A5102889041- Computational Drug Discovery Methods
- Cancer-related Molecular Pathways
- Melanoma and MAPK Pathways
- Ubiquitin and proteasome pathways
- Protein Kinase Regulation and GTPase Signaling
- Click Chemistry and Applications
- Phosphodiesterase function and regulation
- Sulfur-Based Synthesis Techniques
- Synthesis and Catalytic Reactions
- Ion channel regulation and function
- Chemical synthesis and alkaloids
- Stress Responses and Cortisol
- Peptidase Inhibition and Analysis
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Carbohydrate Chemistry and Synthesis
- Protein Degradation and Inhibitors
- Tryptophan and brain disorders
- Multiple Myeloma Research and Treatments
- Enzyme Structure and Function
- Usability and User Interface Design
- Persona Design and Applications
- Blood Coagulation and Thrombosis Mechanisms
- Phytochemicals and Antioxidant Activities
- Sphingolipid Metabolism and Signaling
Newcastle University
2012-2024
Cancer Research UK
2021-2022
Virginia Tech
2022
Newcastle upon Tyne Hospital
2016-2018
Pfizer (United Kingdom)
2007-2018
Pfizer (United States)
2008-2016
Karlsruhe University of Education
1996
National University of Singapore
1996
Cornell University
1996
Utrecht University
1996
Identifying ligand binding sites on proteins is a critical step in target-based drug discovery. Current approaches to this require resource-intensive screening of large libraries lead-like or fragment molecules. Here, we describe an efficient and effective experimental approach mapping interaction using set halogenated compounds expressing paired hydrogen-bonding motifs, termed FragLites. The FragLites identify productive drug-like interactions, which are identified sensitively unambiguously...
Inhibition of murine double minute 2 (MDM2)-p53 protein-protein interaction with small molecules has been shown to reactivate p53 and inhibit tumor growth. Here, we describe rational, structure-guided, design novel isoindolinone-based MDM2 inhibitors. X-ray crystallography, quantum mechanics ligand-based design, metabolite identification all contributed toward the discovery potent
A database of binding kinetic data across multiple targets has been created. Analysis this provides insights into trends for the effects physicochemical properties (molecular weight, clogP, rotatable bond count) on dissociation kinetics ligands from their biological targets.
Thrombin-activatable fibrinolysis inhibitor (TAFI) has emerged as a key link between the coagulation and cascades represents promising new target for treatment of thrombosis. A novel series imidazolepropionic acids been designed that exhibit high potency against activated TAFI (TAFIa) excellent selectivity over plasma carboxypeptidase N (CPN). Structure activity relationships suggest imidazole moiety plays role in binding to catalytic zinc TAFIa, this supported by crystallographic studies...
Structure-guided expansion of a fragment hit for the ATAD2 bromodomain enabled improvement in inhibition and selectivity over BRD4.
NF-κB-inducing kinase (NIK) is a key enzyme in the noncanonical NF-κB pathway, of interest treatment variety diseases including cancer. Validation NIK as drug target requires potent and selective inhibitors. The protein contains cysteine residue at position 444 back pocket active site, unique within kinome. Analysis existing inhibitor scaffolds early structure–activity relationships (SARs) led to design C444-targeting covalent inhibitors based on alkynyl heterocycle warheads. Mass...
Given the large amounts of screening data now available, empirical methods derived from matched-molecular pairs are being used as a means for suggesting bioisosteric replacements to medicinal chemist. The pairwise analysis compounds has been extended series bring further context these suggestions. A validation dataset recent literature demonstrate that, given active compounds, this approach would be expected predict more potent compound, if it exists, in around 46% cases. successfully...
The tetrahydropyran 4-(((3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-4-phenylbutyl)amino)methyl)-N,N-dimethylaniline was reported to disrupt the SCFSKP2 E3 ligase complex. Efficient syntheses of this derivative and analogues, including des-dimethyl 4-(((3-(tetrahydro-2H-pyran-4-yl)-4-phenylbutyl)amino)methyl)-N,N-dimethylaniline, are described. enantiomers compound were obtained using Evans’ chiral auxiliaries. Structure–activity relationships for these tetrahydropyrans analogues have been...
Genes that originate during evolution are an important source of novel biological functions. Retrogenes functional copies genes produced by retroduplication and as such located in different genomic positions. To investigate retroposition patterns retrogene expression, we computationally identified interchromosomal events nine portions the phylogenetic history malaria mosquitoes, making use species do or not have classical sex chromosomes to test roles sex-linkage. We found 40 a significant...
The development of ligands for biological targets is critically dependent on the identification sites proteins that bind molecules with high affinity. A set compounds, called FragLites, can identify such sites, along interactions required to gain affinity, by X-ray crystallography. We demonstrate utility FragLites in mapping binding bromodomain BRD4 and ATAD2 FragLite comparable a full fragment screen identifying ligand key interactions. extend analogous compounds derived from amino acids...
Abstract In response to cellular stress, the tumor suppressor p53 is activated modulate cell cycle progression, DNA repair, and apoptosis. Inhibition of MDM2-p53 interaction in tumors carrying wild-type prevents its degradation can reactivate elicit an anti-cancer effect. Targeting p53-MDM2 therefore remains a promising strategy for cancer therapy. However, development first generation MDM2 antagonists has been challenged by dose-limiting, on-target bone marrow toxicities. Understanding...
Abstract Aim We aimed to design an MDM2-p53 antagonist with a differentiated tolerability profile that could be used treat patients wild-type TP53 malignancies. As part of alliance between Newcastle University, Astex Pharmaceuticals, and Cancer Research Horizons, we discovered ASTX295, potent inhibitor the interaction is currently under clinical investigation in solid tumors (NCT03975387). selected ASTX295 as compound predicted short plasma half-life, which hypothesised would help mitigate...
An improved synthesis from <sc>d</sc>-glucosamine of a purported Sulf-2 inhibitor is described, with assay data for this compound and analogues showing only weak inhibition Sulf-2, sulfatases ARSA or ARSB.
Sulfamates are important functional groups in certain areas of current medicinal chemistry and drug development. Alcohols phenols generally converted into the corresponding primary sulfamates (ROSO(2)NH(2) ArOSO(2)NH(2), respectively) by reaction with sulfamoyl chloride (H(2)NSO(2)Cl). The lability O-sulfamate group, especially to basic conditions, usually restricts this method a later stage synthesis. To enable more flexible approach synthesis phenolic O-sulfamates, protecting group...
Potent and subtype selective Na<sub>v</sub>1.8 inhibitors were designed optimised for selectivity over hERG ion channel inhibition.
The nonclassical extracellular signal-related kinase 5 (ERK5) mitogen-activated protein pathway has been implicated in increased cellular proliferation, migration, survival, and angiogenesis; hence, ERK5 inhibition may be an attractive approach for cancer treatment. However, the development of selective inhibitors challenging. Previously, we described a pyrrole carboxamide high-throughput screening hit into selective, submicromolar inhibitor activity. Improvement potency was necessary...
Two series of inhibitors sulfatase 2, ARSA and ARSB were designed based on biphenyl ether scaffolds substituted with <italic>e.g.</italic> sulfamate carboxylate groups.