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Rognan D.,CNRS Laboratory for Therapeutic Innovation
Pharmacology and Therapeutics | Year: 2017

Drug discovery is a multidisciplinary and multivariate optimization endeavor. As such, in silico screening tools have gained considerable importance to archive, analyze and exploit the vast and ever-increasing amount of experimental data generated throughout the process. The current review will focus on the computer-aided prediction of the numerous properties that need to be controlled during the discovery of a preliminary hit and its promotion to a viable clinical candidate. It does not pretend to the almost impossible task of an exhaustive report but will highlight a few key points that need to be collectively addressed both by chemists and biologists to fuel the drug discovery pipeline with innovative and safe drug candidates. © 2017 Elsevier Inc.

Thuaud F.,CNRS Laboratory for Therapeutic Innovation | Ribeiro N.,CNRS Laboratory for Therapeutic Innovation | Nebigil C.G.,CNRS Biotechnology and Cell Signaling Laboratory | Desaubry L.,CNRS Laboratory for Therapeutic Innovation
Chemistry and Biology | Year: 2013

Prohibitins (PHBs) are scaffold proteins that modulate many signaling pathways controlling cell survival, metabolism, and inflammation. Several drugs that target PHBs have been identified and evaluated for various clinical applications. Preclinical and clinical studies indicate that these PHB ligands may be useful in oncology, cardiology, and neurology, as well as against obesity. This review covers the physiological role of PHBs in health and diseases and current developments concerning PHB ligands. © 2013 Elsevier Ltd.

Thuong M.B.T.,Novalix Pharma | Thuong M.B.T.,CNRS Laboratory for Therapeutic Innovation | Mann A.,CNRS Laboratory for Therapeutic Innovation | Wagner A.,Laboratory of Functional ChemoSystems
Chemical Communications | Year: 2012

The chemo-selective hydration of a wide range of non-activated terminal alkynes catalysed by AgSbF 6 under mild conditions is reported.

Reber L.L.,Stanford University | Frossard N.,CNRS Laboratory for Therapeutic Innovation
Pharmacology and Therapeutics | Year: 2014

Although mast cells have long been known to play a critical role in anaphylaxis and other allergic diseases, they also participate in some innate immune responses and may even have some protective functions. Data from the study of mast cell-deficient mice have facilitated our understanding of some of the molecular mechanisms driving mast cell functions during both innate and adaptive immune responses. This review presents an overview of the biology of mast cells and their potential involvement in various inflammatory diseases. We then discuss some of the current pharmacological approaches used to target mast cells and their products in several diseases associated with mast cell activation. © 2014 Elsevier Inc. All rights reserved.

Rognan D.,CNRS Laboratory for Therapeutic Innovation
Topics in Current Chemistry | Year: 2012

Fragment-based design has significantly modified drug discovery strategies and paradigms in the last decade. Besides technological advances and novel therapeutic avenues, one of the most significant changes brought by this new discipline has occurred in the minds of drug designers. Fragment-based approaches have markedly impacted rational computer-aided design both in method development and in applications. The present review illustrates the importance of molecular fragments in many aspects of rational ligand design, and discusses how thinking in "fragment space" has boosted computational biology and chemistry. © 2011 Springer-Verlag Berlin Heidelberg.

Weill N.,CNRS Laboratory for Therapeutic Innovation | Rognan D.,CNRS Laboratory for Therapeutic Innovation
Journal of Chemical Information and Modeling | Year: 2010

Inferring the biological function of a protein from its three-dimensional structure as well as explaining why a drug may bind to various targets is of crucial importance to modern drug discovery. Here we present a generic 4833-integer vector describing draggable protein-ligand binding sites that can be applied to any protein and any binding cavity. The fingerprint registers counts of pharmacophore triplets from the Ca atomic coordinates of binding-site-lining residues. Starting from a customized data set of diverse protein-ligand binding site pairs, the most appropriate metric and a similarity threshold could be defined for similar binding sites. The method (FuzCav) has been used in various scenarios: (i) screening a collection of 6000 binding sites for similarity to different queries; (ii) classifying protein families (serine endopeptidases, protein kinases) by binding site diversity; (iii) discriminating adenine-binding cavities from decoys. The fingerprint generation and comparison supports ultra-high throughput (ca. 1000 measures/s), does not require prior alignment of protein binding sites, and is able to detect local similarity among subpockets. It is thus particularly well suited to the functional annotation of novel genomic structures with low sequence identity to known X-ray templates. © 2010 American Chemical Society.

Boudhar A.,CNRS Laboratory for Therapeutic Innovation | Charpenay M.,CNRS Laboratory for Therapeutic Innovation | Blond G.,CNRS Laboratory for Therapeutic Innovation | Suffert J.,CNRS Laboratory for Therapeutic Innovation
Angewandte Chemie - International Edition | Year: 2013

The scaffold of fenestranes is quite unique, as it contains four condensed cycles and a distorted tetracoordinated central carbon atom with bond angles greater than the regular 109°28". In this Minireview, a detailed overview on the developments regarding this compound class, including their synthesis, is given for the time period since 2006. In the past years, natural products that belong to the class of heterofenestranes have been isolated and their syntheses will also be discussed. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Petrignet J.,CNRS Laboratory for Therapeutic Innovation | Boudhar A.,CNRS Laboratory for Therapeutic Innovation | Blond G.,CNRS Laboratory for Therapeutic Innovation | Suffert J.,CNRS Laboratory for Therapeutic Innovation
Angewandte Chemie - International Edition | Year: 2011

A quick and easy way to produce tricycles related to the core structure of taxanes has been achieved using a palladium-catalyzed domino reaction (see scheme, Bz=benzoyl). These studies have been performed with function-oriented synthesis in mind. An efficient route for the construction of new taxane scaffolds that could be decorated with various groups to achieve activities comparable or superior to taxol has been proposed. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Rognan D.,CNRS Laboratory for Therapeutic Innovation
Drug Discovery Today: Technologies | Year: 2013

Docking is the computational method of choice to quickly predict how a low molecular-weight ligand binds to its macromolecular target. Despite persistent problems in predicting binding free energies, docking has undergone significant advances in numerous topics (throughput, target flexibility). The ever increasing availability of high-resolution X-ray structures and the development of more reliable comparative models for proteins of pharmacological interest paved the way to apply protein-ligand docking to multiple targets to predict main and off-targets for bioactive compounds and even to repurpose existing drugs. Applying docking to multiple targets brings an additional level of complexity in scoring numerous and heterogeneous docking poses. Despite undeniable successes, proteome-wide docking should, however, be considered with caution with regard to recall and precision of the predictions. © 2012 Elsevier Ltd. All rights reserved.

Meslamani J.,CNRS Laboratory for Therapeutic Innovation | Rognan D.,CNRS Laboratory for Therapeutic Innovation | Kellenberger E.,CNRS Laboratory for Therapeutic Innovation
Bioinformatics | Year: 2011

Background: The sc-PDB database is an annotated archive of druggable binding sites extracted from the Protein Data Bank. It contains all-atoms coordinates for 8166 protein-ligand complexes, chosen for their geometrical and physico-chemical properties. The sc-PDB provides a functional annotation for proteins, a chemical description for ligands and the detailed intermolecular interactions for complexes. The sc-PDB now includes a hierarchical classification of all the binding sites within a functional class.Method: The sc-PDB entries were first clustered according to the protein name indifferent of the species. For each cluster, we identified dissimilar sites (e.g. catalytic and allosteric sites of an enzyme).Scope and applications: The classification of sc-PDB targets by binding site diversity was intended to facilitate chemogenomics approaches to drug design. In ligand-based approaches, it avoids comparing ligands that do not share the same binding site. In structure-based approaches, it permits to quantitatively evaluate the diversity of the binding site definition (variations in size, sequence and/or structure). © The Author 2011. Published by Oxford University Press. All rights reserved.

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