A5064159945- Computational Drug Discovery Methods
- Monoclonal and Polyclonal Antibodies Research
- Protein Structure and Dynamics
- Protein Kinase Regulation and GTPase Signaling
- Pharmacological Effects of Natural Compounds
- Melanoma and MAPK Pathways
- Protein purification and stability
- Enzyme Structure and Function
- Inflammatory mediators and NSAID effects
- Transgenic Plants and Applications
- Peptidase Inhibition and Analysis
- RNA Interference and Gene Delivery
- Nanofabrication and Lithography Techniques
- Multiple Myeloma Research and Treatments
- Gout, Hyperuricemia, Uric Acid
- Protein Degradation and Inhibitors
- Ion channel regulation and function
- Click Chemistry and Applications
- Protein Tyrosine Phosphatases
- Allergic Rhinitis and Sensitization
- Innovative Microfluidic and Catalytic Techniques Innovation
- Viral Infections and Immunology Research
- MicroRNA in disease regulation
- Respiratory viral infections research
- RNA and protein synthesis mechanisms
AstraZeneca (Sweden)
2010-2024
AstraZeneca (United Kingdom)
2014
The development of orally bioavailable PROTACs presents a significant challenge due to the inflated physicochemical properties such heterobifunctional molecules. Molecules occupying this "beyond rule five" space often demonstrate limited oral bioavailability compounding effects elevated molecular weight and hydrogen bond donor count (among other properties), but it is possible achieve sufficient through optimization. Herein, we disclose design evaluation low (≤1 HBD) fragment screening set...
Evaluating the ligandability of a protein target is key component when defining hit-finding strategies or prioritize among drug targets. Computational as well biophysical approaches based on nuclear magnetic resonance (NMR) fragment screening are powerful but suffer from specific constraints that limit their usage. Here, we demonstrate applicability high-throughput thermal scanning (HTTS) simple and generic method to reproduce assessments NMR-based screening. By applying this large set...
Thymic stromal lymphopoietin (TSLP) is an epithelial-derived pro-inflammatory cytokine involved in the development of asthma and other atopic diseases. We used Bicycle Therapeutics' proprietary phage display platform to identify bicyclic peptides (Bicycles) with high affinity for TSLP, a target that difficult drug conventional small molecules due extended protein–protein interactions it forms both receptors. The hit series was shown bind TSLP hotspot, also by IL-7Rα. Guided first X-ray...
The MEK1 kinase plays a critical role in key cellular processes, and as such, its dysfunction is strongly linked to several human diseases, particularly cancer. has consequently received considerable attention drug target, significant number of small-molecule inhibitors this have been reported. majority these target an allosteric pocket proximal the ATP binding site which proven be highly druggable, with four approved date. Despite that received, chemotypes shown structurally bind are...
Fragment based drug discovery is a critical part of the lead generation toolbox and relies heavily on readily available, high quality fragment library. Over years use, AstraZeneca set had become partially depleted instances compound deterioration been found. It was recognised that redevelopment required. This provided an opportunity to evolve our screening sets strategy, whilst ensuring met robust requirements campaigns. In this communication we share strategy employed, in particular...
Two structurally distinct series of novel, MAPK-activated kinase-2 prevention activation inhibitors have been discovered by high throughput screening. Preliminary structure–activity relationship (SAR) studies revealed substructural features that influence the selective inhibition p38α downstream kinase MK2 in preference to an alternative substrate, MSK1. Enzyme kinetics, surface plasmon resonance (SPR), 2D protein NMR, and X-ray crystallography were used determine binding mode molecular...
Surface plasmon resonance (SPR) is a powerful method for obtaining detailed molecular interaction parameters. Modern instrumentation with its increased throughput has enabled routine screening by SPR in hit-to-lead and lead optimization programs, become mainstream drug discovery technology. However, the processing reporting of data are typically performed manually, which both time-consuming tedious. Here, we present workflow concept, design experiences software module relying on single,...
Abstract The aberrant expression of microRNAs (miRs) has been linked to several human diseases. A promising approach for targeting these anomalies is the use small-molecule inhibitors miR biogenesis. These have potential (i) dissect mechanisms action, (ii) discover new drug targets, and (iii) function as therapeutic agents. Here, we designed Förster resonance energy transfer (FRET)-labeled oligoribonucleotides precursor oncogenic miR-21 (pre-miR-21) used them together with a set...
Given the importance of glucocorticoid receptor (GR) agonists in medicine, despite their numerous adverse side effects, it is great interest to fully delineate regulatory network GR. Post-translational modifications form part this including phosphorylation. After phosphorylation GR interacts with 14-3-3, adding another layer regulation beyond ligand-driven activation. Here, we use a screening strategy inspired from traditional hit-finding methods for prospective identification first de novo...
The salt-inducible kinases (SIKs) 1-3, belonging to the AMPK-related kinase family, serve as master regulators orchestrating a diverse set of physiological processes such metabolism, bone formation, immune response, oncogenesis and cardiac rhythm. Owing its key regulatory role, SIK have emerged compelling targets for pharmacological intervention across indications. Therefore, there is interest in developing inhibitors with defined selectivity profiles both further dissect downstream biology...