A5058544519- PI3K/AKT/mTOR signaling in cancer
- Lung Cancer Treatments and Mutations
- Computational Drug Discovery Methods
- Advanced Breast Cancer Therapies
- Receptor Mechanisms and Signaling
- Protein Structure and Dynamics
- Click Chemistry and Applications
- Cell death mechanisms and regulation
- Innovative Microfluidic and Catalytic Techniques Innovation
- Biochemical and Molecular Research
- ATP Synthase and ATPases Research
- Metabolism, Diabetes, and Cancer
- Protein Tyrosine Phosphatases
- Ion channel regulation and function
- Natural Antidiabetic Agents Studies
- Phosphodiesterase function and regulation
- Chronic Lymphocytic Leukemia Research
- Adenosine and Purinergic Signaling
- Cardiac electrophysiology and arrhythmias
- Protein Kinase Regulation and GTPase Signaling
- Mitochondrial Function and Pathology
- Pharmacogenetics and Drug Metabolism
- Chemical Synthesis and Analysis
- Pharmacological Receptor Mechanisms and Effects
- Biosimilars and Bioanalytical Methods
D. E. Shaw Research
2016-2024
AstraZeneca (Sweden)
2008-2022
AstraZeneca (United Kingdom)
2005-2013
Weatherford College
2012
Queen Mary University of London
2002-2005
Nerviano Medical Sciences
2004-2005
University College London
2005
Pfizer (Italy)
2004
Pfizer (United States)
2004
Abstract AMP-activated protein kinase (AMPK) plays a major role in regulating cellular energy balance by sensing and responding to increases AMP/ADP concentration relative ATP. Binding of AMP causes allosteric activation the enzyme binding either or ADP promotes maintains phosphorylation threonine 172 within loop kinase. AMPK has attracted widespread interest as potential therapeutic target for metabolic diseases including type 2 diabetes and, more recently, cancer. A number direct...
Intrinsically disordered proteins (IDPs) are implicated in many human diseases. They have generally not been amenable to conventional structure-based drug design, however, because their intrinsic conformational variability has precluded an atomic-level understanding of binding small molecules. Here we present long-time-scale, molecular dynamics (MD) simulations monomeric α-synuclein (an IDP whose aggregation is associated with Parkinson's disease) the small-molecule fasudil which observed...
Fibroblast growth factor receptor (FGFR) kinase inhibitors have been shown to be effective in the treatment of intrahepatic cholangiocarcinoma and other advanced solid tumors harboring FGFR2 alterations, but toxicity these drugs frequently leads dose reduction or interruption such that maximum efficacy cannot achieved. The most common adverse effects are hyperphosphatemia caused by FGFR1 inhibition diarrhea due FGFR4 inhibition, as current therapies not selective among FGFRs. Designing has...
Four of the most well-known, commercially available docking programs, FlexX, GOLD, GLIDE, and ICM, have been examined for their ligand-docking virtual-screening capabilities. The relative performance programs in reproducing native ligand conformation from starting SMILES strings 164 high-resolution protein-ligand complexes is presented compared. Applying only scoring functions, latest versions these four were also used to conduct virtual screening 12 protein targets therapeutic interest,...
PIK3CA (PI3Kα) is a lipid kinase commonly mutated in cancer, including ∼40% of hormone receptor-positive breast cancer. The most frequently observed mutants occur the and helical domains. Orthosteric PI3Kα inhibitors suffer from poor selectivity leading to undesirable side effects, prominently hyperglycemia due inhibition wild-type (WT) PI3Kα. Here, we used molecular dynamics simulations cryo-electron microscopy identify an allosteric network that provides explanation for how mutations favor...
Protein tyrosine phosphatase SHP2 mediates RAS-driven MAPK signaling and has emerged in recent years as a target of interest oncology, both for treating with single agent combination KRAS inhibitor. We were drawn to the pharmacological potential inhibition, especially following initial observation that drug-like compounds could bind an allosteric site enforce closed, inactive state enzyme. Here, we describe identification characterization GDC-1971 (formerly RLY-1971), inhibitor currently...
A high-throughput method for rapid screening of in vitro drug-brain homogenate binding is presented. The based on a straightforward sample pooling approach combining equilibrium dialysis with liquid chromatography mass spectrometry (LCMS). strong correlation fraction unbound brain (fu) between single compound measurements and 25-pooled compounds (R2 = 0.906) was obtained selection structurally diverse CNS wide range fractions unbound. Effects dilution time were investigated. To the best our...
Six docking programs (FlexX, GOLD, ICM, LigandFit, the Northwestern University version of DOCK, and QXP) were evaluated in terms their ability to reproduce experimentally observed binding modes (poses) small-molecule ligands macromolecular targets. The accuracy a pose was assessed two ways: First, RMS deviation predicted from crystal structure calculated. Second, compared one regarding presence key interactions with protein. latter assessment is referred as interactions-based classification...
High-throughput screening (HTS) represents a major cornerstone of drug discovery. The availability an innovative, relevant and high-quality compound collection to be screened often dictates the final fate discovery campaign. Given that chemical space sampled in research programs is practically infinite sparsely populated, significant efforts resources need invested generation maintenance competitive collection. European Lead Factory (ELF) project addressing this challenge by leveraging...
Profiling of eight stereoisomeric T. cruzi growth inhibitors revealed vastly different in vitro properties such as solubility, lipophilicity, pKa, and cell permeability for two sets four stereoisomers. Using computational chemistry NMR spectroscopy, we identified the formation an intramolecular NH→NR3 hydrogen bond set stereoisomers displaying lower higher permeability. The resulted a significant pKa difference that accounts other structure-property relationships. Application this knowledge...
A “fragment hit”, a molecule of low molecular weight that has been validated to bind target protein, can be an effective chemical starting point for drug discovery project. Our ability find and progress fragment hits could potentially improved by enhancing our understanding their binding properties, which date largely based on tacit knowledge reports from individual projects. In the work reported here, we systematically analyzed properties using 489 published protein–fragment complexes. We...
Despite the availability of X-ray crystal structure data for several members G-protein-coupled receptor (GPCR) superfamily, structure-based discovery GPCR ligands has been exclusively restricted to class A (rhodopsin-like) receptors. Herein we report identification, by a docking-based virtual screening approach, noncompetitive two related B (secretin-like) GPCRs: glucagon (GLR) and glucagon-like peptide 1 (GLP-1R). Starting from knowledge-based three-dimensional model GLR, database 1.9...
Synthesis and structure-activity relationships of ethyl 6-aminonicotinate acyl sulfonamides, which are potent antagonists the P2Y12 receptor, presented. Shifting from 5-chlorothienyl to benzyl sulfonamides significantly increased potency in residual platelet count assay. Evaluation PK parameters vivo dog for six compounds showed a 10-fold higher clearance azetidines than matched-pair piperidines. In modified Folts model dog, both piperidine 3 azetidine 13 dose-dependently induced increases...
A theoretical model of human Janus kinase 2 (JAK2) comprising all seven homology domains is presented. The was generated by application modelling approaches. three-dimensional structure contains, starting from the N-terminus, FERM (4.1, ezrin, radixin, moesin), SH2 (Src region 2), tyrosine kinase-like, and domains. predicted inter-domain orientation in JAK2 discussed currently existing mutational data for kinases are evaluated. Structural details predictions indicate that domain not fully...