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Les s quences d ADN et d ARN riches en Guanines peuvent adopter des conformations inhabituelles connues sous le nom de G-quadruplexes G4 Les topologies et les formes de ces structures fascinantes sont tr s diverses Les G4 sont stabilis s par la pr sence de cations monovalents et des liaisons Hydrog ne de type Hoogsteen De petites mol cules contribuent galement la formation de formes stables principalement par des interactions d empilement p - p Bien que les G4 soient connus depuis des d cennies l int r t de la communaut scientifique a t stimul par la d couverte de leur effet potentiellement inhibiteur sur la t lom rase une transcriptase inverse impliqu e dans la transformation maligne de la plupart des cellules canc reuses En ce qui concerne la t lom rase le cancer et G4 plusieurs groupes ont t impliqu s dans la d couverte de nouveaux stabilisateurs G4 qui peuvent indirectement inhiber l enzyme Des centaines de ligands ont t identifi s par ce biais au cours de la derni re d cennie et c est encore un domaine tr s actif Prenant en compte les avantages et la facilit qu offre l identification de nouvelles structures l aide de techniques de calcul gr ce des mod les math matiques simples et reproductibles nous avons entrepris un criblage haut d bit et faible co t de calcul afin d identifier de nouveaux ligands G4 Avec l utilisation de la mod lisation QSAR nous pouvons pr dire l IC50 d un ensemble de compos s cong n res Nous avons galement t en mesure de relier les descripteurs mol culaires qui apparaissent dans nos mod les avec des caract ristiques structurales que les tudes de la litt rature scientifique et SAR ont rapport s dans les tudes pr c dentes pour un ensemble de ligands cong n res En outre nous avons construit des mod les diff rents utilisant des ensembles non cong n res de compos s en appliquant une strat gie de consensus et pu identifier six ligands approuv s par la FDA qui stabilisent les structures G4 Par la suite en appliquant des techniques non lin aires et un processus pour le traitement de la base de donn es que nous avons contruite partir de publications ant rieures nous avons effectu un criblage virtuel de plus de 500 000 ligands d une base de donn es commerciale de compos s Nous avons pu identifier de nouveaux ligands avec une puissance plus forte que les pr c dentes qui peuvent galement stabiliser d autres structures G4 impliqu s dans les processus li s au cancer Ces observations ouvrent un spectre large de possibilit s explorer Malgr les limites des techniques de mod lisation QSAR explor es tout au long de ce travail nous consid rons qu elles peuvent tre combin es et utilis es avec soin pour r pondre la recherche de nouveaux stabilisateurs G4 DNA and RNA G-rich sequences can adopt unusual arrangements that are known as G-quadruplexes G4 The topologies and forms of these fascinating structures are very diverse G4 are stabilized by the presence of monovalent cations and Hoogsteen Hydrogen bonds Small molecules also contribute to the formation of stable forms mainly via p-p stacking interactions Although G4s are known for decades interest in this field started with their potential effect on inhibition of telomerase enzyme a Reverse Transcriptase involved in the malignant transformation of most cancer cells With regards to telomerase cancer and G4 several groups have been involved in the discovery of new G4 stabilizers that would indirectly inhibit the enzyme Most of the G4 ligands were identified following this paradigm Hundreds of ligands have been identified during the past decade and this is still a very active field in science Taking into account the advantages and easiness that offers the identification of new structures using computational techniques we built single and reproducible mathematical models with high screening capacity and low computational cost in order to use them on the identification of G4 ligands With the use of QSAR modelling we can predict the telIC50 of a congeneric set of compounds We have also been able to relate the molecular descriptors that appear in ours models with some structural features that scientific literature and SAR studies have reported in previous studies as appropriated for describing the above mentioned activity also for congeneric set of ligands Moreover we built different models using non congeneric sets of compounds applying a consensus strategy and could identify six FDA approved ligands that stabilize G4 structures Subsequently by applying nonlinear techniques and a process for the cure of the database proposed for us in previous publications we have performed a virtual screening of more than 500 000 ligands from a commercial database of compounds followed of structure-based model in order to reduce the number of candidates We were able to identify new ligands with stronger potency than the previous ones which can also stabilize other G4 structures involved in processes related to cancer These observations open a wide-ranging spectrum of possibilities to be explored Despite the limitations of the QSAR modelling techniques explored along this work we consider they can be combined and used carefully to address the search for new G4 stabilizers BORDEAUX2-Bib lectronique 335229905 Sudoc BORDEAUX1-Bib electronique 335229901 Sudoc Sudoc France FR

Nouveaux ligands de quadruplexes (approches in silico et in vitro)

Novel Quadruplex ligands (in silico and in vitro approaches) / Nouveaux ligands de quadruplexes (approches in silico et ...

Publication search with Relations structure-activité quantitatives as keyword

Nouveaux ligands de quadruplexes (approches in silico et in vitro)

Novel Quadruplex ligands (in silico and in vitro approaches) / Nouveaux ligands de quadruplexes (approches in silico et ...

Publication search
with Relations structure-activité quantitatives as keyword