HiTS Screening & Drug Design
Eddy Pasquier
Researcher / Team leader
Kevin Muller
Engineer
Magali Saez Ayala
Engineer
Marie-Jeanne Basse
Assistant Engineer
Philippe Roche
Researcher
Sara Scaramuzzino
Engineer
Stéphane Betzi
Researcher
Thomas Miller
Researcher
The HiTS Platform: Accelerating Bioactive Molecule Discovery. The HiTS platform integrates a wide range of expertise and technologies necessary to accelerate the discovery of bioactive molecules using experimental screening (biochemical, in vitro, ex vivo) and in silico drug design strategies (chemoinformatics and molecular modeling). Our objectives are to 1) aide in the discovery, characterization, and validation of novel molecular targets, 2) translate validated targets to actionable drug discovery systems, 3) identify, validate and develop novel bioactive molecules for preclinical and clinical development programs in oncology. The platform is open to the scientific community and can support research projects on a collaborative or service basis.
High-Throughput Screening
The platform offers its collaborators access to a robotic high-throughput screening facility, featuring cutting-edge equipment:
- Chemical library handling: the Echo650 acoustic liquid dispenser for ultra-low volumes (nL), an automatic plate sealer with inert gas exchange, and hermitically-controlled compound storage (PODS) to assure long-term chemical library stability.
- Assay automation: a robotic centrifuge, and a high-performance multi-mode reader (capable of fluorescence, absorbance, and luminescence measurements in up to 1536 well plates), a versatile high-volume dispensing robot, and integration by an Access robotic arm.
The screening platform is configured to maximize experiment automation, data quality and robustness, and the efficiency of data generation. Our unique, state of the art services provide the necessary tools to overcome scientific challenges encountered during the early development of innovative oncology products.
Molecular Modeling for Drug Design
The HiTS platform uniquely integrates high-throughput screening (HTS) expertise with chemoinformatics and molecular modeling, managed by Philippe Roche (from the INT-3D platform). As a result, we offer a comprehensive range of services, including chemical library management and post-screening chemoinformatic analyses, allowing users to perform cost-effective SAR (Structure-Activity Relationship) studies based on available commercial analogs and ready to synthesize commercial libraires. Following our rigorous hit validation procedure, the platform facilitates the transition to the "hit-to-lead" phase, all within the same infrastructure.
Know-how / Technologies
- Expression, production and purification of recombinant proteins
- Assay development for protein-protein or protein-ligand interaction studies (TR-FRET, HTRF, Fluorescence, TSA, enzymatic assays)
- Miniaturization and robotization of assays in 384/1536-well plates
- High-throughput in vitro screening using acoustic technology
- High-throughput in-cell pharmacological screening using 2D and 3D cytotoxicity measurements, in monotherapy and combination, by luminescence, fluorescence and absorbance (Cell Titer Glo, Alamar Blue, Luciferase, Caspase Glo...).
- Biophysical validation of keys (TSA, ITC, X-Ray)
- Chemoinformatics study of key molecules
- Structure-Activity Relationship (SAR) by catalog
- Molecular modeling / Molecular dynamics / Virtual screening
- Hit-to-lead optimization (ChemoDOTS)
- Development of covalent probes (CovaDOTS - CovaLink - CovaGrow - CovaProbe)
Resources
equipment
- ACCESS platform with robotic arm (Beckman)
- Echo650 acoustic transfer (Beckman)
- Versatile distribution Certus Flex (Fritz Gyger)
- Pherastar FS Fluorescence, Absorbance, Luminescence microplate reader (BMG Labtech)
- RT-PCR 384-well CFX384 (Biorad)
- FPLC Akta Pure (Cytivia)
- Microcalorimeter ITC200 (Malvern)
- Incubators (Cell culture/Xray)
- ShortDundee pods (Roylan Developments) for storing chemical libraries under nitrogen.
Chemical libraries
- Protein-protein interaction : Fr-PPIChem 10,314
-Repositioning : Prestwick 1,520
-Fragments : Fragments 1,000
-Crossing the blood-brain barrier : HITCH 110
-Metabolism : METABO 148
-Leukemia : TrGET 42
Database / Servers / Software
- 2P2IDB : protein-protein interaction modulators
- Fr-PPIChemDB : experimental screening
- iscbmolDB : Molecules
- ChemoDOTS : Hit2Lead optimization
- Software used : Modeller - VMD - PyMOL - Charmm - Amber - NAMD - ChemAxon - SeeSAR - LigandScout - RDKit - MOE - PLANTS - DataWarrior - Alphafold - Schrodinger Life Science Suite
Teaching
Platform members are heavily involved in various courses at Aix-Marseilles University and local engineering schools:
- Master 2 Research "Healthcare engineering, drugs and healthcare products" course
- Master 1 Research "Structural Biology and Genomics
- Polytech Marseille
- École Centrale Marseille
Teaching experimental screening for :
- Master 2 Research "Healthcare engineering, drugs and healthcare products" course
- École Centrale Marseille
Featured Publications
04/2024
Hoffer L, Charifi-Hoareau G, Barelier S, Betzi S, Miller T, Morelli X, Roche P.
05/2023
Saez-Ayala M, Hoffer L, Abel S, Ben Yaala K, Sicard B, Andrieu GP, Latiri M, Davison EK, Ciufolini MA, Brémond P, Rebuffet E, Roche P, Derviaux C, Voisset E, Montersino C, Castellano R, Collette Y, Asnafi V, Betzi S, Dubreuil P, Combes S, Morelli X.
09/2023
Ariey-Bonnet J, Berges R, Montero MP, Mouysset B, Piris P, Muller K, Pinna G, Failes TW, Arndt GM, Morando P, Baeza-Kallee N, Colin C, Chinot O, Braguer D, Morelli X, André N, Carré M, Tabouret E, Figarella-Branger D, Le Grand M, Pasquier E.
04/2022
Ganier L, Betzi S, Derviaux C, Roche P, Dessaux C, Muller C, Hoffer L, Morelli X, Borg JP.
03/2020
Ana C. Carrasco, Vanessa Rodríguez-Fanjul, Abraha Habtemariam, and Ana M. Pizarro
04/2020
Bosc N, Muller C, Hoffer L, Lagorce D, Bourg S, Derviaux C, Gourdel ME, Rain JC, Miller TW, Villoutreix BO, Miteva MA, Bonnet P, Morelli X, Sperandio O, Roche P.
