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2P2idb : Une Base De Données Dediée a La Druggabilité Des Aix-Marseille Université CRCM, Inserm UMR 1068, CNRS UMR 7258 --------- a Centre de Recherche en Cancérologie de Marseille --------- Thèse de Doctorat Bioinformatique, Biochimie Structurale et Génomique 2P2I DB : UNE BASE DE DONNÉES DEDIÉE A LA DRUGGABILITÉ DES INTERACTIONS PROTÉINE-PROTÉINE Présentée par Raphaël BOURGEAS Sous la direction du Dr. Philippe ROCHE Devant le jury composé de : Pr. Pedro Coutinho - Président du Jury Dr. Maria Miteva - Rapporteur Dr. Françoise Ochsenbein - Rapporteur Dr. Philippe Roche - Directeur de thèse Soutenance le 20 décembre 2012 TABLE DES MATIERES TABLE DES MATIERES ............................................................................................. 5 REMERCIEMENTS ...................................................................................................... 8 LISTE DES ABREVIATIONS .................................................................................. 10 AVANT-PROPOS ...................................................................................................... 11 LISTE DES PUBLICATIONS ................................................................................... 13 INTRODUCTION ...................................................................................................... 15 PREAMBULE ............................................................................................................................. 15 I.1 LES PROTEINES , CIBLES MOLECULAIRES THERAPEUTIQUES ............................................. 15 I.2 LE XX EME SIECLE : L’ERE DES ENZYMES ........................................................................... 15 I.3 AU-DELA DES CIBLES TRADITIONNELLES .......................................................................... 17 I LES INTERACTIONS PROTEINE -PROTEINE ....................................................................... 19 I.1 LES INTERACTIONS PROTEINE -PROTEINE : ETUDIER ET CLASSIFIER ................................ 19 I.1.A Les réseaux d'interactions ..................................................................................................... 19 I.1.B Les différents types d’interactions protéine -protéine ....................................................... 22 I.2 MODULER L ’INTERACTION ENTRE DEUX PARTENAIRES PROTEIQUES ............................. 25 I.2.A Des dogmes remis en causes ................................................................................................ 26 I.2.B Preuves de concept et réussites ............................................................................................ 26 I.2.C Nouveaux défis : Druggabilité et Chimiothèques ............................................................. 27 II LA DRUGGABILITE DES INTERFACES PROTEINE -PROTEINE ............................................ 29 II.1 QU’EST -CE QUE LA DRUGGABILITE ?................................................................................. 29 II.2 DESCRIPTEURS DES INTERFACES PROTEINE -PROTEINE .................................................... 30 II.2.A « Hot spots » ........................................................................................................................... 30 II.2.B Poches à l’interface ................................................................................................................. 35 II.2.C Taille de l’interface ................................................................................................................. 38 II.2.D Forme de l’interface ............................................................................................................... 40 II.2.E Complémentarité de forme ................................................................................................... 42 II.2.F Composition en acides aminés ............................................................................................. 44 II.2.G Segments à l’interface et classification ................................................................................ 46 II.3 OUTILS BIOINFORMATIQUES ET BASES DE DONNEES ........................................................ 48 III CHIMIOTHEQUES DEDIEES ............................................................................................... 51 III.1 UNIVERS ET ESPACES CHIMIQUES ..................................................................................... 52 III.2 LES OUTILS CHEMOINFORMATIQUES ................................................................................ 53 III.2.A Les descripteurs moléculaires .............................................................................................. 53 III.2.B Diversité moléculaire ............................................................................................................. 55 III.2.C Efficacité de ligand ................................................................................................................. 56 | Table des matières 5 III.3 ESPACE CHIMIQUE DES MODULATEURS PPI S ................................................................... 57 III.4 LES CHIMIOTHEQUES DEDIEES PPI ................................................................................... 60 IV EXEMPLES ET SUCCES ....................................................................................................... 63 IV.1 LE COMPLEXE IL-2/IL-2R ALPHA .......................................................................................... 63 IV.2 LE COMPLEXE BCL -XL/BAK ET LE NAVITOCLAX ............................................................ 66 IV.3 LE COMPLEXE HDM2/ P53 ET LA NUTLINE -3 .................................................................. 68 RESULTATS .............................................................................................................. 73 I LA BASE DE DONNEES STRUCTURALE 2P2I DB ................................................................. 74 I.1 ARTICLE 1 ........................................................................................................................... 75 I.2 DEVELOPPEMENTS ET MISE A JOUR DE LA BASE DE DONNEES 2P2I DB ............................. 89 I.3 ARTICLE 2 ........................................................................................................................... 91 II CHIMIOTHEQUES DEDIEES AUX INTERACTIONS PROTEINE -PROTEINE : 2P2I CHEM ...... 97 II.1 ARTICLE 3 ......................................................................................................................... 101 II.2 CONCLUSION ET PERSPECTIVES ...................................................................................... 137 III ESPACES CHIMIQUES ET MESURES D ’EFFICACITE DES LIGANDS .................................. 141 III.1 MODULATEURS D ’INTERACTIONS PROTEINE-PROTEINE ET INDEX D ’EFFICACITES ...... 141 III.2 ARTICLE 4 ......................................................................................................................... 143 CONCLUSION GENERALE .................................................................................... 153 REFERENCES BIBLIOGRAPHIQUES ................................................................. 157 ANNEXE ................................................................................................................... 169 6 Table des matières | | Table des matières 7 REMERCIEMENTS Je tiens en p remier lieu à remercier le ministère de la recherche ainsi que l’université Aix-Marseille dont les financement m’ont permis de réaliser ce doctorat. Ensuite, bien sûr, merci énormément à mon directeur de thèse, le Dr. Philippe Roche , sans qui je n’aurais p u réaliser cette thèse. Merci pour ta disponiblité : tu es toujours ouvert pour discuter de science, ou plus simplement pour répondre à mes questions, auxquelles tu avais toujours une réponse simple. Merci aussi pour ton soutien et ton implication , tu m’as appris beaucoup. Merci aussi au Dr. Françoise Guerlesquin , qui m’a acceuilli dans son unité lors de mon arrivée dans son laboratoire. Interactions et Modulateurs de Réponses fut une unité merveilleuse pour s’initier à la science. Merci aux membres de notre équipe, « Integrative Structural and Chemical Biology » avec qui j’ai pu partager ces quatre dernières années. Plus particulièrement, merci au Dr. Xavier Morelli , pour tous ses conseils (scientifiques ou non), et d’avoir su créer un climat favorable à l ’émancipation de la chémoinformatique dans son groupe et au Dr. Véronique Hamon pour m’avoir beaucoup appris en chémoinformatique . Merci à tous les étudiants qui se sont un jour arrétés – pour quelques semaines ou quelques années – au bureau 427, pour les agréables moments passés avec vous. Je souhaite aussi remercier tous les enseignants chercheurs avec qui j’ai pu travailler lors de mon monitorat. Merci au Pr. Céline Brochier , pour m’avoir appris à structurer un cours et comment tenir une classe dissipée ! Merci au Dr. Caroline Costedoat , au Dr. Emese Megliecz et au Dr. Benedicte Woerth pour m’avoir appris ce qu’est l’enseignement. Au cours de mon A.T.E.R., j’ai eu la joie de travailler avec le Pr. Jacques Van Helden , merci pour ton enthousiasme et pour m ’avoir montré comment un professeur passioné est capable d’entrainer toute une classe dans sa passion. Merci aussi au Dr. Jean- Pierre Duneau , pour les connaissances sur l’organisation d’un programme universitaire que tu m’as transmis. Je souhaite remercier également les membres d’ UPETEC et particulièrement le Dr. Jean-Pierre Mano , pour avoir partagé avec moi ton savoir sur les systèmes émergents. 8 Remerciements | Et plus personellement…
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