Nathalie Lagarde

Nathalie Lagarde
Conservatoire National des Arts et Métiers | CNAM · Laboratoire GBCM

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36
Publications
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442
Citations

Publications

Publications (36)
Preprint
The study of protein molecular surfaces enable to better understand and predict protein interactions. Different methods have been developed in computer vision to compare surfaces that can be applied to protein molecular surfaces. The present work proposes a method using the the Wave Kernel Signature : Protein LOcal Surficial Similarity Screening (P...
Article
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Cytochrome P450 2C9 (CYP2C9) is a major drug-metabolizing enzyme that represents 20% of the hepatic CYPs and is responsible for the metabolism of 15% of drugs. A general concern in drug discovery is to avoid the inhibition of CYP leading to toxic drug accumulation and adverse drug-drug interactions. However, the prediction of CYP inhibition remains...
Article
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The aim of this study was to investigate the chemical space and interactions of natural compounds with sulfotransferases (SULTs) using ligand- and structure-based in silico methods. An in-house library of natural ligands (hormones, neurotransmitters, plant-derived compounds and their metabolites) reported to interact with SULTs was created. Their c...
Article
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Motivation The investigation of the structure of biological systems at the molecular level gives insight about their functions and dynamics. Shape and surface of biomolecules are fundamental to molecular recognition events. Characterizing their geometry can lead to more adequate predictions of their interactions. In the present work, we assess the...
Article
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We provide an unsupervised adaptive sampling strategy capable of producing μs-timescale molecular dynamics (MD) simulations of large biosystems using many-body polarizable force fields (PFF). The global exploration problem is decomposed into a set of separate MD trajectories that can be restarted within a selective process to achieve sufficient pha...
Article
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The estrogen receptors α (ERα) are transcription factors involved in several physiological processes belonging to the nuclear receptors (NRs) protein family. Besides the endogenous ligands, several other chemicals are able to bind to those receptors. Among them are endocrine disrupting chemicals (EDCs) that can trigger toxicological pathways. Many...
Article
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Background Despite the improvement of relapse-free survival mediated by anti-angiogenic drugs like sunitinib (Sutent®), or by combinations of anti-angiogenic drugs with immunotherapy, metastatic clear cell Renal Cell Carcinoma (mccRCC) remain incurable. Hence, new relevant treatments are urgently needed. The VEGFs coreceptors, Neuropilins 1, 2 (NRP...
Chapter
Prior to any docking study, the virtual compounds database that will be screened must be carefully selected and prepared. This compound collection, often referred to as the virtual library, can encompass up to millions of compounds. Already prepared virtual libraries can be used, but users can also generate their own. In this chapter, we will prese...
Preprint
Full-text available
Background Despite the improvement of relapse-free survival mediated by anti-angiogenic drugs like sunitinib (Sutent ®), or by combinations of anti-angiogenic drugs with immunotherapy, metastatic clear cell Renal Cell Carcinoma (mccRCC) remain incurable. Hence, new relevant treatments are urgently needed. The VEGFs coreceptors, Neuropilins 1, 2 (NR...
Preprint
Full-text available
We provide a new unsupervised adaptive sampling strategy capable of producing microsecondtimescale molecular dynamics (MD) simulations using many-body polarizable force fields (PFF) on modern supercomputers. The global exploration problem is decomposed into a set of separate MD trajectories that can be restarted within an iterative/selective proces...
Preprint
Full-text available
We provide an unsupervised adaptive sampling strategy capable of producing microseconds-timescale molecular dynamics (MD) simulations of large biosystems using many-body polarizable force fields (PFF). The global exploration problem is decomposed into a set of separate MD trajectories that can be restarted within a selective process to achieve suff...
Preprint
Full-text available
Background: Despite the improvement of relapse-free survival mediated by anti-angiogenic drugs like sunitinib (Sutent ®), or by combinations of anti-angiogenic drugs with immunotherapy, metastatic clear cell Renal Cell Carcinoma (mccRCC) remain incurable. Hence, new relevant treatments are urgently needed. The VEGFs coreceptors, Neuropilins 1, 2 (N...
Article
Full-text available
Background: Different types of in silico approaches can be used to predict the phenotypic consequence of missense variants. Such algorithms are often categorized as sequence based or structure based, when they necessitate 3D structural information. In addition, many other in silico tools, not dedicated to the analysis of variants, can be used to g...
Article
We describe herein the synthesis, characterization and biological studies of novel PEGylated triarylmethanes. Non-symmetrical and symmetrical triarylmethanes series have been synthesized by Friedel-Crafts hydroxyalkylation or directly from bisacodyl respectively followed by a functionalization with PEG fragments in order to increase bioavailability...
Article
Full-text available
The androgen receptor (AR) is a transcription factor that plays a key role in sexual phenotype and neuromuscular development. AR can be modulated by exogenous compounds such as pharmaceuticals or chemicals present in the environment, and particularly by AR agonist compounds that mimic the action of endogenous agonist ligands and whether restore or...
Article
Full-text available
Chemical biology and drug discovery are complex and costly processes. In silico screening approaches play a key role in the identification and optimization of original bioactive molecules and increase the performance of modern chemical biology and drug discovery endeavors. Here, we describe a free web-based protocol dedicated to small-molecule virt...
Article
Full-text available
Clear cell Renal Cell (RCC) and Head and Neck Squamous Cell Carcinomas (HNSCC) are characterized by a pro-angiogenic/pro-inflammatory context. Despite conventional or targeted therapies, metastatic RCC and HNSCC remain incurable. Alternative treatments to reference therapies (sunitinib, a multi tyrosine kinase inhibitor for RCC or cisplatin for HNS...
Article
Full-text available
Nuclear receptors (NRs) are transcription factors that regulate gene expression in various physiological processes through their interactions with small hydrophobic molecules. They constitute an important class of targets for drugs and endocrine disruptors and are widely studied for both health and environment concerns. Since the integration of neg...
Article
Full-text available
Drug discovery is a long and difficult process that benefits from the integration of virtual screening methods in experimental screening campaigns such as to generate testable hypotheses, accelerate and/or reduce the cost of drug development. Current drug attrition rate is still a major issue in all therapeutic areas and especially in the field of...
Article
Protein‐protein interactions control a large range of biological processes and their identification is essential to understand the underlying biological mechanisms. To complement experimental approaches, in silico methods are available to investigate protein‐protein interactions. Cross‐docking methods, in particular, can be used to predict protein...
Preprint
Full-text available
Protein-protein interactions control a large range of biological processes and their identification is essential to understand the underlying biological mechanisms. To complement experimental approaches, in silico methods are available to investigate protein-protein interactions. Cross-docking methods, in particular, can be used to predict protein...
Article
In this work, a serie of cyclocoumarol derivatives was designed, synthesized, characterized and studied for their potentialities as selective inhibitors of COX-2. All target compounds have been screened for their anti-inflammatory activity by the assay of PGE2 production. Among them, compound 5d exhibited the most potent inhibitory activity with a...
Article
Full-text available
Virtual Screening (VS) is designed to prospectively help identifying potential hits, i.e., compounds capable of interacting with a given target and potentially modulate its activity, out of large compound collections. Among the variety of methodologies, it is crucial to select the protocol that is the most adapted to the query/target system under s...
Article
Full-text available
Inflammation is a complex phenomenon necessary in human defense mechanisms but also involved in the development of some human diseases. The discovery of cyclooxygenase-2 (COX-2) improved the pharmacology of nonsteroidal anti-inflammatory drugs (NSAID) giving a clear mechanism for prostaglandin regulation in vivo and providing a new target for the d...
Article
Nuclear receptors (NRs) constitute an important class of therapeutic targets. During the last 4 years, we tackled the pharmacological profile assessment of NR ligands for which we constructed the NRLiSt BDB. We evaluated and compared the performance of different virtual screening approaches: mean of molecular descriptor distribution values, molecul...
Article
Full-text available
Nuclear receptors (NRs) constitute an important class of therapeutic targets. We evaluated the performance of 3D structure-based and ligand-based pharmacophore models in predicting the pharmacological profile of NRs ligands using the NRLiSt BDB database. We could generate selective pharmacophores for agonist and antagonist ligands and we found that...
Article
Virtual screening methods are commonly used nowadays in drug discovery processes. However, to ensure their reliability, they have to be carefully evaluated. The evaluation of these methods is often realized in a retrospective way, notably by studying the enrichment of benchmarking datasets. To this purpose, numerous benchmarking datasets were devel...
Article
Virtual screening is widely used in drug discovery processes.Structure selection in structure-based virtual screening methods is still problematic. We showed that simple and “low cost” binding site physico-chemical properties could be used to guide structure selection.The evaluation of virtual screening methods, necessary to ensure their reliabilit...
Article
The evaluation of virtual ligand screening methods is of major importance to ensure their reliability. Taking into account the agonist/antagonist pharmacological profile should improve the quality of the benchmarking datasets since the ligand binding can induce conformational changes in the nuclear receptor structure and such changes may vary accor...
Article
Nuclear receptors (NRs) constitute an important class of drug targets. We created the most exhaustive NR-focused benchmarking database to date, the NRLiSt BDB (NRs ligands and structures benchmarking database). The 9905 compounds and 339 structures of the NRLiSt BDB are ready for structure-based and ligand-based virtual screening. In the present st...
Article
We describe the synthesis of a library of new pseudopeptides and their inhibitory activity of the rabbit 20S proteasome chymotrypsin-like (ChT-L) activity. We replaced a natural a-amino acid by an alpha- or a beta-hydrazino acid and obtained inhibitors of proteasome up to a submicromolar range (0.7 mu M for molecule 24b). Structural variations infl...
Article
Structure Based Virtual Ligand Screening (SBVLS) methods are widely used in drug discovery programs. When several structures of the target are available, protocols based either on single structure docking or on ensemble docking can be used. The performance of the methods depends on the structure(s) used as a reference, whose choice requires retrosp...
Article
Zanthoxylum chiloperone var. angustifolium root bark was studied with the aim of finding novel molecules able to overcome cancer stem cell chemoresistance. Purification of a methanol-soluble extract resulted in the isolation of a known pyranocoumarin, trans-avicennol (1). Compound 1 demonstrated antiproliferative activity on glioma-initiating cells...

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