A5080565832- Chemical Synthesis and Analysis
- Computational Drug Discovery Methods
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Catalytic C–H Functionalization Methods
- DNA and Nucleic Acid Chemistry
- Analytical Chemistry and Chromatography
- Machine Learning in Materials Science
- RNA and protein synthesis mechanisms
- Catalytic Cross-Coupling Reactions
- RNA Interference and Gene Delivery
- Carbohydrate Chemistry and Synthesis
- Crystallography and molecular interactions
- Mast cells and histamine
- Radical Photochemical Reactions
- Microbial Natural Products and Biosynthesis
- Synthesis and Catalytic Reactions
- Protein Structure and Dynamics
- HIV/AIDS drug development and treatment
- Click Chemistry and Applications
- Organoboron and organosilicon chemistry
- Molecular spectroscopy and chirality
- Peptidase Inhibition and Analysis
- RNA modifications and cancer
- Enzyme Structure and Function
AstraZeneca (Sweden)
2018-2025
AstraZeneca (Canada)
2024
AstraZeneca (Brazil)
2023-2024
Sanofi (Germany)
2012-2021
University of Sheffield
2011-2017
Institute of Molecular Biology and Biophysics
2013
Harvard University
2002-2004
ETH Zurich
2001
Therapeutic oligonucleotides (ONs) commonly incorporate phosphorothioate (PS) modifications. These introduce chiral centers and generate ON diastereomers. The increasing number of ONs undergoing clinical trials reaching the market has led to a growing interest better characterize diastereomer composition, especially for small interfering ribonucleic acids (siRNAs). In this study, first time, we identify higher-order structures as major cause separation in hydrophilic interaction...
Abstract A main challenge in drug discovery is finding molecules with a desirable balance of multiple properties. Here, we focus on the task molecular optimization, where goal to optimize given starting molecule towards This can be framed as machine translation problem natural language processing, our case, translated into optimized properties based SMILES representation. Typically, chemists would use their intuition suggest chemical transformations for being optimized. widely used strategy...
Molecular optimization aims to improve the drug profile of a starting molecule. It is fundamental problem in discovery but challenging due (i) requirement simultaneous multiple properties and (ii) large chemical space explore. Recently, deep learning methods have been proposed solve this task by mimicking chemist's intuition terms matched molecular pairs (MMPs). Although MMPs widely used strategy medicinal chemists, it offers limited capability exploring structural modifications, therefore...
Introducing trifluoromethyl groups is a common strategy to improve the properties of biologically active compounds. However, N-trifluoromethyl moieties on amines and azoles are very rarely used. To evaluate their suitability in drug design, we synthesized series azoles, determined stability aqueous media, investigated properties. We show that prone hydrolysis, whereas have excellent stability. Compared N-methyl analogues, higher lipophilicity can increased metabolic Caco-2 permeability....
Proteins exist in several different conformations. These structural changes are often associated with fluctuations at the residue level. Recent findings show that co-evolutionary analysis coupled machine-learning techniques improves precision by providing quantitative distance predictions between pairs of residues. The predicted statistical distribution from Multi Sequence Analysis reveals presence local maxima suggesting flexibility key pairs. Here we investigate ability residue-residue...
Abstract Non-natural amino acids are increasingly used as building blocks in the development of peptide-based drugs they expand available chemical space to tailor function, half-life and other key properties. However, while modified (mAAs) such residues containing post-translational modifications (PTMs) is potentially vast, experimental methods for measuring developability properties mAA-containing peptides expensive time consuming. To facilitate programs through computational methods, we...
Abstract microRNA (miRNA) mimics are an emerging class of oligonucleotide therapeutics, with a few compounds already in clinical stages. Synthetic miRNAs able to restore downregulated levels intrinsic miRNAs, allowing for parallel regulation multiple genes involved particular disease. In this work, we examined the influence chemical modifications patterns miR-200c mimics, assessing selection target messenger RNAs (mRNA) and, subsequently, whole transcriptome A549 cells. We have probed 37 and...
A novel integrated discovery platform has been used to synthesize and biologically assay a series of xanthine-derived dipeptidyl peptidase 4 (DPP4) antagonists. Design, synthesis, purification, quantitation, dilution, bioassay have all fully allow continuous automated operation. The system validated against set known DPP4 inhibitors shown give excellent correlation between traditional medicinal chemistry generated biological data data. Each iterative loop synthesis through took two hours in...
Efficient R-group exploration in the vast chemical space, enabled by increasingly available building blocks or generative AI, remains an open challenge. Here, we developed enhanced Free-Wilson QSAR model embedding R-groups atom-centric pharmacophoric features. Regioisomers of can be distinguished explicitly accounting for atomic positions. Good predictivity is observed consistently across 12 public data sets. Integrated into open-source program, showcase its application performing analysis...
On the basis of 1,2,3-triols 1a approximately d, 1,2,3,4-tetraols 2a h, and 1,2,3,4,5-pentaols 3a p, NMR databases with four types profile-descriptors ((13)C-, (1)H-, (1)H(OH)-chemical shifts vicinal spin-coupling constants) for contiguous polyols are reported. To systematically assess relative values these databases, a case study has been conducted on heptaols 4a through which gamma- delta-effects have recognized to refine (13)C (1)H chemical shift profile predicted via an application...
A new and efficient synthesis of pyridine-based heteroaromatic boronic acid derivatives is reported through a novel diboration/6π-electrocyclization strategy. This method delivers range functionalized heterocycles from readily available starting materials.
Anabaenopeptins isolated from cyanobacteria were identified as inhibitors of carboxypeptidase TAFIa. Cocrystal structures these macrocyclic natural product in a modified porcine B revealed their binding mode and provided the basis for rational design small molecule with previously unknown central urea motif. Optimization based on concepts allowed rapid evaluation SAR delivered potent TAFIa promising overall profile.
The regioselective condensation of hydrazines and ynone trifluoroborates provides access to a range pyrazole 5-trifluoroborates. stability the borate unit allows chemoselective halogenation heteroaromatic ring, thereby delivering scaffolds that allow orthogonal functionalization at C5 C4. modular reactivity these intermediates is exemplified by cross-coupling reactions, enabling regiocontrolled synthesis fully functionalized derivatives.
Ynone trifluoroborate salts undergo a base-promoted condensation reaction with alkylthiols to generate thiophene boronates complete regiocontrol. The products are isolated in high yield and can be further derivatized through conventional C–B bond functionalization reactions.
The enantiospecific and diastereocontrolled total synthesis of alkaloid (-)-217A is described that employs a stepwise [3+3] annelation strategy piperidine 2,3-cyclopropanation-ring opening reaction as the key steps.
A series of novel, highly potent P2Y₁₂ antagonists as inhibitors platelet aggregation based on a phenylpyrazole glutamic acid piperazine backbone is described. Exploration the structural requirements substituents by probing structure-activity relationship along this led to discovery N-acetyl-(S)-proline cyclobutyl amide moiety privileged motif. Combining most favorable remarkably displaying not only low nanomolar binding affinity receptor but also inhibition in human rich plasma assay with...
Designing compounds with a range of desirable properties is fundamental challenge in drug discovery. In pre-clinical early discovery, novel are often designed based on an already existing promising starting compound through structural modifications for further property optimization. Recently, transformer-based deep learning models have been explored the task molecular optimization by training pairs similar molecules. This provides point generating molecules to given input molecule, but has...
ADVERTISEMENT RETURN TO ISSUEPREVLetterNEXTComplete Stereochemistry of TetrafibricinYoshihisa Kobayashi, Werngard Czechtizky, and Yoshito KishiView Author Information Department Chemistry Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138 Cite this: Org. Lett. 2003, 5, 1, 93–96Publication Date (Web):December 13, 2002Publication History Received15 November 2002Published online13 December inissue 1 January...
Abstract A main challenge in drug discovery is finding molecules with a desirable balance of multiple properties. Here, we focus on the task molecular optimization, where goal to optimize given starting molecule towards This can be framed as machine translation problem natural language processing, our case, translated into optimized properties based SMILES representation. Typically, chemists would use their intuition suggest chemical transformations for being optimized. widely used strategy...
A protocol for simulating intrinsically disordered peptides in aqueous and hydrophobic solvents is proposed. Results from four force fields are compared with experiment. CHARMM36m performs the best simulated IDPs all environments.
Stacks of croconate dianions separated by K+ ions and H2O molecules: the crystal structure potassium dihydrate, K2(C5O5)⋅2 H2O, isolated described Leopold Gmelin more than 170 years ago, has now been established X-ray analysis (see picture). Since anions have a formal charge −2 an interplanar separation only 3.30 Å, is not easily explained in terms simple ionic model.