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Doctoral Thesis
DOI
Document
Author
Full name
Thales Kronenberger
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2017
Supervisor
Committee
Wrenger, Carsten (President)
Nascimento, Alessandro Silva
Palmisano, Giuseppe
Sairre, Mirela Ines de
Title in Portuguese
Sítios de interação alternativos em receptores nucleares e sua viabilidade como alvos terapêuticos usando triagem computacional e experimental.
Keywords in Portuguese
Agonistas inversos
Antagonistas
Descoberta de fármacos
High-throughput screening
Receptor Constitutivo de Androstano
Receptor X de Pregnano
Abstract in Portuguese
Receptores nucleares controlam a transcrição em células eucarióticas quando ativados por ligantes e, além do sítio de interação com ligantes, há outros sítios alternativos em sua superfície que podem ser alvo de compostos capazes de interferir com as interações proteína-proteína desativando o RN. A ativação do Receptor X de Pregnano (RXP) e do Receptor Constitutivo de Androstano (RCA) resulta na indução do metabolismo e efluxo de fármacos. Portanto, RXP/RCA sao responsáveis por causar reações adversas ou falhar terapias. Uma abordagem combinando a triagem experimental à nível cellular, em uma biblioteca de fármacos, e validação com ensaios in vitro e in silico, conseguimos identificar três novos antagonistas de RXP e cinco novos contra RCA, cada um com um perfil único de interação.
Title in English
Targeting alternative ligand-binding sites in nuclear receptors using computational and experimental screening.
Keywords in English
Antagonist
Constitutive Andronstane Receptor
Drug-Discovery
High-throughput screening
Inverse Agonist
Pregnane X Receptor
Abstract in English
Nuclear receptors can control transcription in eukaryotic cells in a ligand-dependent manner and, besides the ligand-binding pocket there is evidence of the existence of alternative ligand-binding sites on the surface, which can be addressed by small organic molecules that disrupt specific protein-protein interactions and thereby may antagonise NR function. Activation of pregnane X receptor (PXR) and constitutive androstane receptor (CAR) results in the induction of first-pass metabolism and drug efflux. Hereby PXR/CAR may cause adverse drug reactions or therapeutic failure of drugs. Therefore, PXR and/or CAR antagonists can minimise adverse effects or improve therapeutic efficiencies. Combination of cellular high-throughput screen identified CAR and PXR potent antagonists in a library of approved and investigational drugs. Further validated by cellular and in vitro assays, as well as molecular docking, suggesting additional or exclusive binding outside the classical ligand binding pocket. In conclusion, we here have identified three approved drugs as novel potent PXR antagonists and five potential CAR inverse agonists with differential receptor interaction profiles.
 
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Release Date
2019-11-17
Publishing Date
2017-11-21
 
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