Targeting alternative ligand-binding sites in nuclear receptors using computational and experimental screening

• Grant number: 14/03644-9
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: November 01, 2014
• End date: May 31, 2017
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal Investigator: Carsten Wrenger
• Grantee: Thales Kronenberger
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated scholarship(s): 14/27313-1 - Targeting alternative ligand-binding sites in nuclear receptors using computational and experimental screening, BE.EP.DR

Abstract

Nuclear receptors are fundamental regulators of several biological processes in which they are controlling the transcription in eukaryotic cells that are modulated in a ligand-dependent manner. Besides the ligand-binding pocket there is experimental evidence of the existence of alternative ligand-binding sites on the surface of the ligand-binding domain which can be addressed by small organic molecules that disrupt specific protein-protein interactions and thereby may antagonize NR function. Mutational studies showed the importance of these sites for the functionality of the protein in vitro, and thereby validating their drug ability. Although the pharmacological potency is obvious there are no inhibitors under clinical investigation yet. This approach opens a door to develop a set of novel nuclear receptor modulators against several diseases such as cancer or diabetes. There is a large amount of structural information about the mechanism and regulation of NR and - in this sense - the implementation of computational approaches for drug screening combined with experimental high-throughputscreening (HTS) technologies will be a milestone in the identification of specific NRligand mimicking inhibitors. This project aims to use the combination of in silico and in vitro drug discovery approaches to interfere with alternative NR ligand binding sites in human cells. (AU)

Scientific publications

(9)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

BURK, OLIVER; KUZIKOV, MARIA; KRONENBERGER, THALES; JESKE, JUDITH; KEMINER, OLIVER; THASLER, WOLFGANG E.; SCHWAB, MATTHIAS; WRENGER, CARSTEN; WINDSHUEGEL, BJOERN. Identification of approved drugs as potent inhibitors of pregnane X receptor activation with differential receptor interaction profiles. ARCHIVES OF TOXICOLOGY, v. 92, n. 4, p. 1435-1451, APR 2018. (14/27313-1, 14/03644-9)

KRONENBERGER, THALES; ASSE, JR., LEONARDO RANDER; WRENGER, CARSTEN; GOULART TROSSINI, GUSTAVO HENRIQUE; HONORIO, KATHIA MARIA; MALTAROLLO, VINICIUS GONCALVES. Studies of Staphylococcus aureus FabI inhibitors: fragment-based approach based on holographic structure-activity relationship analyses. Future Medicinal Chemistry, v. 9, n. 2, p. 135-151, JAN 2017. (14/03644-9, 13/10288-1)

MALTAROLLO, VINICIUS GONCALVES; KRONENBERGER, THALES; WINDSHUEGEL, BJOERN; WRENGER, CARSTEN; GOULART TROSSINI, GUSTAVO HENRIQUE; HONORIO, KATHIA MARIA. Advances and Challenges in Drug Design of PPAR delta Ligands. CURRENT DRUG TARGETS, v. 19, n. 2, p. 144-154, 2018. (14/03644-9, 14/27313-1)

BURK, OLIVER; KRONENBERGER, THALES; KEMINER, OLIVER; LEE, SERENE M. L.; SCHIERGENS, TOBIAS S.; SCHWAB, MATTHIAS; WINDSHUEGEL, BJOERN. Nelfinavir and Its Active Metabolite M8 Are Partial Agonists and Competitive Antagonists of the Human Pregnane X Receptor. MOLECULAR PHARMACOLOGY, v. 99, n. 3, p. 184+, MAR 1 2021. (14/03644-9, 14/27313-1)

GAO, KAI; WANG, WENJIA; KRONENBERGER, THALES; WRENGER, CARSTEN; GROVES, MATTHEW R.. The Crystal Structure of the Plasmodium falciparum PdxK Provides an Experimental Model for Pro-Drug Activation. CRYSTALS, v. 9, n. 10, OCT 2019. (17/03966-4, 14/03644-9, 15/26722-8)

KRONENBERGER, THALES; WINDSHUGEL, BJORN; WRENGER, CARSTEN; HONORIO, KATHIA M.; MALTAROLLO, VINICIUS G.. On the relationship of anthranilic derivatives structure and the FXR (Farnesoid X receptor) agonist activity. JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS, v. 36, n. 16, p. 4378-4391, DEC 10 2018. (14/03644-9, 14/27313-1)

CANDIDO-FERREIRA, IVAN LAVANDER; KRONENBERGER, THALES; ROSA SAYEGH, RAPHAEL SANTA; CORREIA BATISTA, ISABEL DE FATIMA; DA SILVA JUNIOR, PEDRO ISMAEL. Evidence of an Antimicrobial Peptide Signature Encrypted in HECT E3 Ubiquitin Ligases. FRONTIERS IN IMMUNOLOGY, v. 7, JAN 9 2017. (14/03644-9, 13/07467-1)

MEISSNER, KAMILA ANNA; KRONENBERGER, THALES; MALTAROLLO, VINICIUS GONCALVES; GOULART TROSSINI, GUSTAVO HENRIQUE; WRENGER, CARSTEN. Targeting the Plasmodium falciparum plasmepsin V by ligand-based virtual screening. CHEMICAL BIOLOGY & DRUG DESIGN, v. 93, n. 3, p. 300-312, MAR 2019. (14/03644-9, 16/24790-9, 17/03966-4, 15/26722-8)

MALTAROLLO, VINICIUS G.; KRONENBERGER, THALES; WRENGER, CARSTEN; HONORIO, KATHIA M.. Current trends in quantitative structure-activity relationship validation and applications on drug discovery. FUTURE SCIENCE OA, v. 3, n. 4, p. 3-pg., 2017-11-01. (14/27313-1, 14/03644-9)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

KRONENBERGER, Thales. Targeting alternative ligand-binding sites in nuclear receptors using computational and experimental screening.. 2017. Doctoral Thesis - Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI) São Paulo.