Date : 4/03/2010

Laboratory

MTi UMR-S 973 (INSERM, Paris 7)
35 rue Hélène Brion, 75205 Paris Cedex 13. 75205 Paris
Director : Villoutreix

PhD Supervisor

Michel Petitjean
email : Cet e-mail est protégé contre les robots collecteurs de mails, votre navigateur doit accepter le Javascript pour le voir
phone : +33 33157278434

Subjects / Tools-Methodologies

1 : drug design/virtual screening
2 : structural bioinformatics/structure-based modeling
3 : P450 cytochromes/geometric modeling of channels

Summary of lab's interests

The MTi (\"Molecules Therapeutiques in-silico\") is a joint research unit Inserm-University Paris 7. The staff includes 18 people permanently affiliated either to the Inserm or the University Paris 7, plus four temporary researchers, four doctoral students and several other graduate students. The MTi projects focussed on (a) the development of new methods in bioinformatics and chemoinformatics, (b) the identification of small bio-active chemical compounds using in silico screening experiments, (c) the validation of new therapeutic targets through bioinformatics strategies, and (d) providing free computer packages to the scientific community. The MTi has several national and international collaborations in the fields of genomics, proteomics, computational biology and chemistry, and drug design.

Summary of project

The cytochrome P450 3A4 (CYP3A4) is a human liver enzyme involved in the metabolization of numerous low molecular weight compounds, including drugs and cosmetics. Hundreds of thousands potential substrates are known, but testing all them biologically is a tedious task. Instead, in-silico tests can be applied in order to detect and rank potential substrates or eliminate the most improbable ones. However, known screening tests are based on empirical rules mainly oriented for pharmacological applications. The virtual screening that we propose is performed through a geometrical modeling of the active site access channels, based on an enhanced alpha-shape model of the enzyme, taking into account the flexibility of the enzyme and of its substrates. The alpha-shapes of the protein are derived from its Delaunay triangulation, and the channels specific to each substrate are computed on the basis of the geometric constraints defined by the tetrahedral cells. The crystallographic structure of the CYP 3A4 is available in the Protein Data Bank, and a large set of its recognized substrates is known. The methodology will be extended to some other human P450 cytochromes having at least one crystallographic structure available in the PDB, such as 1A2, 2D6 (genetic polymorphism), and various isoforms of the 2C and 3A families. This project is a collaborative work with the P450 team of the URA 2096 (CNRS-CEA) located at Saclay. Applicants must be graduated in bioinformatics, chemoinformatics, or computer sciences. They must have good programming skills (C or f77) and a basic knowledge of unix systems. Students in computer science must have a real interest in protein structure modeling.