In silico interaction of 1,2,4-thiadiazol-containing antibiotics with viral and bacterial molecular targets

• Grant number: 22/11792-4
• Support Opportunities: Scholarships in Brazil - Program to Stimulate Scientific Vocations
• Start date: January 10, 2023
• End date: February 27, 2023
• Field of knowledge: Biological Sciences - Biochemistry - Chemistry of Macromolecules
• Principal Investigator: Joao Batista Teixeira da Rocha
• Grantee: João Vitor Guimarães Ferreira
• Host Institution: Centro de Ciências Naturais e Exatas (CCNE). Universidade Federal de Santa Maria. Santa Maria , SP, Brazil

Abstract

The cysteine proteases of SARS-CoV-2, Mpro and PLpro are potential targets for the development of antivirals against COVID-19. In the same sense, bacterial cysteine proteases can also be molecular targets for the development of antibiotics. The 1,2,4-thiadiazole functional group can inhibit cysteine proteases, e.g. papain and cathepsins. The thiadiazole moiety is found in a new class of cephalosporin antibiotics in therapeutic use in several countries or in experimental studies. We highlight Ceftolozane, Ceftaroline fosamil, Ceftobiprole, Cefozopran and Ceftobiprole medocaril. Two other drugs, called Fezolinetant and Tideglusib, also contain thiadiazol functional group. In this work, we will compare the interactions of some of these drugs with SARS-CoV-2 proteases (Delgado et al. 2023) with cysteine proteases from pathogenic bacteria to be selected during the João V. G. Ferreira internship, using in silico methods (eg example, molecular docking, density functional theory (DFT), and molecular dynamics (MD) calculations). Basically, we will determine how the different active centers of viral proteases and selected bacteria(ies) behave in terms of reactivity towards the 1,2,4-thiadiazol moiety. We intend to give an overview of methodologies used in silico that may be important for future studies by the IC João Vitor G. Ferreira, particularly in the search for new antibiotics. If time allows and the candidate is interested, he can also perform some in vitro studies with cysteine proteases, using simple UV-VIS methodologie. (AU)