A5023050947- Protein Structure and Dynamics
- Computational Drug Discovery Methods
- Enzyme Structure and Function
- Receptor Mechanisms and Signaling
- Ion channel regulation and function
- Bioinformatics and Genomic Networks
- Microbial Natural Products and Biosynthesis
- Hemoglobin structure and function
- Cardiac electrophysiology and arrhythmias
- Lipid Membrane Structure and Behavior
- Neuroscience and Neural Engineering
- Trace Elements in Health
- RNA and protein synthesis mechanisms
- Metabolism, Diabetes, and Cancer
- Photoreceptor and optogenetics research
- Enzyme Catalysis and Immobilization
- Pancreatic function and diabetes
- Signaling Pathways in Disease
- Glycosylation and Glycoproteins Research
- Ubiquitin and proteasome pathways
- Machine Learning in Bioinformatics
- Silk-based biomaterials and applications
- Circadian rhythm and melatonin
- NMR spectroscopy and applications
- Crystallization and Solubility Studies
Servier (France)
2013-2022
Institut des Hautes Études Scientifiques
2014-2022
Plateforme Technologique d'Innovation Biomédicale
2022
Inserm
2000-2001
Institut Curie
2000-2001
Institut Pasteur
2000-2001
University of Geneva
2001
Ligand-target residence time is emerging as a key drug discovery parameter because it can reliably predict efficacy in vivo. Experimental approaches to binding and unbinding kinetics are nowadays available, but we still lack reliable computational tools for predicting time. Most attempts have been based on brute-force molecular dynamics (MD) simulations, which CPU-demanding not yet particularly accurate. We recently reported new scaled-MD-based protocol, showed potential prediction...
Over the last 10 years, protein-protein interactions (PPIs) have shown increasing potential as new therapeutic targets. As a consequence, PPIs are today most screened target class in high-throughput screening (HTS). The development of broad chemical libraries dedicated to these particular targets is essential; however, space associated with this 'high-hanging fruit' still under debate. Here, we analyse properties 40 non-redundant small molecules present 2P2I database...
7-Azaindole has been identified as a novel bidentate anchor point for allosteric glucokinase activators. A systematic investigation around three principal parts of the new small molecule activators led to robust SAR in agreement with structural data that also helped assess conformational flexibility activation site. The increase glucose uptake resulting from hepatocytes vitro translated into efficient lowering levels vivo best compounds.
Today, drug discovery routinely uses experimental assays to determine very early if a lead compound can yield certain types of off-target activity. Among such off targets is hERG. The ion channel plays primordial role in membrane repolarization and altering its activity cause severe heart arrhythmia sudden death. Despite routine tests for hERG activity, rather little information available helping medicinal chemists molecular modelers rationally circumvent In this article novel insights into...
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...
Calcium vector protein (CaVP) from amphioxus is a two-domain, calcium-binding (18.3 kDa) of the calmodulin superfamily. Only two four EF-hand motifs (sites III and IV) have significant binding affinity for calcium ions. We determined solution structure domain containing these active sites (C-CaVP: W81−S161), in Ca2+-saturated state, using NMR spectroscopy restrained molecular dynamics. The tertiary similar to other Ca2+-binding domains pair motifs. apo state has spectroscopic thermodynamic...
CaVP (calcium vector protein) is a Ca(2+) sensor of the EF-hand protein family which highly abundant in muscle Amphioxus. Its three-dimensional structure not known, but according to sequence analysis, composed two domains, each containing pair motifs. We determined recently solution C-terminal domain (Trp81-Ser161) and characterized large conformational dynamic changes induced by binding. In contrast, N-terminal (Ala1-Asp86) has lost capacity bind metal ion due critical mutations insertions...
Abstract CaVP is a calcium‐binding protein from amphioxus. It has modular composition with two domains, but only the EF‐hand motifs localized in C‐terminal domain are functional. We recently determined solution structure of this regulatory half (C‐CaVP) Ca 2+ ‐saturated form and characterized stepwise ion binding. This paper reports 15 N nuclear relaxation rates C‐CaVP, measured at four different NMR fields (9.39, 11.74, 14.1, 18.7 T), which were used to map spectral density function for...
For the investigation of protein-ligand interaction patterns, current accessibility a wide variety sampling methods allows quick access to large-scale data. The main example is intensive use molecular dynamics simulations applied crystallographic structures which provide dynamic information on binding interactions in complexes. Chemical feature based pharmacophore models extracted from these simulations, were recently used with consensus scoring approaches identify potentially active...
A lot of attention has been drawn to the voltage gated potassium channel Kv11.1 during last decades. In past, both, ligand and structure based methods intended predict if a small molecule could cause fatal heart arrhythmias, “torsades de pointe” sudden death. However, despite wide interest for hERG, still no experimental 3D is available therefore homology modelling parts (generally only pore domain) currently used gain structural insights [1]. Here novel model hERG presented encompassing...