A5026373941- Chemical Synthesis and Analysis
- Computational Drug Discovery Methods
- Synthesis and Biological Evaluation
- Biochemical and Molecular Research
- Cellular transport and secretion
- Monoclonal and Polyclonal Antibodies Research
- Genomics, phytochemicals, and oxidative stress
- Receptor Mechanisms and Signaling
- Synthetic Organic Chemistry Methods
- Neuropeptides and Animal Physiology
- Cancer therapeutics and mechanisms
- Synthesis and pharmacology of benzodiazepine derivatives
- X-ray Diffraction in Crystallography
- Chronic Lymphocytic Leukemia Research
- Crystallization and Solubility Studies
- Chemical Synthesis and Reactions
- Cholinesterase and Neurodegenerative Diseases
- Ubiquitin and proteasome pathways
- Cancer-related Molecular Pathways
- Protein Structure and Dynamics
- Calcium signaling and nucleotide metabolism
- Pharmacogenetics and Drug Metabolism
- Fluorine in Organic Chemistry
- Estrogen and related hormone effects
- Drug Transport and Resistance Mechanisms
University of Cambridge
1997-2025
Alzheimer’s Research UK
2024
Takeda (United Kingdom)
2016
Newcastle University
2006
Addenbrooke's Hospital
1994-1996
Leiden University
1992-1993
Saarland University
1980
KEAP1 is the key regulator of NRF2-mediated cytoprotective response, and increasingly recognized as a target for diseases involving oxidative stress. Pharmacological intervention has focused on molecules that decrease NRF2-ubiquitination through covalent modification cysteine residues, but such electrophilic compounds lack selectivity may be associated with off-target toxicity. We report here first use fragment-based approach to directly Kelch-NRF2 interaction. X-ray crystallographic...
The KEAP1–NRF2-mediated cytoprotective response plays a key role in cellular homoeostasis. Insufficient NRF2 signaling during chronic oxidative stress may be associated with the pathophysiology of several diseases an inflammatory component, and pathway activation through direct modulation KEAP1–NRF2 protein–protein interaction is being increasingly explored as potential therapeutic strategy. Nevertheless, physicochemical nature interface suggests that achieving high affinity for...
From a set of weakly potent lead compounds, using in silico screening and small library synthesis, series 2-alkyl-3-aryl-3-alkoxyisoindolinones has been identified as inhibitors the MDM2-p53 interaction. Two most 2-benzyl-3-(4-chlorophenyl)-3-(3-hydroxypropoxy)-2,3-dihydroisoindol-1-one (76; IC50 = 15.9 ± 0.8 μM) 3-(4-chlorophenyl)-3-(4-hydroxy-3,5-dimethoxybenzyloxy)-2-propyl-2,3-dihydroisoindol-1-one (79; 5.3 0.9 μM), induced p53-dependent gene transcription, dose-dependent manner, MDM2...
Bifunctional molecules known as PROTACs simultaneously bind an E3 ligase and a protein of interest to direct ubiquitination clearance that protein, they have emerged in the past decade exciting new paradigm drug discovery. In order investigate permeability properties these large molecules, we synthesized two panels PROTAC constructed from range protein-target ligands, linkers, ligands. The androgen receptor, which is well-studied field was used model system. physicochemical are discussed.
The protein kinase NUAK1 has been implicated in various biological functions including cell adhesion, migration and proliferation. Genetic reduction of expression notably shown to lower total levels human tau a tauopathy mouse model, identifying this as potential therapeutic target for neurodegenerative disease. In paper, we describe improvement the potency, kinase-selectivity pharmacokinetic properties brain-penetrant but unselective CDK4/CDK6/NUAK1 inhibitor ON123300. Through...
The NRF2-mediated cytoprotective response is central to cellular homoeostasis, and there increasing interest in developing small-molecule activators of this pathway as therapeutics for diseases involving chronic oxidative stress. protein KEAP1, which regulates NRF2, a key point pharmacological intervention, we recently described the use fragment-based drug discovery develop tool compound that directly disrupts protein-protein interaction between NRF2 KEAP1. We now present identification...
Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are emerging as attractive therapeutic targets in diseases, such cancer, immunological disorders, and neurodegeneration, owing to their central role regulating cell signaling pathways that either dysfunctional or can be modulated promote survival. Different modes of binding may enhance inhibitor selectivity reduce off-target effects cells. Here, we describe efforts improve the physicochemical properties selective PI5P4Kγ inhibitor,...
Owing to their central role in regulating cell signaling pathways, the phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are attractive therapeutic targets diseases such as cancer, neurodegeneration, and immunological disorders. Until now, tool molecules for these kinases have been either limited potency or isoform selectivity, which has hampered further investigation of biology drug development. Herein we describe virtual screening workflow identified a series thienylpyrimidines...
A de novo design approach to generating novel estrogen receptor (ER) ligands is described. The SkelGen program was used generate in the active sites of seven crystal structures ERα. Seventeen high-scoring, diverse were selected from output and synthesized without introducing any modifications structures. Five ligands, four which are novel, showed ≤25 μM affinity, with best compound displaying an IC50 340 nM. can, therefore, be a powerful tool for designing molecules.
Fatty acid binding protein 6 (FABP6) is a potential drug discovery target, which, if inhibited, may have therapeutic benefit for the treatment of diabetes. Currently, there are no published inhibitors FABP6, and with target believed to be amenable fragment-based discovery, structurally enabled program was initiated. This successfully identified fragment hits using surface plasmon resonance (SPR) platform. Several were validated SAR found displaced by natural ligand taurocholate. We report...
The phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) play a central role in regulating cell signalling pathways and, as such, have become therapeutic targets for diseases such cancer, neurodegeneration and immunological disorders. Many of the PI5P4Kα inhibitors that been reported to date suffered from poor selectivity and/or potency availability better tool molecules would facilitate biological exploration. Herein we report novel inhibitor chemotype was identified through virtual...
Neuropathology is often mediated by interactions between neurons and glia that cannot be modeled monocultures. However, cocultures are difficult to use analyze for high-content screening. Here, we perform compound screening using primary neuron-glia cultures model inflammatory neurodegeneration, live-cell stains, automated classification of neurons, astrocytes or microglia open-source software. Out 227 compounds with known bioactivities, 29 protected against lipopolysaccharide-induced...
Reflex is a recent algorithm in the de novo ligand design software, SkelGen, that allows flexibility of amino acid side chains protein to be taken into account during drug-design process. In this paper impact on solutions generated by algorithm, when applied carboxypeptidase A, acetylcholinesterase, and estrogen receptor (ER), investigated. The results for each targets indicate allowing side-chain movement active site, are were not accessible from multiple static conformations available...
Drug discovery is a complex and resource-intensive process, with significant time cost investments required to bring new medicines patients. Recent advancements in generative machine learning (ML) methods offer promising avenues accelerate early-stage drug by efficiently exploring chemical space. This paper addresses the gap between silico approaches practical vitro methodologies, highlighting need for their integration optimize molecule discovery. We introduce SynthFormer, novel ML model...
A major difficulty in structure-based molecular design is the prediction of structure protein-ligand complex because enormous number degrees freedom. Commonly, target protein kept rigid a single low-energy conformation. However, this does not reflect dynamic nature structures. In work, we investigate influence receptor flexibility virtual screening reagents on common scaffold S1' pocket human collagenase (matrix metalloproteinase-1). We compare using single-crystal and multiple NMR...
Abstract 2-Phenoxypropene (2) was applied as a novel protective reagent of chiral alcohols, yielding 2-phenoxy-isopropyl (PIP) ethers. Introduction and cleavage the group achieved under mild conditions.