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Thesis proposal csc 2014

Thesis proposal CSC 2013
Rational antitubercular drug design for targeting the NADH/NAD cofactor bindingsite of enoyl-ACP of Mycobacterium tuberculosis Thesis supervisor:
E-mail address:
PhD School name:
Physics, Chemistry & Material Sciences (SDM) Research Laboratory:
Laboratoire de Chimie de Coordination du CNRS UPR 8241 Laboratory website:
Scientific domain:
Organic chemistry /Medicinal chemistry/ Organic synthesis Subject short description:
Rational antitubercular drug design for targeting the NADH/NAD cofactor bindingsite of enoyl-ACP reductase of Mycobacterium tuberculosis (InhA)» Infections with Mycobacterium tuberculosis (MTB) remain the leading causes ofdeath in the world from a single infectious disease. This unfortunate reality is atleast in part attributable to the resistance of pathogen agents to the two majorantibiotics used in the treatment of this pathology: isoniazid (INH) and rifampicine.
INH is indeed a pro-drug, which need to be activated by an oxidative step. Its activation is ensured by a catalase-peroxidase of MTB called KatG and the activemetabolite formed is an adduct resulting from the association of the isonicotinoylradical and the NAD cofactor (Isonicotinoyl-NADH). This active metabolite targetsdirectly InhA, an enzyme implicated in the system Fatty Acid Synthase-II of MTBthat is responsible for the elongation of fatty acids and hence involved in thesynthesis of mycolic acids, essential constituents of the mycobacterial cell wall.
The isonicotinoyl-NADH adduct is a competitive inhibitor of InhA occupyingessentially the cofactor-binding site. The great interest of InhA as target isassociated to the fact that the FAS-II system, to which the enzyme InhA belongs, isnot found in the humans and that this enzyme is the target of a first-lineantitubercular drug, INH. InhA is so a very interesting target for the discovery ofmedicines with few side effects expected to the host.
Taking into account that INH resistance of MTB strains is mainly due to a fallingactivity of the enzyme responsible for the INH activation (KatG), compoundsnon-KatG dependent targeting directly InhA seems very attractive to overcomesuch resistance phenomena.
In the literature, we have found several works reporting the development of newmolecules targeting directly InhA through interactions with the substrate-bindingsite. However, no drug-candidate arose from this strategy.
Face to this problematic, we propose to design and synthesize a new and anoriginal category of InhA inhibitors targeting, as for the validated antituberculardrug INH, the NADH/NAD+ cofactor-binding site. The design of these newcompounds, analogues of the cofactor, will be assisted by a rational computedmethodology involving structure-based and ligand-based techniques for thedefinition of a pharmacophore. The proof of concept will be validated by acombination of approaches such as: enzymology tests of InhA inhibitory activity,X-ray crystallographic analysis and by biological tests of MTB growth inhibition.
The candidate should be someone of motivated, creative, persevering, with apronounced team spirit and analytical skills in order to be able to successfullyrealize this work in the interface of biology. A good formation in chemistry-biology,a solid know-how in organic chemistry and in multi-step synthesis will be veryappreciated.
Two major publications in the domain of PhD:
V. Bernardes-Génisson, C. Deraeve, A. Chollet, J. Bernadou, G. Pratviel "An updateon the multiple mechanisms for a singularaction". Curr. Med. Chem. 2013, 20, in press.
C. Deraeve, I.M. Dorobantu, F. rebbah, F. Le Quéméner, P. Constant, A. Quémard,V. Bernardes-Génisson, J. Bernadou, G. Pratviel.
Chemical synthesis, biological evaluation and structure-activity relationshipanalysis of azaisoindolinones, a novel class of direct enoy-ACP reductase inhibitorsas potential antimycobacterial agents. Bioorganic & Medicinal Chemistry 2011, 19,6225-6232.
Keywords: InhA, isoniazide, NADH analogue, inhibitors, tuberculosis
Expected collaboration in China:
First name and family name of the laboratory director:
Address of the laboratory director:
205, route de Narbonne 31077 Toulouse cedex 4 Signature and stamp of the laboratory director:
%signature_et_cachet_du_directeur_du_laboratoire

Source: http://www.univ-toulouse.fr/sites/default/files/csc2013/8088_rational_antitubercular_drug_design_for_t.pdf

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Microsoft word - organic lab notebook guidelines.doc

Organic Chemistry Laboratory - Guidelines for Writing the Laboratory Notebook General Information: Each student is required to keep a bound (not spiral or loose-leaf) laboratory notebook that will be collected and graded at various times during the semester. For each experiment you should prepare a written report. These reports do not need to be lengthy. Your aim should be to write repo

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