Barbosa, Euzébio GuimarãesViana, Jéssika de Oliveira2023-09-272023-06-16VIANA, Jéssika de Oliveira. Triagem virtual e identificação do potencial biológico de derivados espiro-acridínicos. Orientador: Euzébio Guimarães Barbosa. 2023. 114f. Tese (Doutorado em Bioinformática) - Instituto Metrópole Digital, Universidade Federal do Rio Grande do Norte, Natal, 2023.https://repositorio.ufrn.br/handle/123456789/54922Bioactive compounds have been studied in order to offer better efficacy and selectivity against various diseases, representing a promising scenario in drug development. Recently, a series of acridinic derivatives was synthesized and exhibiting antileishmanial activity. However, the concept of "one drug, one disease, one target" is not always true, as compounds with previously described therapeutic applications can act on more than one target. Based on this, this work aimed to identify, through inverse virtual screening based on the receptor, the probable mechanism of action of spiro-acridinic derivatives. Additionally, the mechanism of action was confirmed through in vitro enzymatic assays. Using these approaches, Chapter I of this work presents the identification, through computational methodologies, of the pteridine reductase 1 (PTR1) enzyme of L. major as a potential target for spiro-acridinic compounds. Additionally, we found the chitinase B1 (CHIB1) enzyme of Aspergillus fumigatus as a potential target against Aspergillosis. For PTR1, docking and molecular dynamics studie presented the high stability of compound 1 at the active site of the enzyme. For CHIB1, other derivatives were subjected to molecular docking and dynamics, identifying 3 compounds with the best profile against the target. In Chapter II, in vitro assays were performed to experimentally confirm the action of spiro-acridinic derivatives on the studied enzymes. For PTR1, in vitro assays demonstrated a KD of 33.1 µM for the best compound, while for chitinase, the best compound showed an IC50 of 0.6 ng/µL. Therefore, this work demonstrated the high efficiency of inverse virtual screening as a target prediction approach. Additionally, the program allowed for characterizing its potency, inhibition modality, and interaction profile with its therapeutic target. Thus, spiro-acridinic derivatives can act as multi-target inhibitors of Leishmania's PTR1 and fungal chitinase.Acesso EmbargadoEspiro-acridinasTriagem virtual inversaPteridina redutase 1QuitinaseLeishmaniadoctoralThesisCNPQ::CIENCIAS BIOLOGICAS