A5081802485- Receptor Mechanisms and Signaling
- Chemical Synthesis and Analysis
- Computational Drug Discovery Methods
- Neuropeptides and Animal Physiology
- Adenosine and Purinergic Signaling
- Click Chemistry and Applications
- Neuroscience and Neuropharmacology Research
- Analytical Chemistry and Chromatography
- Monoclonal and Polyclonal Antibodies Research
- Innovative Microfluidic and Catalytic Techniques Innovation
- Synthesis and biological activity
- Enzyme Structure and Function
- Various Chemistry Research Topics
- Free Radicals and Antioxidants
- Sleep and Wakefulness Research
- Synthetic Organic Chemistry Methods
- Heat shock proteins research
- Protein Structure and Dynamics
- Peptidase Inhibition and Analysis
- Crystallization and Solubility Studies
- Pharmacological Receptor Mechanisms and Effects
- Asymmetric Synthesis and Catalysis
- Chemistry and Chemical Engineering
- Enzyme Production and Characterization
- ATP Synthase and ATPases Research
Heptares Therapeutics (United Kingdom)
2013-2022
Hertfordshire Community NHS Trust
2015
University of Nottingham
2015
MRC Laboratory of Molecular Biology
2015
Queen's Medical Centre
2015
High Energy Accelerator Research Organization
2015
University of Hertfordshire
1996-2013
Weatherford College
2013
Institute of Medicinal Plant Development
2010
University of Cambridge
1993-2008
Abstract The introduction of AlphaFold 2 1 has spurred a revolution in modelling the structure proteins and their interactions, enabling huge range applications protein design 2–6 . Here we describe our 3 model with substantially updated diffusion-based architecture that is capable predicting joint complexes including proteins, nucleic acids, small molecules, ions modified residues. new demonstrates improved accuracy over many previous specialized tools: far greater for protein–ligand...
Potent, ligand efficient, selective, and orally efficacious 1,2,4-triazine derivatives have been identified using structure based drug design approaches as antagonists of the adenosine A(2A) receptor. The X-ray crystal structures compounds 4e 4g bound to GPCR illustrate that molecules bind deeply inside orthosteric binding cavity. In vivo pharmacokinetic efficacy data for compound 4k are presented, demonstrating potential this series treatment Parkinson's disease.
Inhibitors of the molecular chaperone heat shock protein 90 (Hsp90) are currently generating significant interest in clinical development as potential treatments for cancer. In a preceding publication (DOI: 10.1021/jm100059d ) we describe Astex's approach to screening fragments against Hsp90 and subsequent optimization two hits into leads with inhibitory activities low nanomolar range. This paper describes structure guided 2,4-dihydroxybenzamide lead molecule 1 details some drug discovery...
Fragment-based lead generation has led to the discovery of a novel series cyclic amidine-based inhibitors β-secretase (BACE-1). Initial fragment hits with an isocytosine core having millimolar potency were identified via NMR affinity screening. Structure-guided evolution these fragments using X-ray crystallography together determination surface plasmon resonance and functional enzyme inhibition assays afforded micromolar inhibitors. Similarity searching around identification related...
Inhibitors of the chaperone Hsp90 are potentially useful as chemotherapeutic agents in cancer. This paper describes an application fragment screening to using a combination NMR and high throughput X-ray crystallography. The identified aminopyrimidine with affinity micromolar range subsequent structure-based design allowed its optimization into low nanomolar series good ligand efficiency. A phenolic chemotype was also found bind close 1 mM. optimized structure based resorcinol lead which has...
We describe the structure-guided optimization of molecular fragments 2-amino-3-benzyloxypyridine 1 (IC(50) 1.3 mM) and 3-(2-(4-pyridyl)ethyl)indole 2 35 microM) identified using X-ray crystallographic screening p38alpha MAP kinase. Using two separate case studies, article focuses on key compounds synthesized, structure-activity relationships binding mode observations made during this process, resulting in potent lead series that demonstrate significant increases activity. process compound...
Biophysical fragment screening of a thermostabilized β1-adrenergic receptor (β1AR) using surface plasmon resonance (SPR) enabled the identification moderate affinity, high ligand efficiency (LE) arylpiperazine hits 7 and 8. Subsequent hit to lead follow-up confirmed activity chemotype, structure-based design approach protein-ligand crystal structures β1AR resulted in several fragments that bound with higher including indole 19 quinoline 20. In first example GPCR crystallography ligands...
Fragment screening of a thermostabilized mGlu5 receptor using high-concentration radioligand binding assay enabled the identification moderate affinity, high ligand efficiency (LE) pyrimidine hit 5. Subsequent optimization structure-based drug discovery methods led to selection 25, HTL14242, as an advanced lead compound for further development. Structures stabilized complexed with 25 and another molecule in series, 14, were determined at resolutions 2.6 3.1 Å, respectively.
Virtual screening was performed against experimentally enabled homology models of the adenosine A(2A) receptor, identifying a diverse range ligand efficient antagonists (hit rate 9%). By use docking and Biophysical Mapping (BPM), hits 1 5 were optimized to potent selective lead molecules (11-13 from 5, pK(I) = 7.5-8.5, 13- >100-fold versus A(1); 14-16 1, 7.9-9.0, 19- 59-fold selective).