Date : 29/04/2009

Laboratory
Molecules Therapeutiques in silico (MTi)
Université Paris Diderot - Inserm U973
Batiment Lamarck, 5e etage
5 rue Marie-Andrée Lagroua Weill-Halle
75205 PARIS CEDEX 13
Director : Bruno VILLOUTREIX

PhD Supervisor
Maria Miteva
email : Cet e-mail est protégé contre les robots collecteurs de mails, votre navigateur doit accepter le Javascript pour le voir
phone : +33 157278392

Subjects / Tools-Methodologies:
1 : drug design / in silico lead discovery and optimisation
2 : in silico screening / structure-based, ligand-based, docking
3 : structural bioinformatics / protein electrostatics, molecular dynamics

Website : www.mti.univ-paris-diderot.fr

Summary of lab's interests

The laboratory MTi Inserm-Univ. Paris 7 Unit U973 has been created in 2001 by Dr. Villoutreix who has been awarded the "Inserm Avenir" grant (MTi stands for Search for therapeutic molecules using in silico approaches). Since January 2009, MTi includes 15 staff researchers, 6 postdocs, 5 PhD students and 6 MSc students. Integrated bioinformatics and chemoinformatics approaches are known to facilitate investigation of therapeutic targets and identification of drug-like compounds. Indeed, recent reports suggest that computational methods can save about 2-3 years and significantly lower the cost of the overall process. The MTI project entitled holistic in silico approaches to support effective design of Therapeutic Molecules aims at: the development of new methods in the fields of bioinformatics and chemoinformatics, the identification of small bio-active chemical compounds using in silico screening experiments, the validation of new therapeutic targets through bioinformatics strategies, providing free computer packages to the scientific community. MTi has tight collaborations with two IBiSA platforms called RPBS (structural bioinformatics) and cDithem (drug discovery). During the last 4 years, our group working on in silico screening has published 85 research articles while we have 7 patents issued or pending.
The PhD supervisor is the senior scientist Dr. Maria Miteva, CR1 Inserm HDR (author and co-author of 34 papers, 11 reviews, 1 patent in the fields of structure-based virtual screening/drug design, computational biophysics; large experience on development of new bioinformatics and chemoinformatics methods; a member of the editorial board of Computational Biololy and Chemistry., Dove, and extensive international research experience).

Summary of project

Virtual screening has become an established tool for discovering new hits or chemical probes. The screening of large, lead-like libraries in silico against a given target very often results in the identification of active compounds (1-5). In recent years fragment-based drug discovery (FBDD) has emerged as an important tool for discovery of new hit compounds or molecular probes for studying protein functions. This technique focuses on low-molecular-weight compounds (<300 Da) that target subpockets within an active site, which once identified, can be joined or merged to make high affinity ligands. The relative smaller size of fragments means the chemical space of an active site can be probed with significantly fewer compounds (several thousand compared to several hundred of thousand for HTS). Virtual screening of a fragment library tends to be a primary filter used when selecting fragments before a more labour and resource intensive biophysical screening assay is used to confirm active compounds. In spite of the growing interest in fragment based virtual screening the applicability of existing in silico methodology to FBDD has not been fully investigated. The objective of this proposal is to evaluate existing in silico tools for fragment-based virtual screening, to propose an optimised workflow of fragment-based virtual screening, and to apply it to discovering new hit molecules or chemical probes for relevant protein targets. Using existing fragment data a variety of procedures such as docking, pharmacophore based methods and scoring functions will be assessed for their applicability to FBDD, and where possible, refinements and improvements will be made. Further to this, the Drug Design group of Sanofi Aventis, who have vast experience in the virtual screening of fragments is ready to follow the advancement of the study together with our laboratory and will provide advice and recommendations during regular common meetings.

1.Receptor-based virtual ligand screening for the identification of novel CDC25 phosphatase inhibitors. Montes M, Braud E, Miteva MA, Goddard ML, Mondésert O, Kolb S, Brun MP, Ducommun B, Garbay C, Villoutreix BO. J Chem Inf Model. 2008 Jan;48(1):157-65.
2.Design of protein membrane interaction inhibitors by virtual ligand screening, proof of concept with the C2 domain of factor V. Segers K, Sperandio O, Sack M, Fischer R, Miteva MA, Rosing J, Nicolaes GA, Villoutreix BO. Proc Natl Acad Sci U S A. 2007 Jul 31;104(31):12697-702.
3.MS-DOCK: accurate multiple conformation generator and rigid docking protocol for multi-step virtual ligand screening. Sauton N, Lagorce D, Villoutreix BO, Miteva MA.BMC Bioinformatics. 2008 Apr 10;9:184.
4.AMMOS: Automated Molecular Mechanics Optimization tool for in silico Screening. Pencheva T, Lagorce D, Pajeva I, Villoutreix BO, Miteva MA. BMC Bioinformatics. 2008 Oct 16;9:438. 5.Personal communication members of Drug Design group Sanofi Aventis, Paris research centre.