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2019 | 79 | Suppl.1 |

Tytuł artykułu

Identification of potential Keap1 inhibitors through database analysis based on the designated pharmacophore and QSAR models

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INTRODUCTION: Oxidative stress is the cause of various pathophysiological conditions, including neurodegenerative diseases. Under physiological conditions, Nrf2 transcription factor is associated with the Keap1 inhibitory protein and anchored in the actin cytoskeleton, and hence its transcriptional activity is limited. The Keap1‑Nrf2 regulatory pathway plays an important role in cell protection, therefore the search and design of Nrf2 modulators (inhibitors or activators) becomes a potential therapeutic target. Recent research shows that Keap1 is the key negative Nrf2 regulator, and the development of effective inhibitors that activate the Nrf2 transactivation function by inhibiting the Keap1‑Nrf2 interaction is a promising research direction. AIM(S): Attempt to find Keap1 inhibitors by determining the pharmacophore and analysis of the QSAR models. METHOD(S): The set of data used in the study was composed of activators collected from the literature. Structures of the data set were drawn using ChemBioDraw ultra 12.0. Crystal structure and retrieved from the Protein Data Bank. The 3D‑QSAR pharmacophore model was developed using DS software. RESULTS: Analysis of Keap1 structural features, including active sites and binding sites, and analysis of the privileged structures of already described inhibitors enabled the generation of a pharmacophore. This allowed us to prepare quantitative structure‑activity relationships (QSAR) models. Next, based on the received models, attempts were made to search virtual databases, which resulted in the designation of five potential inhibitors for the Keap1‑Nrf2 complex. CONCLUSIONS: The test effect can be considered satisfactory. Certainly, the analyses carried out were new to the researcher and constitute important grounds for further research. Such analyses provide interesting insights, not only on the problem of Keap1 inhibitors, but also on the use of chemo- and bioinformatic tools in neurobiological sciences.

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  • School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
  • Institute of Chemistry, University of Silesia, Katowice, Poland
  • Faculty of Health Sciences, University of Bielsko‑Biala, Bielsko‑Biala, Poland


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