A5088118838- Computational Drug Discovery Methods
- Alzheimer's disease research and treatments
- Cholinesterase and Neurodegenerative Diseases
- Heat shock proteins research
- Synthesis and Biological Evaluation
- Neuropeptides and Animal Physiology
- Receptor Mechanisms and Signaling
- Synthesis and Reactions of Organic Compounds
- Structural and Chemical Analysis of Organic and Inorganic Compounds
- Bioinformatics and Genomic Networks
- thermodynamics and calorimetric analyses
- Peptidase Inhibition and Analysis
- Estrogen and related hormone effects
- Chemical Synthesis and Analysis
- Diabetes Treatment and Management
- Monoclonal and Polyclonal Antibodies Research
- Microtubule and mitosis dynamics
- Chemical Reaction Mechanisms
- Neuroblastoma Research and Treatments
- Biomedical Text Mining and Ontologies
- Asymmetric Synthesis and Catalysis
- Chemical Reactions and Mechanisms
- ATP Synthase and ATPases Research
- Radiopharmaceutical Chemistry and Applications
- Migraine and Headache Studies
Reed College
2024
Heptares Therapeutics (United Kingdom)
2014-2023
Novartis (Switzerland)
2011
Newcastle University
2011
GlaxoSmithKline (United Kingdom)
2006-2010
Institute of Medicinal Plant Development
2010
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...
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...
BACE-1 inhibition has the potential to provide a disease-modifying therapy for treatment of Alzheimer's disease. Optimization first generation inhibitors led discovery novel hydroxyethylamines (HEAs) bearing tricyclic nonprime side. These derivatives have nanomolar cell potency and are orally bioavailable.
Abstract Soluble adenylate cyclases catalyse the synthesis of second messenger cAMP through cyclisation ATP and are only known enzymes to be directly activated by bicarbonate. Here, we report first crystal structure human enzyme that reveals a pseudosymmetrical arrangement two catalytic domains produce single competent active site novel discrete bicarbonate binding pocket. Crystal structures apo protein, protein in complex with α,β‐methylene adenosine 5′‐triphosphate (AMPCPP) calcium,...
Abstract We describe here the identification and characterization of 2 novel inhibitors fibroblast growth factor receptor (FGFR) family tyrosine kinases. The compounds exhibit selective inhibition FGFR over closely related VEGFR2 in cell lines vivo. pharmacologic profile these was defined using a panel human tumor characterized for specific mutations, amplifications, or translocations known to activate one four isoforms. This pharmacology defines that are likely be use clinical settings...
HTL0041178 (1), a potent GPR52 agonist with promising pharmacokinetic profile and exhibiting oral activity in preclinical models, has been identified. This molecule was the outcome of judicious molecular property-based optimization approach, focusing on balancing potency against metabolic stability, solubility, permeability, P-gp efflux.
Structure-based drug design enabled the discovery of 8, HTL22562, a calcitonin gene-related peptide (CGRP) receptor antagonist. The structure 8 complexed with CGRP was determined at 1.6 Å resolution. Compound is highly potent, selective, metabolically stable, and soluble compound suitable for range administration routes that have potential to provide rapid systemic exposures resultant high levels coverage (e.g., subcutaneous). low lipophilicity coupled anticipated clinically efficacious...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTStereochemical aspects and metabolite formation in the vivo metabolism of psychotomimetic amine, 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropaneS. B. Matin, P. S. Callery, J. Zweig, A. O'Brien, R. Rapoport, N. Castagnoli Jr.Cite this: Med. Chem. 1974, 17, 8, 877–882Publication Date (Print):August 1, 1974Publication History Published online1 May 2002Published inissue 1 August...
A series of macrocyclic calcitonin gene-related peptide (CGRP) receptor antagonists identified using structure-based design principles, exemplified by HTL0028016 (1) and HTL0028125 (2), is described. Structural characterization X-ray crystallography the interaction two macrocycle with CGRP ectodomain described, along structure–activity relationships associated point changes to antagonists. The identification non-peptidic/natural product-derived, ligands for a G protein coupled (GPCR) noteworthy.
Molecular interaction networks are a vital tool for studying biological systems. While many tools exist that visualize protein or pathway within network, no provides the ability researcher to consider protein's position in network context of specific process pathway. We developed ProteinWeaver, web-based designed and analyze non-human by integrating known functions. ProteinWeaver users with an intuitive interface situate user-specified user-provided (as Gene Ontology term) five model...
Abstract ChemInform is a weekly Abstracting Service, delivering concise information at glance that was extracted from about 200 leading journals. To access Abstract, please click on HTML or PDF.
Abstract ChemInform is a weekly Abstracting Service, delivering concise information at glance that was extracted from about 200 leading journals. To access Abstract, please click on HTML or PDF.
Abstract Heat Shock Protein 90 (HSP90) is a member of family molecular chaperone proteins which directs the folding polypeptides into functional configurations affecting stabilisation and activation. Many these are oncogenes regulating tumor cell growth, survival apoptosis. This poster will focus on screening medicinal chemistry work that led to identification AT13387, high affinity HSP90 inhibitor currently in clinical trials for treatment cancer. A fragment campaign was conducted against...
Abstract Methionine aminopeptidases (MetAP) are metalloenzymes that remove the N-terminal initiator methionine from newly synthesized polypeptides allowing essential post-translational modifications such as acetylation and myristoylation to take place. MetAP2, one of two eukaryotic forms enzyme, was identified target fumagillin, a natural product with anti-angiogenic properties inhibits proliferation endothelial cells. Clinical activity has been seen for semi-synthetic analogue TNP470,...