Fiorillo, Bianca (2022) Computationally-driven design of bile acids multi-targeting modulators for metabolic and inflammatory diseases. [Tesi di dottorato]


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Item Type: Tesi di dottorato
Resource language: English
Title: Computationally-driven design of bile acids multi-targeting modulators for metabolic and inflammatory diseases
Date: 10 March 2022
Number of Pages: 215
Institution: Università degli Studi di Napoli Federico II
Department: Farmacia
Dottorato: Scienza del farmaco
Ciclo di dottorato: 34
Coordinatore del Corso di dottorato:
D'Auria, Maria
Catalanotti, BrunoUNSPECIFIED
Date: 10 March 2022
Number of Pages: 215
Keywords: Medicinal Chemistry; Computational Chemistry; Molecular Modeling; Molecular Docking; Virtual Screening; Molecular Dynamics; Metadynamics
Settori scientifico-disciplinari del MIUR: Area 03 - Scienze chimiche > CHIM/08 - Chimica farmaceutica
Date Deposited: 16 Mar 2022 15:50
Last Modified: 28 Feb 2024 10:48

Collection description

The PhD thesis is focused on the applications of both classical and advanced computational techniques to the medicinal chemistry field, implemented in various drug discovery campaigns, dealing with different kinds of biological targets. In particular, it focuses on the pharmaceutical design and optimization of new compounds targeting bile acids (BA) receptors, including both Nuclear (NRs) and G-Protein Coupled (GPCRs) receptors. It first deals with the design of steroidal derivatives targeting the nuclear retinoic acid-related orphan receptor γ (ROR-γ) and the membrane receptor G-protein bile acid receptor 1 (GPBAR1) for the treatment of metabolic diseases. Subsequently, the mechanism of action and the pharmacological activity of bile acid derivatives are explored on other different targets. The research activity explored chemical classes of compounds other than bile acids scaffold endowed with pharmacological activity on bile acid receptors, as GPBAR1, leading to the discovery of quinoline scaffold derivatives with dual activity on both GPBAR1 and the cysteinyl leukotriene receptor 1 (CysLT1R). Starting from the characterization of REV5901, the first GPBAR1 agonist with a quinoline moiety studied, and exploring its scaffold, its derivatives with double activity on GPBAR1 and CysLT1R were discovered with therapeutic potential in the treatment of colitis and other inflammatory processes. Additionally, the epidemiological emergency due to the COVID-19 disease was addressed to help fight the current pandemic situation starting a drug-repurposing virtual screening campaign was realized to identify natural and semisynthetic FDA approved drugs binding the SARS-CoV-2 region binding domain (RBD) of the Spike protein and host cell receptor angiotensin-converting enzyme 2 (ACE2). Interestingly, among the FDA-approved drugs, some natural and semisynthetic steroidal scaffold compounds have shown promising results to inhibit the Spike RBD/ACE2 interaction. Furthermore, the research activity has evolved into other scientific projects not related to the identification of dual-activity compounds targeting bile acid receptors. First, the defects underlying the biogenesis of primary cilia, which cause ciliopathies, have been investigated combining in vitro, in vivo and in silico approaches. Second, the characterization of pelargonidin, an AHR agonist, as natural compound for the use in the prevention and treatment of SARS-CoV-2 infection has also been studied and discussed. The last section of this thesis, finally, describes the theoretical computational methods employed to carry out the PhD research activity.


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