Implementing a fragment-based screening approach to find news therapeutics molecules : application to the design of news humans cyclophilins inhibitors.

La découverte et le développement d'un médicament est un processus long et très coûteux. Pour améliorer ce processus, une nouvelle approche de criblage et de conception rationnelle de nouveaux ligands est apparue durant la dernière décennie. Elle se base sur le criblage par des techniques de biophysique structurale, de petites molécules organiques appelées "fragments". Ces fragments sont caractérisés par une faible affinité pour la cible mais par une grande efficacité de liaison. Cette approche a été mise en place au CBS et appliquée à la découverte de nouveaux inhibiteurs des cyclophilines humaines. Les cyclophilines (Cyps) sont des protéines ubiquitaires chez l'Homme. Elles possèdent une activité peptidyl-prolyl cis-trans isomèrase et aident au repliement des protéines. Il a été montré que le développement d'inhibiteurs de ces protéines pourrait déboucher sur de nouveaux traitements pour des pathologies telles que le VIH, le VHC, certains cancers ou Alzheimer. Nous avons découvert, par un criblage RMN puis une validation par cristallographie aux rayons X, 14 fragments-touches millimolaires sur les Cyps. Ces fragments-touches ont permis de déterminer une nouvelle famille chimique d'inhibiteurs des Cyps. Le meilleur inhibiteur possède une activité 1-10 µM sur CypA, B et D, et de la dizaine de micromolaires sur la réplication du VHC dans les cellules. Un brevet a été déposé sur cette famille chimique.Drug discovery and development is a long and expensive process. To improve this process, a new approach of creening and rational drug design appeared during the last decade. This approach is based on screening of small organic compounds called "fragments" by structural biophysic techniques. These fragments are characterized by low affinity for the target but high ligand efficiency. This approach was implemented at the CBS and applied to find new human cyclophilin inhibitors. Cyclophilins (Cyps) are ubiquitous proteins in Human. They have a peptidyl-prolyl cis-transisomerase activity and help protein folding. It was shown that development of inhibitors for these proteins could lead to new treatments against HIV, HCV, cancers or Alzheimer diseases for example. We discovered 14 fragment hits in the millimolar range on the Cyps by NMR screening and further validation by X-ray crystallography. With these fragment hits, we identified a new family of chemical inhibitors of the Cyps. The best inhibitor has 1-10 µM activity on CypA, B and D, and around 10 micromolar activity on HCV replication in cells. A patent has been deposited for this family of chemical inhibitors

e-Drug3D: 3D structure collections dedicated to drug repurposing and fragment-based drug design

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Visual Characterization and Diversity Quantification of Chemical Libraries: 2. Analysis and Selection of Size-Independent, Subspace-Specific Diversity Indices

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AI4DR: Development and implementation of an annotation system for high-throughput dose-response experiments

One of the common strategies to identify novel chemical matter in drug discovery consists in performing a High Throughput Screening (HTS). However, the large amount of data generated at the dose-response (DR) step of an HTS campaign requires a careful analysis to detect artifacts and correct erroneous datapoints before validating the experiments. This step which requires to review each DR experiment can be time consuming and prone to human errors or inconsistencies. AI4DR is a system that has been developed for the classification of DR curves based on a Convolutional Neural Network (CNN) acting on normalized images of the DR curves. AI4DR allows the annotation in minutes of thousands of curves among 14 categories to help the High Throughput Screening biologists in their analyses. Several categories are associated with active and inactive compounds, other categories correspond to features of interest such as the presence of noise, a weaker effect at high doses, or a suspiciously weak or strong slope at the inflexion point of the DR curves of actives. The classifier has been trained on an algorithmically generated dataset curated and refined by experts, tested using real screening campaigns and improved using thousands of annotations by experts. The solution is deployed using a MLFlow model server interfaced with the Genedata Screener data analysis software used by the end users. AI4DR improves the consistency, the robustness, and the speed of HTS data analysis as well as reducing the human effort to identify faster new medicines for patients

Mining collections of compounds with Screening Assistant 2

International audienceHigh-throughput screening assays have become the starting point of many drug discovery programs for large pharmaceutical companies as well as academic organisations. Despite the increasing throughput of screening technologies, the almost infinite chemical space remains out of reach, calling for tools dedicated to the analysis and selection of the compound collections intended to be screened

Visual Characterization and Diversity Quantification of Chemical Libraries: 2. Analysis and Selection of Size-Independent, Subspace-Specific Diversity Indices

High Throughput Screening (HTS) is a standard technique widely used to find hit compounds in drug discovery projects. The high costs associated with such experiments have highlighted the need to carefully design screening libraries in order to avoid wasting resources. Molecular diversity is an established concept that has been used to this end for many years. In this article, a new approach to quantify the molecular diversity of screening libraries is presented. The approach is based on the Delimited Reference Chemical Subspace (DRCS) methodology, a new method that can be used to delimit the densest subspace spanned by a reference library in a reduced 2D continuous space. A total of 22 diversity indices were implemented or adapted to this methodology, which is used here to remove outliers and obtain a relevant cell-based partition of the subspace. The behavior of these indices was assessed and compared in various extreme situations and with respect to a set of theoretical rules that a diversity function should satisfy when libraries of different sizes have to be compared. Some gold standard indices are found inappropriate in such a context, while none of the tested indices behave perfectly in all cases. Five DRCS-based indices accounting for different aspects of diversity were finally selected, and a simple framework is proposed to use them effectively. Various libraries have been profiled with respect to more specific subspaces, which further illustrate the interest of the method

Visual Characterization and Diversity Quantification of Chemical Libraries: 1. Creation of Delimited Reference Chemical Subspaces

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Synthesis and biological evaluation of 2,3-bis(het)aryl-4-azaindole derivatives as protein kinase inhibitors

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