the identification and development of new A 2A receptor ligands, particularly antagonists (Bacilieri et al 2013;Carlsson et al 2010;Pang et al 2013;Rodriguez et al 2015;Wei et al 2010). Three years later, the agonist-bound structure of the A 2A AR in its activated conformation was reported with a similarly high resolution by the same group.…”

Section: Structure Elucidation By X-ray Crystallographymentioning

confidence: 97%