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Special Issue "Allosteric Modulators"

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A special issue of Pharmaceuticals (ISSN 1424-8247).

Deadline for manuscript submissions: closed (15 April 2014)

Special Issue Editor

Guest Editor
Dr. Marlene A. Jacobson

Moulder Center for Drug Discovery Research, Temple University School Of Pharmacy, 3307 North Broad Street, Philadelphia, PA 19140, USA
Website | E-Mail
Interests: allosteric modulators of G-protein coupled receptors including muscarinic and metabotropic glutamate receptors

Special Issue Information

Dear Colleagues,

Recent advancements in the discovery of allosteric modulators for G protein-coupled receptors (GPCRs) and kinases have revolutionized drug discovery and development. While most currently marketed drugs bind to the orthosteric site for the endogenous ligand, allosteric modulators bind to topographically distinct sites. Orthosteric sites are in general highly conserved across protein superfamilies and identification of highly selective ligands is challenging. Targeting allosteric sites on GPCRs and kinases has emerged as a successful strategy for identification of highly selective ligands with therapeutic utility for the treatment of disease states which previously could not be addressed due to inability to identify subtype selective ligands. In recent years, the discovery of GPCR allosteric modulators as treatments for CNS disorders including schizophrenia, Fragile X and Alzheimer’s disease and allosteric inhibitors for kinases have advanced into clinical development. This special issue invites original research including review articles on the pharmacology, chemical biology and medicinal chemistry of allosteric modulators including assay development and screening technologies, mechanism of action, structural features of binding sites and clinical research and development.

Dr. Marlene A. Jacobson
Guest Editor

Submission

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed Open Access quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 800 CHF (Swiss Francs).

Keywords

  • allosteric modulation
  • drug discovery
  • G protein coupled receptors
  • kinases
  • positive allosteric modulator
  • negative allosteric modulator
  • allosteric inhibitor
  • bitopic ligand
  • pharmacology

Published Papers (3 papers)

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Research

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Open AccessArticle Structural Bioinformatics and Protein Docking Analysis of the Molecular Chaperone-Kinase Interactions: Towards Allosteric Inhibition of Protein Kinases by Targeting the Hsp90-Cdc37 Chaperone Machinery
Pharmaceuticals 2013, 6(11), 1407-1428; doi:10.3390/ph6111407
Received: 29 July 2013 / Revised: 30 October 2013 / Accepted: 5 November 2013 / Published: 11 November 2013
Cited by 2 | PDF Full-text (879 KB) | HTML Full-text | XML Full-text
Abstract
A fundamental role of the Hsp90-Cdc37 chaperone system in mediating maturation of protein kinase clients and supporting kinase functional activity is essential for the integrity and viability of signaling pathways involved in cell cycle control and organism development. Despite significant advances in understanding
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A fundamental role of the Hsp90-Cdc37 chaperone system in mediating maturation of protein kinase clients and supporting kinase functional activity is essential for the integrity and viability of signaling pathways involved in cell cycle control and organism development. Despite significant advances in understanding structure and function of molecular chaperones, the molecular mechanisms and guiding principles of kinase recruitment to the chaperone system are lacking quantitative characterization. Structural and thermodynamic characterization of Hsp90-Cdc37 binding with protein kinase clients by modern experimental techniques is highly challenging, owing to a transient nature of chaperone-mediated interactions. In this work, we used experimentally-guided protein docking to probe the allosteric nature of the Hsp90-Cdc37 binding with the cyclin-dependent kinase 4 (Cdk4) kinase clients. The results of docking simulations suggest that the kinase recognition and recruitment to the chaperone system may be primarily determined by Cdc37 targeting of the N-terminal kinase lobe. The interactions of Hsp90 with the C-terminal kinase lobe may provide additional “molecular brakes” that can lock (or unlock) kinase from the system during client loading (release) stages. The results of this study support a central role of the Cdc37 chaperone in recognition and recruitment of the kinase clients. Structural analysis may have useful implications in developing strategies for allosteric inhibition of protein kinases by targeting the Hsp90-Cdc37 chaperone machinery. Full article
(This article belongs to the Special Issue Allosteric Modulators)

Review

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Open AccessReview Allosteric Modulation of GABAA Receptors by an Anilino Enaminone in an Olfactory Center of the Mouse Brain
Pharmaceuticals 2014, 7(12), 1069-1090; doi:10.3390/ph7121069
Received: 15 April 2014 / Revised: 24 November 2014 / Accepted: 4 December 2014 / Published: 17 December 2014
Cited by 2 | PDF Full-text (1124 KB) | HTML Full-text | XML Full-text
Abstract
In an ongoing effort to identify novel drugs that can be used as neurotherapeutic compounds, we have focused on anilino enaminones as potential anticonvulsant agents. Enaminones are organic compounds containing a conjugated system of an amine, an alkene and a ketone. Here, we
[...] Read more.
In an ongoing effort to identify novel drugs that can be used as neurotherapeutic compounds, we have focused on anilino enaminones as potential anticonvulsant agents. Enaminones are organic compounds containing a conjugated system of an amine, an alkene and a ketone. Here, we review the effects of a small library of anilino enaminones on neuronal activity. Our experimental approach employs an olfactory bulb brain slice preparation using whole-cell patch-clamp recording from mitral cells in the main olfactory bulb. The main olfactory bulb is a key integrative center in the olfactory pathway. Mitral cells are the principal output neurons of the main olfactory bulb, receiving olfactory receptor neuron input at their dendrites within glomeruli, and projecting glutamatergic axons through the lateral olfactory tract to the olfactory cortex. The compounds tested are known to be effective in attenuating pentylenetetrazol (PTZ) induced convulsions in rodent models. One compound in particular, KRS-5Me-4-OCF3, evokes potent inhibition of mitral cell activity. Experiments aimed at understanding the cellular mechanism underlying the inhibitory effect revealed that KRS-5Me-4-OCF3 shifts the concentration-response curve for GABA to the left. KRS-5Me-4-OCF3 enhances GABA affinity and acts as a positive allosteric modulator of GABAA receptors. Application of a benzodiazepine site antagonist blocks the effect of KRS-5Me-4-OCF3 indicating that KRS-5Me-4-OCF3 binds at the classical benzodiazepine site to exert its pharmacological action. This anilino enaminone KRS-5Me-4-OCF3 emerges as a candidate for clinical use as an anticonvulsant agent in the battle against epileptic seizures. Full article
(This article belongs to the Special Issue Allosteric Modulators)
Open AccessReview Are AMPA Receptor Positive Allosteric Modulators Potential Pharmacotherapeutics for Addiction?
Pharmaceuticals 2014, 7(1), 29-45; doi:10.3390/ph7010029
Received: 28 October 2013 / Revised: 13 December 2013 / Accepted: 24 December 2013 / Published: 30 December 2013
Cited by 2 | PDF Full-text (280 KB) | HTML Full-text | XML Full-text
Abstract
Positive allosteric modulators (PAMs) of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are a diverse class of compounds that increase fast excitatory transmission in the brain. AMPA PAMs have been shown to facilitate long-term potentiation, strengthen communication between various cortical and subcortical regions, and some of
[...] Read more.
Positive allosteric modulators (PAMs) of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are a diverse class of compounds that increase fast excitatory transmission in the brain. AMPA PAMs have been shown to facilitate long-term potentiation, strengthen communication between various cortical and subcortical regions, and some of these compounds increase the production and release of brain-derived neurotrophic factor (BDNF) in an activity-dependent manner. Through these mechanisms, AMPA PAMs have shown promise as broad spectrum pharmacotherapeutics in preclinical and clinical studies for various neurodegenerative and psychiatric disorders. In recent years, a small collection of preclinical animal studies has also shown that AMPA PAMs may have potential as pharmacotherapeutic adjuncts to extinction-based or cue-exposure therapies for the treatment of drug addiction. The present paper will review this preclinical literature, discuss novel data collected in our laboratory, and recommend future research directions for the possible development of AMPA PAMs as anti-addiction medications. Full article
(This article belongs to the Special Issue Allosteric Modulators)

Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Type of Paper: Review
Title: Cross-antagonism as Example of Allosteric Regulation in G-protein-coupled Receptor Heteromers—Cross-antagonism in GPCR Heteromers
Authors: Rafael Franco
Affiliation: 1 Dept. of Biochem. & Mol. Biol. University of Barcelona. Catalonia. Spain
2 Cell and Mol. Neuropharmacol. Laboratory. Nerusociences division. Center for Applied Medical Research. University of Navarra. Spain
Abstract: G-protein-coupled receptors are expressed on the cell surface as heteromers: from heterodimers to hetero-oligomers. In the simplest case an heterodimer is constituted by two different receptors and, importantly, it provides a novel function, which is not merely the addition of the signaling properties of the individual receptors. Although the ultimate consequences of heteromer formation are still under scrutiny and under debate, it has been already demonstrated how dimerization and/or occupancy of one receptor in the dimer affects the binding of agonists to the partner receptor and/or affects the function of the heteromer. According to the current nomenclature these phenomena are considered allosteric. In fact heterodimers are prone to allosteric regulation, and these two mechanisms come by default. In the report the allosteric consequences of heteromerization and of agonist binding to the orthosteric centers in an heteromer are reviewed. Furthermore cross-antagonism, which is a frequently found allosteric modulation in heteromers, is presented and examples are provided and discussed from a physiological and a pharmacological point of view.

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