Study of the aryl hydrocarbon receptor mediated effects through in silico modeling and in vitro bioassays

  1. Goya Jorge, Elizabeth
Supervised by:
  1. Stephen Jones Barigye Director
  2. Rafael Gozalbes Botella Co-director
  3. Rosa Maria Giner Pons Co-director

Defence university: Universitat de València

Fecha de defensa: 20 October 2020

Committee:
  1. Jorge Gálvez Álvarez Chair
  2. Maite Ibarreta Secretary
  3. M. Mar Orzáez Calatayud Committee member
Department:
  1. PHARMACOLOGY

Type: Thesis

Teseo: 638903 DIALNET

Abstract

The aryl hydrocarbon receptor (AhR) is a cytoplasmatic sensor of diverse endogenous and exogenous substances. In a toxicological context, the former known as “dioxin receptor” has been investigated as a xenobiotic chemoreceptor and due to its roles in mediating carcinogenesis, endocrine disruption, among other immunological, hepatic, cardiovascular, and dermal toxicity mechanisms. The deep physiological implications of AhR in cellular proliferation, adhesion, division, differentiation, as well as in the reproductive, immunological and cardiovascular homeostasis have opened a new field of research in order to harness AhR’s pharmacological potential. Hence, AhR has become a therapeutic target of inflammatory, infectious, malignant, and immunological conditions. Toxicological and pharmacological fields could benefit from discovering novel AhR modulators to elucidate further on the chemical-biological implications of this crucial transcription factor. In this Thesis, the following objective was proposed in order to contribute to such understanding. General Objective: Evaluate diverse chemical compounds as modulators of AhR by means of in silico and in vitro methods. The general objective was concretized in specific aims distributed in the five Chapters of this Thesis as follow: Chapter 1. Review the literature on AhR mediated effects and the existing theoretical and experimental methods employed to study the structural and functional aspects of the receptor. Chapter 2. Develop and experimentally validate QSAR models to predict the AhR agonist activity of chemical compounds. Chapter 3. Analyze the dual effects of a set of benzothiazoles as AhR modulators and antimicrobial agents. Chapter 4. Evaluate a novel set of triarylmethane compounds as AhR ligands. Chapter 5. Study the AhR antagonism discovered in potentially harmful substances using computational methods.