A5089192232- Computational Drug Discovery Methods
- Analytical Chemistry and Chromatography
- Synthetic Organic Chemistry Methods
- Machine Learning in Materials Science
- Asymmetric Synthesis and Catalysis
- Coordination Chemistry and Organometallics
- Click Chemistry and Applications
- Protein Structure and Dynamics
- Respiratory viral infections research
- Microbial Natural Products and Biosynthesis
- Cancer therapeutics and mechanisms
- Synthesis and Reactivity of Heterocycles
- Chemical Reaction Mechanisms
- Cancer, Lipids, and Metabolism
- Cancer-related Molecular Pathways
- Catalytic Alkyne Reactions
- Carbohydrate Chemistry and Synthesis
- Inorganic and Organometallic Chemistry
- Protein Degradation and Inhibitors
- HIV/AIDS drug development and treatment
- Catalytic Cross-Coupling Reactions
- Tuberculosis Research and Epidemiology
- Endoplasmic Reticulum Stress and Disease
- Cyclopropane Reaction Mechanisms
- Enzyme Structure and Function
Institut des Hautes Études Scientifiques
2022
Servier (France)
2021-2022
Robert Bosch (Germany)
2019-2021
Laboratoire de Chimie Moléculaire et Thioorganique
2021
Magneto Special Anodes (Netherlands)
2021
Weatherford College
2021
Janssen (France)
2011-2020
Janssen (Belgium)
2013-2019
Sorbonne Université
1995-2016
Centre National de la Recherche Scientifique
1993-2015
The number of protein kinase inhibitors (PKIs) approved worldwide continues to grow steadily, with 39 drugs in the period between 2001 and January 2018. PKIs on market have been subject many reviews, structure-property relationships specific this class inferred. However, large under development is often overlooked. In paper, we present PKIDB (Protein Kinase Inhibitor Database), a monthly-updated database gathering as well currently clinical trials. compiles 180 ranging from phase 0 4 trials...
In the treatment of AIDS, efficacy all drugs, including non-nucleoside inhibitors (NNRTIs) HIV-1 reverse transcriptase (RT), has been limited by rapid appearance drug-resistant viruses. Lys103Asn, Tyr181Cys, and Tyr188Leu are some most common RT mutations that cause resistance to NNRTIs in clinic. We report X-ray crystal structures for complexed with three different pyridinone derivatives, R157208, R165481, R221239, at 2.95, 2.9, 2.43 Å resolution, respectively. All ligands exhibit nanomolar...
The emergence of multidrug-resistant strains Mycobacterium tuberculosis and resistance to current anti-TB drugs call for the discovery development new effective drugs. TMC207 is lead candidate a novel class antimycobacterial agents, diarylquinolines, which specifically inhibit mycobacterial ATP synthase displays high activity against both drug-susceptible tuberculosis. This article covers synthesis pathways as well qualitative quantitative analyses structure-activity relationships...
Since the first approval of a protein kinase inhibitor (PKI) by Food and Drug Administration (FDA) in 2001, 55 new PKIs have reached market, many inhibitors are currently being evaluated clinical trials. This is clear indication that kinases still represent major drug targets for pharmaceutical industry. In previous work, we introduced PKIDB, publicly available database, gathering already been approved (Phase 4), as well those trials (Phases 0 to 3). database updated frequently, an analysis...
ADVERTISEMENT RETURN TO ISSUEPREVCommunicationNEXTRing Opening in the Hydrostannation of Methylenecyclopropanes: Effect Catalyst and SubstrateMark Lautens, Christophe Meyer, Alexander LorenzView Author Information Department Chemistry, University Toronto Toronto, Ontario Canada M5S 3H6 Cite this: J. Am. Chem. Soc. 1996, 118, 43, 10676–10677Publication Date (Web):October 30, 1996Publication History Received26 July 1996Published online30 October inissue 1 January...
A preceding paper (Bonfanti et al. J. Med Chem. 2007, 50, 4572−4584) reported the optimization of pharmacokinetic profile substituted benzimidazoles by reducing their tissue retention. However, modifications that were necessary to achieve this goal also led a significant drop in anti-RSV activity. This describes molecular modeling study followed lead program recovery initial potent antiviral activity and selection TMC353121 as clinical candidate.
Compound selectivity is an important issue when developing a new drug. In many instances, lack of can translate to increased toxicity. Protein kinases are particularly concerned with this because they share high sequence and structural similarity. However, may be assessed early on using data generated from protein kinase profiling panels. To guide lead optimization in drug discovery projects, we propose herein two metrics, namely window score (WS) ranking (RS). These metrics applied standard...
The accurate prediction of molecular properties, such as lipophilicity and aqueous solubility, are great importance pose challenges in several stages the drug discovery pipeline. Machine learning methods, graph-based neural networks (GNNs), have shown exceptionally good performance predicting these properties. In this work, we introduce a novel GNN architecture, called directed edge graph isomorphism network (D-GIN). It is composed two distinct sub-architectures (D-MPNN, GIN) achieves an...
R207910 is an enantiomeric compound from a new class of antimycobacterial agents, the diarylquinolines [Science; 307 :223 (2005)]. As enantiospecific interaction required for biologic activity, we have undertaken combined nuclear magnetic resonance and molecular modeling study to gain insights into its conformation in solution absolute configuration. A conformational analysis using Monte‐Carlo method has been performed on each four possible stereomers this leading identification their most...
3- and 4-Hydroxypyridines exist in their enolic form, the gas phase, as evidenced by similarity of deuterium isotope effects on loss CO, calculated nearly equimolar mixtures HO- DO-pyridines. This is confirmed analysis metastable ratios evaluated hydroxypyridine fragment ions same produced direct ionization. 2-Hydroxypyridine shows a weaker effect for reaction this study an mixture 2-ethoxy- 2-ethoxy-d 5 -pyridines. It shown that 2-hydroxypyridine also exists its phase.
Abstract As the application of computational methods in drug discovery pipelines becomes more widespread it is increasingly important to understand how reproducible their results are and sensitive they choices made simulation setup analysis. Here we use ensemble protocols, termed ESMACS (enhanced sampling molecular dynamics with approximation continuum solvent), investigate sensitivity popular mechanics Poisson-Boltzmann surface area (MMPBSA) methodology. Using bromodomain-containing protein...
In a program to optimize the anti-HIV activity of 4-benzyl and 4-benzoyl-3-dimethylaminopyridinones 9 10, lead compounds in new class highly potent non-nucleoside type inhibitors HIV-1 reverse transcriptase, modification alkyl substitutents at C-5 C-6 positions on pyridinone ring C-3 amino group has been studied. Of 17 5/6-modified analogues prepared, 31b 32b substituted by an extended nonpolar chain containing ether function methyl compound 35 bearing ethyl/C-6 hydroxymethyl substituent...
Fragment-based drug design is an established routine approach in both experimental and computational spheres. Growing fragment hits into viable ligands has increasingly shifted the spotlight. FastGrow application based on a shape search algorithm that addresses this challenge at high speeds of few milliseconds per fragment. It further features pharmacophoric interaction description, ensemble flexibility, as well geometry optimization to become fully fledged structure-based modeling tool. All...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTConformational analysis of 4,1',6'-trichloro-4,1',6'-trideoxy-galacto-sucrose (Sucralose) by a combined molecular-modeling and NMR spectroscopy approachChristophe Meyer, Serge Perez, Catherine Herve du Penhoat, Veronique MichonCite this: J. Am. Chem. Soc. 1993, 115, 22, 10300–10310Publication Date (Print):November 1, 1993Publication History Published online1 May 2002Published inissue 1 November...
Because of the success imatinib, first type-II kinase inhibitor approved by FDA in 2001, sustained efforts have been made pharmaceutical industry to discover novel compounds stabilizing inactive conformation protein kinases. On seven inhibitors having reached market, four were released 2012, suggesting an acceleration research such a class compounds. Still, they represent less than third available patients today. The identification key residues involved binding this type ligands active site...
Over the past two decades, use of fragment-based lead generation has become a common, mature approach to identify tractable starting points in chemical space for drug discovery process. This naturally involves study binding properties highly heterogeneous ligands. Such datasets challenge computational techniques provide comparable free energy estimates from different modes. The performance range statistically robust ensemble-based calculation protocols, called ESMACS (enhanced sampling...
So far, 518 protein kinases have been identified in the human genome. They share a common mechanism of phosphorylation and are involved many critical biological processes eukaryotic cells. Deregulation kinase function induces severe illnesses such as cancer, diabetes, or inflammatory diseases. Many actors pharmaceutical domain made significant efforts to design potent selective inhibitors new potential drugs. Because ATP binding site is highly conserved family, remains challenge has...
Starting from the (Z)-β-iodo acrylate, (E)-or (Z)-γ-iodo allylic alcohols, amines, as well acroleins are very easily obtained.