Structural study and identification of new lead compounds using fragment-based drug discovery for enzymes of CoA and arabinomannan biosynthesis from Mycobacterium tuberculosis

• Grant number: 19/24836-7
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: October 01, 2020
• End date: April 30, 2024
• Field of knowledge: Biological Sciences - Microbiology
• Principal Investigator: Marcio Vinicius Bertacine Dias
• Grantee: Bruno Kaik Alves
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Tuberculosis is one of the 10 leading causes of death worldwide and is caused by the agent Mycobacterium tuberculosis. The increasingly recurring emergence of resistant strains of this pathogen motivates researchers around the world and leads to the need for developing new drugs to combat it M. tuberculosis, requiring constant validation of new effective drugs. In this sense, PanK (CoaA) and DprE1 enzymes have recently been validated as potential drug targets; therefore, inhibition of these enzymes, and consequently inhibition of the metabolic pathways in which they are involved are presented as new alternatives in the fight against Tuberculosis. PanK (CoaA) is responsible for the phosphorylation of pantothenic acid during coenzyme A biosynthesis. DprE1, together with DprE2, catalyzes the conversion of DPR to DPA, which is fundamental for mycobacterial wall formation; This reaction has DPX as the intermediate compound. Recently, by molecular modeling, a complex between DprE1 and DprE2 that seems to be necessary for the synthesis of DPA has been presented. Thus, the in vitro reproduction of DprE1-DprE2 complex is an important step in a better understanding of this process and, therefore, in a better understanding of mycobacterial cell wall formation. In this context, this project aims to perform identification and validation of small molecules (fragments) that may be starting points for the synthesis of new inhibitors for PanK and DprE1 using fragment-based drug planning (FBDD) techniques. The synthesis of compounds based on the identified fragments will be performed in collaboration with organic synthesis research groups. At the same time, it is aimed to obtain the M. tuberculosis enzyme complex DprE1 and DprE2. Thus, we hope to pave the way for the development of new therapies that can be used in the fight against Tuberculosis and to understand key processes of mycobacterial cell wall biosynthesis. (AU)