Uso da ferramenta computacional alphafold para estudo do potencial das lisinas desacetilases de fungos patogenicos como alvos de drogas

Abstract

Fungal infections have been a major problem for public health and the economy. In addition, the treatments available for these infections are limited and the emergence of resistant fungi is frequently reported. In this sense, it is necessary to identify new targets that can be explored for the development of new treatments. In recent years, with technological advances and artificial intelligence, several tools have emerged to the study of protein structures, which could be explored for pre-validation of specific proteins as drug targets. Among these tools, the Alphafold, which allows analysis of various proteins, generating three-dimensional models. In this project we focused on the study of lysine deacetylases (KDACs) of two fungal species of global health importance, Candida albicans and Aspergillus fumigatus, in order the validate these enzymes as possible drug targets. Thus, we initially obtained the sequences of all KDACs from C. albicans and A. fumigatus using the Uniprot database, which were submitted to AlphaFold to obtain the predicted 3D models of each enzyme. As a comparative model in our analyzes we used Saccharomyces cerevisiae and human KDACs. We were able to obtain all 3D protein models of the KDACs of interest that were then used in structural analyzes to determine the important regions of the active site that characterize lysine deacetylases. We found that all KDACs from C. albicans and A. fumigatus have these characteristics. After the initial structural characterization of fungal KDACs, we performed several comparatives analyzes with human enzymes, to ascertain their potential as drug targets. Important structural differences with human proteins is one of the main factors that allows exploring a particular protein as a target for the development of specific inhibitors. Finally, we performed molecular docking analyzes using the classic inhibitor of KDACs, Trichostatin A (TSA), and CaHos3, CaHda1 and AfHdaB, and verified that the inhibitor can interact in the active site region of CaHos3 and CaHda1. In conclusion, we confirmed the robustness of the AlphaFold tool for structural analysis studies and obtained data that indicate the possibility of using KDACs from C. albicans and A. fumigatus in future studies to identify specific inhibitors and further be used in the treatment of diseases caused by these fungi.

Date of Award	6 Dec 2022
Original language	Portuguese
Awarding Institution	Universidade Católica Portuguesa
Supervisor	Nilmar Silvio Moretti (Supervisor) & Antoniel Augusto Severo Gomes (Co-Supervisor)