Design of Novel Phosphopantetheine Adenylyltransferase Inhibitors: A Potential New Approach to Tackle Mycobacterium tuberculosis
Autor: | Marina Candido Primi, Tina Izard, Larry L. Klein, Carlos Mauricio R. Sant'Anna, Mauricio Temotheo Tavares, Elizabeth Igne Ferreira, Scott G. Franzblau |
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Rok vydání: | 2021 |
Předmět: |
Drug
Tuberculosis medicine.drug_class media_common.quotation_subject Antibiotics Antitubercular Agents Microbial Sensitivity Tests Drug resistance Computational biology Mycobacterium tuberculosis Docking (dog) Drug Discovery medicine Phosphopantetheine adenylyltransferase QUIMIOTERAPIA Enzyme Inhibitors media_common Molecular Structure biology business.industry Rational design General Medicine medicine.disease biology.organism_classification Nucleotidyltransferases Drug Design business |
Zdroj: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP |
ISSN: | 1568-0266 |
DOI: | 10.2174/1568026621666210728094804 |
Popis: | Background: Tuberculosis (TB) has been a challenging disease worldwide, especially for the neglected poor populations. Presently, there are approximately 2 billion people infected with TB worldwide and 10 million people in the world fell ill with active TB, leading to 1.5 million deaths. Introduction: The classic treatment is extensive and the drug- and multi-drug resistance of Mycobacterium tuberculosis has been a threat to the efficacy of the drugs currently used. Therefore, the rational design of new anti-TB candidates is urgently needed. Methods: With the aim of contributing to face this challenge, 78 compounds have been proposed based on SBDD (Structure-Based Drug Design) strategies applied to target the M. tuberculosis phosphopantetheine adenylyltransferase (MtPPAT) enzyme. Ligand-Based Drug Design (LBDD) strategies were also used for establishing Structure-Activity Relationships (SAR) and for optimizing the structures. MtPPAT is important for the biosynthesis of coenzyme A (CoA) and it has been studied recently toward the discovery of new inhibitors. Results: After docking simulations and enthalpy calculations, the interaction of selected compounds with MtPPAT was found to be energetically favorable. The most promising compounds were then synthesized and submitted to anti-M. tuberculosis and MtPPAT inhibition assays. Conclusion: One of the compounds synthesized (MCP163), showed the highest activity in both of these assays. |
Databáze: | OpenAIRE |
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