A5082329935- Computational Drug Discovery Methods
- Analytical Chemistry and Chromatography
- Pharmacogenetics and Drug Metabolism
- Asymmetric Synthesis and Catalysis
- Receptor Mechanisms and Signaling
- Molecular spectroscopy and chirality
- Machine Learning in Materials Science
- Metabolomics and Mass Spectrometry Studies
- Chemical Synthesis and Analysis
- Synthesis and biological activity
- Chemical synthesis and alkaloids
- Protein Structure and Dynamics
- Cyclopropane Reaction Mechanisms
- Ion channel regulation and function
- Alzheimer's disease research and treatments
- Neuroscience and Neuropharmacology Research
- Multicomponent Synthesis of Heterocycles
- Neuropeptides and Animal Physiology
- Nicotinic Acetylcholine Receptors Study
- Synthesis of Organic Compounds
- Synthesis and Reactivity of Sulfur-Containing Compounds
- Microbial Natural Products and Biosynthesis
- Synthesis and Reactions of Organic Compounds
- Cholinesterase and Neurodegenerative Diseases
- Liver Disease Diagnosis and Treatment
Novartis (United Kingdom)
2011-2025
Novartis (France)
2025
Optibrium (United Kingdom)
2015-2024
Novartis (Switzerland)
2009-2014
Merck & Co., Inc., Rahway, NJ, USA (United States)
2000-2006
MSD (UK) Limited (United Kingdom)
1999-2005
United States Military Academy
2005
Imperial College London
1988-2000
Loughborough University
1992
Goucher College
1986
Progressive cerebral amyloid β-protein (Aβ) deposition is believed to play a central role in the pathogenesis of Alzheimer's disease (AD). Elevated levels Aβ(42) peptide formation have been linked early-onset familial AD-causing gene mutations precursor (AβPP) and presenilins. Sequential cleavage AβPP by β- γ-secretases generates N- C-termini Aβ peptide, making both γ-secretase enzymes potential therapeutic targets for AD. The identity mechanism which are formed remain uncertain, although it...
We describe a novel deep learning neural network method and its application to impute assay pIC50 values. Unlike conventional machine approaches, this is trained on sparse bioactivity data as input, typical of that found in public commercial databases, enabling it learn directly from correlations between activities measured different assays. In two case studies domain sets we show the outperforms traditional quantitative structure–activity relationship (QSAR) models other leading approaches....
The idea of a "transformation", making small change to chemical structure, for instance removing or replacing substituent, is familiar chemists. We suggest two ways representing transformation in silico, as substructure descriptor difference vector, and the set atoms remaining once maximum common eliminated. Such transformations can be filtered sensibly, it easy compare one another. These representations have applications. First, we use these methods automatically organize display sets...
SUMMARY.— The vasoconstrictor test of McKenzie and Stoughton (1962) has been adapted for studying the release betamethasone 17‐valerate 21‐desoxy 17‐propionate from ointments. Vasoconstriction on skin volunteers was assessed quantally by noting presence or absence vasoconstriction quantitatively measuring diameters vasoconstricted areas. quantitative method employs corticosteroid doses higher than those used in quantal Stoughton. potencies 3 derivatives have compared using order to confirm...
We describe methods for predicting cytochrome P450 (CYP) metabolism incorporating both pathway-specific reactivity and isoform-specific accessibility considerations. Semiempirical quantum mechanical (QM) simulations, parametrized using experimental data ab initio calculations, estimate the of each potential site (SOM) in context whole molecule. Ligand-based models, trained high-quality regioselectivity data, correct orientation steric effects different CYP isoform binding pockets. The...
G-protein coupled receptors (GPCRs) are the targets of over half all prescribed drugs today. The UniProt database has records for about 800 proteins classified as GPCRs, but have only been developed against 50 these. Thus, there is huge potential in terms number new therapies to be designed. Several breakthroughs GPCRs biased pharmacology, structural biology, modelling and scoring resulted a resurgence interest drug targets. Therefore, an international conference, sponsored by Royal Society,...
We have previously identified the 7,8,9,10-tetrahydro-7,10-ethano-1,2,4-triazolo[3,4-a]phthalazine (1) as a potent partial agonist for alpha(3) receptor subtype with 5-fold selectivity in binding affinity over alpha(1). This paper describes detailed investigation of substituents on this core structure at both 3- and 6-positions. Despite evaluating wide range groups, maximum that could be achieved terms alpha(1) was 12-fold (for 57). Although most analogues showed no efficacy, some did show...
The acid dissociation constant (pKa) has an important influence on molecular properties crucial to compound development in synthesis, formulation, and optimization of absorption, distribution, metabolism, excretion properties. We will present a method that combines quantum mechanical calculations, at semi-empirical level theory, with machine learning accurately predict pKa for diverse range mono- polyprotic compounds. resulting model been tested two external data sets, one specifically used...
Leukotriene C4 synthase (LTC4S) is a glutathione S-transferase that mediates the biosynthesis of cysteinyl leukotriene (LTC4). Cysteinyl leukotrienes (CysLTs) are lipid mediators drive type 2 inflammation, bronchoconstriction, and itch. Thus, LTC4S represents an attractive drug target for treatment allergic inflammatory diseases, but to date, no inhibitor has been tested in patients. Herein, we disclose discovery preclinical profiling highly selective, oral GJG057 (compound 1), which...
Unexpected metabolism in modification and conjugation phases can lead to the failure of many late-stage drug candidates or even withdrawal approved drugs. Thus, it is critical predict sites (SoM) for enzymes, which interact with drug-like molecules, early stages research. This study presents methods predicting isoform-specific human AOs, FMOs, UGTs general CYP preclinical species. The models use semi-empirical quantum mechanical simulations, validated using experimentally obtained data DFT...
Communication of data and ideas within a medicinal chemistry project on global as well local level is crucial aspect in the drug design cycle. Over time frame eight years, we built optimized FOCUS, platform to produce, visualize, share information various aspects discovery such cheminformatics, analysis, structural information, design. FOCUS tightly integrated with internal services that involve-among others-data retrieval systems in-silico models provides easy access automated modeling...
Unexpected metabolism could lead to the failure of many late-stage drug candidates or even withdrawal approved drugs. Thus, it is critical predict and study dominant routes in early stages research.We describe development validation a 'WhichEnzyme' model that accurately predicts enzyme families most likely be responsible for drug-like molecule's metabolism. Furthermore, we combine this with our previously published regioselectivity models Cytochromes P450, Aldehyde Oxidases,...
Abstract This review discusses the involvement of structure and modeling in design β‐secretase (BACE‐1) γ‐secretase inhibitors as putative Alzheimer's Disease therapeutics. The early broad availability structural information for BACE‐1, a membrane‐tethered aspartyl protease, has led to use silico methods overall optimization process. However, γ‐secretase, an integral membrane protein, lack detailed 3D limited application computational methods. Drug Dev Res 70, 2009. © 2009 Wiley‐Liss, Inc.
The water soluble porphyrin tetrakis(4-N-methylpyridyl)porphine (H 2 TMpyP) and its copper(ll) derivative (CuTMpyP) convert Z-poly(dG-dC) to the B-form. For H TMpyP, fraction Z character (fr-Z) is given by fr-Z=1.0–21 r 0 for CuTMpyP, fr-Z=.94–12 o where O s [Porphyrin] /[DNA] . Neither manganese(lll) of this (MnTMpyP) nor tetrakis(2-N-methylpyridyl)porphine (H2TMpyP-2) nearly as effective at causing conversion. former two porphyrins have been shown intercalate into B-poly(dG-dC) whereas...
Pulmonary arterial hypertension (PAH) has demonstrated multi-serotonin receptor dependent pathologies, characterized by increased tone (5-HT1B receptor) and complex lesions (SERT, 5-HT1B, 5-HT2B receptors) of the pulmonary vasculature together with right ventricular hypertrophy, ischemia fibrosis (5-HT2B receptor). Selective inhibitors individual signaling elements - SERT, 5-HT2A, 5HT2B, combined 5-HT2A/B receptors, have all been tested clinically failed. Thus, inhibition tryptophan...
Cytosolic sulfotransferases (SULTs) are a family of enzymes responsible for the sulfation small endogenous and exogenous compounds. SULTs contribute to conjugation phase metabolism share substrates with uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes. UGTs considered be most important in phase, an auxiliary enzyme system them. Understanding how regioselectivity differs from that is essential perspective developing novel drug candidates. We present general ligand-based SULT model...