A5001823251- Enzyme function and inhibition
- Cellular transport and secretion
- Protein Kinase Regulation and GTPase Signaling
- Computational Drug Discovery Methods
- Forensic Toxicology and Drug Analysis
- Peptidase Inhibition and Analysis
- Chemical Synthesis and Analysis
- Microbial metabolism and enzyme function
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Receptor Mechanisms and Signaling
- Enzyme Structure and Function
- Microbial Metabolic Engineering and Bioproduction
- Renin-Angiotensin System Studies
- Estrogen and related hormone effects
- Metabolomics and Mass Spectrometry Studies
- Mass Spectrometry Techniques and Applications
- Biochemical and Molecular Research
- PI3K/AKT/mTOR signaling in cancer
- Protein Hydrolysis and Bioactive Peptides
- Nicotinic Acetylcholine Receptors Study
- Calcium signaling and nucleotide metabolism
- Psychedelics and Drug Studies
- Insect Resistance and Genetics
- Neuropeptides and Animal Physiology
- Adenosine and Purinergic Signaling
University of Bath
2016-2025
University of Cape Town
2018
University of Bristol
1999-2005
University of Southampton
1995-2000
Synthetic cannabinoids (SCs) are novel psychoactive substances (NPS) that highly potent and associated with a range of severe toxicities. SC use, which is common in UK prisons homeless communities, typically involves combustion SC-soaked herb or paper material. Recently, e-cigarettes (or vapes) have emerged as popular delivery vehicles for SCs, consumption among the general population has risen significantly. SC-containing e-liquids) sold imitation cannabis-containing products carry...
Recent studies have shown that phox homology (PX) domains act as phosphoinositide-binding motifs. The majority of PX studied show binding to phosphatidylinositol 3-monophosphate (PtdIns(3)P), an association allows the host protein localize membranes endocytic pathway. One issue, however, is whether may alternative phosphoinositide specificities could target their distinct subcellular compartments or allow allosteric regulation by phosphoinositides other than PtdIns(3)P. It has been reported...
Single agents against multiple drug targets are of increasing interest. Hormone-dependent breast cancer (HDBC) may be more effectively treated by dual inhibition aromatase and steroid sulfatase (STS). The inhibitory pharmacophore was thus introduced into a known biphenyl STS inhibitor to give series novel aromatase−sulfatase inhibitors (DASIs). Several compounds good or DASI 20 (IC50: aromatase, 2.0 nM; STS, 35 nM) its chlorinated congener 23 0.5 5.5 examples that show exceptional potency in...
Angiotensin-1-converting enzyme (ACE) is a key in the renin-angiotensin-aldosterone and kinin systems where it cleaves angiotensin I bradykinin peptides, respectively. However, ACE also participates numerous other physiological functions, can hydrolyse many peptide substrates has various exo- endopeptidase activities. achieves this complexity by containing two homologous catalytic domains (N- C-domains), which exhibit different substrate specificities. Here, we present first open...
Angiotensin-1-converting enzyme (ACE) is a zinc-dependent carboxypeptidase of therapeutic interest for the treatment hypertension, inflammation and fibrosis. It consists two homologous N C catalytic domains, nACE cACE, respectively. Unfortunately, current clinically available ACE inhibitors produce undesirable side effects due to nonselective inhibition these domains. Through structure-based drug design, we previously identified series diprolyl-derived (SG3, SG15, SG16, SG17 SG18) in an...
Dual angiotensin-converting enzyme (ACE) and neprilysin (NEP) inhibitors such as omapatrilat showed promise potent treatments for hypertension but produced adverse effects due to their high affinity both domains of ACE (nACE cACE). This led the search compounds that retained NEP potency selectively inhibit cACE, leaving nACE active degrade other peptides bradykinin. Lisinopril-tryptophan (LisW) has previously been reported have cACE selectivity. Three mercapto-3-phenylpropanoyl were...
Aims: To characterise edible products seized in the United Kingdom (UK) illicit market by (1) analysing packaging designs, (2) quantifying tetrahydrocannabinol (THC) content and identifying other psychoactive substances, including synthetic cannabinoids (SCs), (3) evaluating a field-portable device for rapid drug identification directly from food with an substance added (edibles). Design: Laboratory-based chemical analysis of evaluation point-of-care diagnostic device. Setting: University...
The group I family of pleckstrin homology (PH) domains are characterized by their inherent ability to specifically bind phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P(3)) and its corresponding inositol head-group 1,3,4,5-tetrakisphosphate (Ins(1,3,4,5)P(4)). In vivo this interaction results in the regulated plasma membrane recruitment cytosolic PH domain-containing proteins following agonist-stimulated PtdIns(3,4,5)P(3) production. Among proteins, Ras GTPase-activating protein...
The structure of methanol dehydrogenase (MDH) at 0.194 nm (1.94 A) has been used to provide a model for part membrane quinoprotein glucose (GDH). basic superbarrel is retained, along with the tryptophan-docking motifs. active-site regions are similar, but there important differences, most being that GDH lacks novel disulphide ring formed from adjacent cysteines in MDH; equivalent region occupied by His-262. Because overall similarities region, mechanism action likely be similar MDH....
The activation of at least 23 different mammalian kinases requires the phosphorylation their hydrophobic motifs by kinase PDK1. A linker connects phosphoinositide-binding PH domain to catalytic domain, which contains a docking site for substrates called PIF pocket. Here, we used chemical biology approach show that PDK1 existed in equilibrium between three distinct conformations with differing substrate specificities. inositol polyphosphate derivative HYG8 bound and disrupted dimerization...
Phosphoinositides regulate many cellular processes, and levels are controlled by kinases phosphatases. SHIP2 (SH2 (Src homology 2)-domain-containing inositol-phosphatase-2) plays a critical role in phosphoinositide signaling, cleaving the 5-phosphate from phosphatidylinositol 3,4,5-trisphosphate. is thought to be involved type-2 diabetes obesity, conditions that could therefore open pharmacological modulation of enzyme. However, rational design inhibitors has been limited absence...
Angiotensin-1-converting enzyme (ACE) is a zinc metallopeptidase that consists of two homologous catalytic domains (known as nACE and cACE) with different substrate specificities. Based on kinetic studies it was previously reported sampatrilat, tight-binding inhibitor ACE, Ki = 13.8 nm 171.9 for cACE respectively [Sharma et al., Journal Chemical Information Modeling (2016), 56, 2486-2494], 12.4-fold more selective cACE. In addition, samAsp, in which an aspartate group replaces the...
Synthetic cannabinoids (SCs) make up a class of novel psychoactive substances (NPS), used predominantly in prisons and homeless communities the U.K. SCs can have severe side effects, including psychosis, stroke, seizures, with numerous reported deaths associated their use. The chemical diversity presents major challenge to detection since approaches relying on specific molecular recognition become outdated almost immediately. Ideally one would generic approach detecting portable settings....
Omapatrilat was designed as a vasopeptidase inhibitor with dual activity against the zinc metallopeptidases angiotensin-1 converting enzyme (ACE) and neprilysin (NEP). ACE has two homologous catalytic domains (nACE cACE), which exhibit different substrate specificities. Here, we report high-resolution crystal structures of omapatrilat in complex nACE cACE show subnanomolar affinity for both domains. The nearly identical binding interactions each domain, explaining lack domain selectivity....
Angiotensin-I converting enzyme (ACE) is a zinc metalloprotease consisting of two catalytic domains (N- and C-). Most clinical ACE inhibitor(s) (ACEi) have been shown to inhibit both nonselectively, resulting in adverse effects such as cough angioedema. Selectively inhibiting the individual likely reduce these potentially treat fibrosis addition hypertension. ACEi from GVK Biosciences database were inspected for possible N-domain selective binding patterns. From this set, diprolyl chemical...
Neprilysin (NEP) and angiotensin-converting enzyme (ACE) are two key zinc-dependent metallopeptidases in the natriuretic peptide kinin systems renin–angiotensin–aldosterone system, respectively. They play an important role blood pressure regulation reducing risk of heart failure. Vasopeptidase inhibitors omapatrilat sampatrilat possess dual activity against these enzymes by blocking ACE-dependent conversion angiotensin I to potent vasoconstrictor II while simultaneously halting NEP-dependent...
The requirements for substrate binding in the quinoprotein glucose dehydrogenase (GDH) membranes of Escherichia coli are described, together with changes activity a site-directed mutant which His262 has been altered to tyrosine residue (H262Y-GDH). differences catalytic efficiency between substrates mainly related their affinity enzyme. Remarkably, it appears that, if hexose is able bind active site, then also oxidized, whereas some pentoses (and act as competitive inhibitors), but not...
A chimeric approach is used to discover microtubule disruptors with excellent in vitro activity and oral bioavailability; a ligand–protein interaction carbonic anhydrase that enhances bioavailability characterised by protein X-ray crystallography. Dosing of representative chimera tumour xenograft model confirms the therapeutic potential class.
Synthetic cannabinoids (SCs) are novel psychoactive substances (NPS) that highly potent and associated with a range of severe toxicities. SC use, which is common in UK prisons homeless communities, typically involves combustion SC-soaked herb or paper material. Recently, e-cigarettes (or vapes) have emerged as popular delivery vehicles for SCs, consumption amongst the general population has risen significantly. SC-containing e-liquids) sold through street dealers on black market, often...
The 1.94 A structure of methanol dehydrogenase has been used to provide a model for part membrane quinohaemoprotein alcohol dehydrogenase. basic superbarrel and the active-site region are retained, indicating essentially similar mechanisms action, but there considerable differences in external loops, particularly those involved formation shallow funnel leading active site.