ORCID Profile
0000-0002-2900-828X
Current Organisations
University of Madras - Taramani Campus
,
University of Madras
,
Saveetha Institute of Medical and Technical Sciences [SIMATS], Saveetha University Saveetha Dental College
,
Meenakshi Academy of Higher Education and Research
,
Indian Board of Alternative Medicine
,
Bharathidasan University
,
University of Nottingham
,
Excellerate Bioscience Ltd
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Publications
Extrapyramidal side effects of antipsychotics are linked to their association kinetics at dopamine D2 receptors
Publisher: Springer Science and Business Media LLC
Date: 02-10-2017
DOI: 10.1038/S41467-017-00716-Z
Abstract: Atypical antipsychotic drugs (APDs) have been hypothesized to show reduced extrapyramidal side effects (EPS) due to their rapid dissociation from the dopamine D 2 receptor. However, support for this hypothesis is limited to a relatively small number of observations made across several decades and under different experimental conditions. Here we show that association rates, but not dissociation rates, correlate with EPS. We measured the kinetic binding properties of a series of typical and atypical APDs in a novel time-resolved fluorescence resonance energy transfer assay, and correlated these properties with their EPS and prolactin-elevating liabilities at therapeutic doses. EPS are robustly predicted by a rebinding model that considers the microenvironment of postsynaptic D 2 receptors and integrates association and dissociation rates to calculate the net rate of reversal of receptor blockade. Thus, optimizing binding kinetics at the D 2 receptor may result in APDs with improved therapeutic profile.
THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: G protein-coupled receptors.
Publisher: Wiley
Date: 16-09-2021
DOI: 10.1111/BPH.15538
Abstract: The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at oi/bph.15538. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is ided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
Synthetic routes to the Neuropeptide y Y1 receptor antagonist 1229U91 and related analogues for SAR studies and cell-based imaging
Publisher: Royal Society of Chemistry (RSC)
Date: 2014
DOI: 10.1039/C4OB00176A
Abstract: The potent Y 1 receptor antagonist, 1229U91 has an unusual cyclic dimer structure. We have developed three new routes to the synthesis of analogues. Such variants, including fluorescent conjugates, show potent Y 1 antagonism.
ThermoBRET: a ligand-engagement nanoscale thermostability assay applied to GPCRs
Publisher: Cold Spring Harbor Laboratory
Date: 06-08-2020
DOI: 10.1101/2020.08.05.237982
Abstract: Measurements of membrane protein thermostability allows indirect detection of ligand binding. Current thermostability assays require protein purification or rely on pre-existing radiolabelled or fluorescent ligands, limiting their application to established target proteins. Alternative methods detect protein aggregation which requires sufficiently high level of protein expression. Here, we present a ThermoBRET method to quantify the relative thermostability of G protein coupled receptors (GPCRs), using cannabinoid receptors (CB 1 and CB 2 ) and the β 2 -adrenoceptor (β 2 AR) as model systems. ThermoBRET reports receptor unfolding, does not need labelled ligands and can be used with non-purified proteins. It uses Bioluminescence Resonance Energy Transfer (BRET) between Nanoluciferase (Nluc) and a thiol-reactive fluorescent dye that binds cysteines exposed by unfolding. We demonstrate that the melting point (T m ) of Nluc-fused GPCRs can be determined in non-purified detergent solubilised membrane preparations or solubilised whole cells, revealing differences in thermostability for different solubilising conditions and in the presence of stabilising ligands. We extended the range of the assay by developing the thermostable tsNLuc by incorporating mutations from the fragments of split-Nluc ( T m of 87 ⁰C vs 59 ⁰C). ThermoBRET allows determination of GPCR thermostability, which is useful for protein purification optimisation and as part of drug discovery screening strategies.
Propargyloxyproline Regio- and Stereoisomers for Click-Conjugation of Peptides: Synthesis and Application in Linear and Cyclic Peptides
Publisher: CSIRO Publishing
Date: 2015
DOI: 10.1071/CH15146
Abstract: The use of the click reaction for the introduction of conjugate groups, such as affinity or fluorescent labels, to a peptide for the study of peptide biochemistry and pharmacology is widespread. However, the nature and location of substituted 1,2,3-triazoles in peptide sequences may markedly affect conformation or binding as compared with native sequences. We have examined the preparation and application of propargyloxyproline (Pop) residues as a precursor to such peptide conjugates. Pop residues are available in a range of regio- and stereoisomers from hydroxyproline precursors and are readily prepared in Fmoc-protected form. They can be incorporated routinely in peptide synthesis and broadly retain the conformational properties of the parent proline containing peptides. This is exemplified by the preparation of biotin- and fluorophore-labelled peptides derived from linear and cyclic peptides.
A G Protein–Coupled Receptor Dimer Imaging Assay Reveals Selectively Modified Pharmacology of Neuropeptide Y Y1/Y5 Receptor Heterodimers
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 30-01-2015
Abstract: The ability of G protein-coupled receptors (GPCRs) to form dimers, and particularly heterodimers, offers potential for targeted therapeutics with improved selectivity. However, studying dimer pharmacology is challenging, because of signaling cross-talk or because dimerization may often be transient in nature. Here we develop a system to isolate the pharmacology of precisely defined GPCR dimers, trapped by bimolecular fluorescence complementation (BiFC). Specific effects of agonist activation on such dimers are quantified using automated imaging and analysis of their internalization, controlled for by simultaneous assessment of endocytosis of one coexpressed protomer population. We applied this BiFC system to study ex le neuropeptide Y (NPY) Y1 receptor dimers. Incorporation of binding-site or phosphorylation-site mutations into just one protomer of a Y1/Y1 BiFC homodimer had no impact on efficient NPY-stimulated endocytosis, demonstrating that single-site agonist occupancy, and one phosphorylated monomer within this dimer, was sufficient. For two Y1 receptor heterodimer combinations (with the Y4 receptor or β2-adrenoceptor), agonist and antagonist pharmacology was explained by independent actions on the respective orthosteric binding sites. However, Y1/Y5 receptor BiFC dimers, compared with the constituent subtypes, were characterized by reduced potency and efficacy of Y5-selective peptide agonists, the inactivity of Y1-selective antagonists, and a change from surmountable to nonsurmountable antagonism for three unrelated Y5 antagonists. Thus, allosteric interactions between Y1 and Y5 receptors modify the pharmacology of the heterodimer, with implications for potential antiobesity agents that target centrally coexpressed Y1 and Y5 receptors to suppress appetite.
Heterodimeric Analogues of the Potent Y1R Antagonist 1229U91, Lacking One of the Pharmacophoric C-Terminal Structures, Retain Potent Y1R Affinity and Show Improved Selectivity over Y4R
Publisher: American Chemical Society (ACS)
Date: 04-05-2020
Antimicrobial potential of Chlorella sorokiniana on MRSA – An in vitro study and an in silico analysis on ClpP protease
Publisher: Elsevier BV
Date: 07-2023
Optically Pure, Structural, and Fluorescent Analogues of a Dimeric Y4 Receptor Agonist Derived by an Olefin Metathesis Approach
Publisher: American Chemical Society (ACS)
Date: 28-06-2016
DOI: 10.1021/ACS.JMEDCHEM.6B00310
Abstract: The dimeric peptide 1 (BVD-74D, as a diastereomeric mixture) is a potent and selective neuropeptide Y Y4 receptor agonist. It represents a valuable candidate in developing traceable ligands for pharmacological studies of Y4 receptors and as a lead compound for antiobesity drugs. Its optically pure stereoisomers along with analogues and fluorescently labeled variants were prepared by exploiting alkene metathesis reactions. The (2R,7R)-diaminosuberoyl containing peptide, (R,R)-1, had markedly higher affinity and agonist efficacy than its (S,S)-counterpart. Furthermore, the sulfo-Cy5 labeled (R,R)-14 retained high agonist potency as a novel fluorescent ligand for imaging Y4 receptors.
THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: Overview
Publisher: Wiley
Date: 21-10-2017
DOI: 10.1111/BPH.13882
Identification of a Cyanine-Dye Labeled Peptidic Ligand for Y1 R and Y4 R, Based upon the Neuropeptide y C-Terminal Analogue, BVD-15
Publisher: American Chemical Society (ACS)
Date: 25-08-2016
DOI: 10.1021/ACS.BIOCONJCHEM.6B00376
Abstract: Traceable truncated Neuropeptide Y (NPY) analogues with Y1 receptor (Y1R) affinity and selectivity are highly desirable tools in studying receptor location, regulation, and biological functions. A range of fluorescently labeled analogues of a reported Y1R/Y4R preferring ligand BVD-15 have been prepared and evaluated using high content imaging techniques. One peptide, [Lys(2)(sCy5), Arg(4)]BVD-15, was characterized as an Y1R antagonist with a pKD of 7.2 measured by saturation analysis using fluorescent imaging. The peptide showed 8-fold lower affinity for Y4R (pKD = 6.2) and was a partial agonist at this receptor. The suitability of [Lys(2)(sCy5), Arg(4)]BVD-15 for Y1R and Y4R competition binding experiments was also demonstrated in intact cells. The nature of the label was shown to be critical with replacement of sCy5 by the more hydrophobic Cy5.5 resulting in a switch from Y1R antagonist to Y1R partial agonist.
Related Organisations
King's College London
Location: United Kingdom of Great Britain and Northern Ireland
Saveetha Institute Of Medical And Technical Sciences [SIMATS], Saveetha University Saveetha Dental College
Location: India
University Of Nottingham
Location: United Kingdom of Great Britain and Northern Ireland
University Of Cambridge Saint John's College
Location: United Kingdom of Great Britain and Northern Ireland
Excellerate Bioscience Ltd
Location: United Kingdom of Great Britain and Northern Ireland
Related Funding Activities
No related grants have been discovered for Nicholas Holliday.