A combination of pharmacophore modeling, molecular docking, and virtual screening for P2Y12 receptor antagonists from Chinese herbs

2015 ◽  
Vol 93 (3) ◽  
pp. 311-316 ◽  
Author(s):  
Yusu He ◽  
Ludi Jiang ◽  
Zhen Yang ◽  
Yanjiang Qiao ◽  
Yanling Zhang
Keyword(s):  
Drug Target ◽  
Thrombus Formation ◽  
Pharmacophore Modeling ◽  
G Protein Coupled Receptors ◽  
Chinese Herbs ◽  
Receptor Antagonists ◽  
Hydrogen Bond Acceptor ◽  
Reliable Source ◽  
G Protein Coupled ◽  
Pharmacophore Models

P2Y12, a member of the G-protein-coupled receptors, is associated with abnormal platelet aggregation, a condition that contributes to thrombus formation. As receptor antagonists are effective solutions for anti-thrombus, the P2Y12 receptor is a popular drug target. After the recent resolution of the P2Y12 receptor’s crystal structure, pharmacophore modeling and docking were combined to discover potential natural antagonists. Various approaches were used for the validation of the pharmacophore models and the optimization of docking algorithms. Hypo18, which was generated by 24 known antagonists, was determined to be the best hypothesis and is comprised of one ring aromatic, one hydrogen bond acceptor, one exclude volume, and three hydrophobic features. Hypo18 was thus utilized to screen TCMD (version 2009) to identify any potential active compounds, which then resulted in a hit list of 121 compounds with drug-likeness analysis. In addition, docking was used to refine the pharmacophore-based screening results as a cross-linking method. Then, the top 20 compounds with high docking scores were reserved. This paper provides a reliable source for discovering natural P2Y12 receptor antagonists from traditional Chinese herbs.

Promiscuous drugs as therapeutics for chemokine receptors

2009 ◽  
Vol 11 ◽  
Author(s):  
Richard Horuk
Keyword(s):  
Chemokine Receptor ◽  
Chemokine Receptors ◽  
Drug Target ◽  
Inflammatory Diseases ◽  
Molecular Target ◽  
G Protein Coupled Receptors ◽  
Pharmaceutical Companies ◽  
Receptor Antagonists ◽  
Autoimmune And Inflammatory Diseases ◽  
G Protein Coupled

Chemokine receptor antagonists that held much promise for the treatment of autoimmune and inflammatory diseases have recently performed poorly in clinical trials, resulting in disappointment for both pharmaceutical companies and patients. This review focuses on the redundancy of the molecular target as one potential reason for the failure of some of these antagonists to fulfil their initial promise, and discusses the use of drugs that are capable of interacting with more than one drug target – so-called promiscuous drugs – as possible approaches to overcome this difficulty. Several clinically approved promiscuous drugs, such as aspirin and olanzapine, are already used successfully. This review discusses examples of promiscuous drugs for G-protein-coupled receptors, including progress in developing dual-specific chemokine receptor antagonists, and considers evidence for the possible therapeutic utility of such drugs.

Current Status in the Design and Development of Agonists and Antagonists of Adenosine A3 Receptor as Potential Therapeutic Agents

2019 ◽  
Vol 25 (25) ◽  
pp. 2772-2787 ◽  
Author(s):  
Raghu P. Mailavaram ◽  
Omar H.A. Al-Attraqchi ◽  
Supratik Kar ◽  
Shinjita Ghosh
Keyword(s):  
Drug Target ◽  
Therapeutic Agents ◽  
G Protein Coupled Receptors ◽  
Current Status ◽  
Renal Diseases ◽  
Adenosine A3 Receptor ◽  
Drug Candidates ◽  
Novel Drugs ◽  
The Family ◽  
G Protein Coupled

Adenosine receptors (ARs) belongs to the family of G-protein coupled receptors (GPCR) that are responsible for the modulation of a wide variety of physiological functions. The ARs are also implicated in many diseases such as cancer, arthritis, cardiovascular and renal diseases. The adenosine A3 receptor (A3AR) has emerged as a potential drug target for the progress of new and effective therapeutic agents for the treatment of various pathological conditions. This receptor’s involvement in many diseases and its validity as a target has been established by many studies. Both agonists and antagonists of A3AR have been extensively investigated in the last decade with the goal of developing novel drugs for treating diseases related to immune disorders, inflammation, cancer, and others. In this review, we shall focus on the medicinal chemistry of A3AR ligands, exploring the diverse chemical classes that have been projected as future leading drug candidates. Also, the recent advances in the therapeuetic applications of A3AR ligands are highlighted.

Drug-Target Residence Time-A Case for G Protein-Coupled Receptors

2014 ◽  
Vol 34 (4) ◽  
pp. 856-892 ◽  
Author(s):  
Dong Guo ◽  
Julia M. Hillger ◽  
Adriaan P. IJzerman ◽  
Laura H. Heitman
Keyword(s):  
G Protein ◽  
Residence Time ◽  
Drug Target ◽  
G Protein Coupled Receptors ◽  
G Protein Coupled

scholarly journals The tyrosine phosphatase CD148 is an essential positive regulator of platelet activation and thrombosis

Blood ◽  
2009 ◽  
Vol 113 (20) ◽  
pp. 4942-4954 ◽  
Author(s):  
Yotis A. Senis ◽  
Michael G. Tomlinson ◽  
Stuart Ellison ◽  
Alexandra Mazharian ◽  
Jenson Lim ◽  
...  
Keyword(s):  
G Protein ◽  
Platelet Activation ◽  
Drug Target ◽  
Tyrosine Phosphatase ◽  
Underlying Mechanism ◽  
G Protein Coupled Receptors ◽  
Bleeding Tendency ◽  
Platelet Surface ◽  
Surface Receptors ◽  
G Protein Coupled

Abstract Platelets play a fundamental role in hemostasis and thrombosis. They are also involved in pathologic conditions resulting from blocked blood vessels, including myocardial infarction and ischemic stroke. Platelet adhesion, activation, and aggregation at sites of vascular injury are regulated by a diverse repertoire of tyrosine kinase–linked and G protein–coupled receptors. Src family kinases (SFKs) play a central role in initiating and propagating signaling from several platelet surface receptors; however, the underlying mechanism of how SFK activity is regulated in platelets remains unclear. CD148 is the only receptor-like protein tyrosine phosphatase identified in platelets to date. In the present study, we show that mutant mice lacking CD148 exhibited a bleeding tendency and defective arterial thrombosis. Basal SFK activity was found to be markedly reduced in CD148-deficient platelets, resulting in a global hyporesponsiveness to agonists that signal through SFKs, including collagen and fibrinogen. G protein–coupled receptor responses to thrombin and other agonists were also marginally reduced. These results highlight CD148 as a global regulator of platelet activation and a novel antithrombotic drug target.

scholarly journals Platelet Signaling in Primary Haemostasis and Arterial Thrombus Formation: Part 2

2018 ◽  
Vol 38 (04) ◽  
pp. 211-222
Author(s):  
Rüdiger Scharf
Keyword(s):  
Thrombus Formation ◽  
Fluid Phase ◽  
G Protein Coupled Receptors ◽  
Microbial Pathogens ◽  
Extracellular Traps ◽  
Signaling Mechanisms ◽  
Arterial Thrombus ◽  
Platelet Signaling ◽  
Genetically Determined ◽  
G Protein Coupled

AbstractPlatelet signal transduction is the focus of this review. While ‘classic’ platelet signaling through G protein–coupled receptors in response to fluid-phase agonists has been extensively studied, signaling mechanisms linking platelet adhesion receptors such as GPIb-IX-V, GPVI and α2β1 to the activation of αIIbβ3 are less well established. Moreover, ‘non-haemostatic’ pathways can also activate platelets in various settings, including platelet–immune or platelet–tumour cell interactions, platelet responses to neutrophil extracellular traps, or stimulation by microbial pathogens. Genetically determined integrin variants can modulate platelet function and increase thrombogenicity. A typical example is the Pro33 (HPA-1b) variant of αIIbβ3. Recent advances in the genotype–phenotype relation of this prothrombotic variant and its impact on outside-in signaling will be reviewed.

Challenges in Design and Development of PAR Inhibitors

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. SCI-45-SCI-45
Author(s):  
Patricia Andrade-Gordon
Keyword(s):  
Drug Target ◽  
Human Platelet ◽  
Bleeding Risk ◽  
G Protein Coupled Receptors ◽  
Protease Activated Receptors ◽  
Small Molecule Antagonist ◽  
Clinical Benefits ◽  
Platelet Aggregates ◽  
G Protein Coupled ◽  
Sustained Activation

Abstract Abstract SCI-45 Inappropriate and sustained activation of platelets is a major cause of vascular occlusive diseases such as angina, myocardial infarction, and stroke. The development of thrombi within blood vessels results from the formation of platelet aggregates and fibrin deposits, and heavily depends on the actions of α-thrombin. It is now well recognized that human platelet responses to α-thrombin are mediated by the protease-activated receptors PAR1 and PAR4. Protease-activated receptors (PARs) represent a unique family of seven-transmembrane G-protein-coupled receptors, which are enzymatically cleaved to expose a new extracellular N-terminus that acts as a “tethered” activating ligand. Since the discovery of PAR1 as the major contributor to human platelet aggregation, there has been a keen interest to develop antagonist as potential antithrombotics. However, there have been many issues and challenges in this endeavor. One crucial challenge to the discovery of potent antagonists is the strong entropy advantage offered by the intramolecular binding mechanism of PARs activation, which presents a great disadvantage to a circulating small molecule antagonist. To be an effective therapeutic agent, a PAR1 antagonist not only should bind tightly to the receptor but also possess suitable binding kinetics. Another issue for the discovery of PAR1 antagonists is the preclinical logistics associated with species variability of PAR1 on platelets. Despite these challenges, PAR1 has been an attractive drug target and there has been considerable activity and progress in the discovery and development of PAR1 antagonist as therapeutic agents. The promise of these novel therapeutics is reflected by two antiplatelet PAR1 antagonists in advanced clinical trials. The clinical benefits derived from these agents will be determined by the tight balance between delivering efficacy in the context of thrombotic disease and controlling the bleeding risk. The discussion will focus on the challenges from discovery to development of these great potential opportunities in the prevention of atherothrombotic disease. Disclosures: Andrade-Gordon: Johnson & Johnson: Employment.

Continuous signaling via PI3K isoforms β and γ is required for platelet ADP receptor function in dynamic thrombus stabilization

Blood ◽  
2006 ◽  
Vol 108 (9) ◽  
pp. 3045-3052 ◽  
Author(s):  
Judith M. E. M. Cosemans ◽  
Imke C. A. Munnix ◽  
Reinhard Wetzker ◽  
Regine Heller ◽  
Shaun P. Jackson ◽  
...  
Keyword(s):  
Thrombus Formation ◽  
G Protein Coupled Receptors ◽  
Platelet Aggregate ◽  
Platelet Aggregates ◽  
Adp Receptor ◽  
Phosphoinositide 3 Kinase ◽  
Novel Concept ◽  
Induced Aggregation ◽  
G Protein Coupled ◽  
Intrinsic Dynamic

Abstract Signaling from collagen and G protein–coupled receptors leads to platelet adhesion and subsequent thrombus formation. Paracrine agonists such as ADP, thromboxane, and Gas6 are required for platelet aggregate formation. We hypothesized that thrombi are intrinsically unstable structures and that their stabilization requires persistent paracrine activity and continuous signaling, maintaining integrin αIIbβ3 activation. Here, we studied the disassembly of human and murine thrombi formed on collagen under high shear conditions. Platelet aggregates rapidly disintegrated (1) in the absence of fibrinogen-containing plasma; (2) by blocking or inhibiting αIIbβ3; (3) by blocking P2Y12 receptors; (4) by suppression of phosphoinositide 3-kinase (PI3K) β. In murine blood, absence of PI3Kγ led to formation of unstable thrombi, leading to dissociation of multiplatelet aggregates. In addition, blocking PI3Kβ delayed initial thrombus formation and reduced individual platelet-platelet contact. Similarly without flow, agonist-induced aggregation was reversed by late suppression of P2Y12 or PI3K isoforms, resulting in single platelets that had inactivated αIIbβ3 and no longer bound fibrinogen. Together, the data indicate that continuous outside-in signaling via P2Y12 and both PI3Kβ and PI3Kγ isoforms is required for perpetuated αIIbβ3 activation and maintenance of a platelet aggregate. This novel concept of intrinsic, dynamic thrombus instability gives possibilities for the use of antiplatelet therapy.

Dual-targeting approach on histamine H3 and sigma-1 receptor ligands as promising pharmacological tools in the treatment of CNS-linked disorders

2020 ◽  
Vol 27 ◽  
Author(s):  
Katarzyna Szczepańska ◽  
Kamil J. Kuder ◽  
Katarzyna Kieć-Kononowicz
Keyword(s):  
G Protein Coupled Receptors ◽  
Receptor Ligands ◽  
Receptor Antagonists ◽  
Histamine H3 Receptor ◽  
Sigma 1 Receptor ◽  
Biological Targets ◽  
H3 Receptor ◽  
Sigma 1 ◽  
G Protein Coupled ◽  
Histamine H3

: With the recent market approval of Pitolisant (Wakix®), the interest in clinical application for novel multifunctional histamine H3 receptor antagonists has clearly increased. Several combinations of different H3R pharmacophores with pharmacophoric elements of other G-protein coupled receptors, transporters or enzymes have been synthesized by numerous pharmaceutical companies and academic institutions. Since central nervous system disorders are characterized by diverse physiological dysfunctions and deregulations of a complex network of signaling pathways, optimal multipotent drugs should simultaneously and peculiary modulate selected groups of biological targets. Interestingly, very recent studies have shown that some of clinically evaluated histamine H3 receptor antagonists possess nanomolar affinity for sigma-1 receptor binding sites, suggesting that this property might play a role in their overall efficacy. The sigma-1 receptor, unusual and yet obscure protein, is supposed to be involved in numerous CNS pathologies through neuroprotection and neuroplasticity. These two different biological structures, histamine H3 and sigma-1 receptors, combined can represent potential fruitful target for therapeutic developments in tackling numerous human diseases.

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