Discovery of 3H-pyrrolo[2,3-c]quinolines with activity against Mycobacterium tuberculosis by allosteric inhibition of the glutamate-5-kinase enzyme
| Autor: | Michele Panciera, Emilio Lence, Ángela Rodríguez, Begoña Gracia, José A. Aínsa, Clara Marco-Marín, Vicente Rubio, Carlos Roque Duarte Correia, Concepción González-Bello |
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| Přispěvatelé: | Ministerio de Ciencia e Innovación (España), Axencia Galega de Innovación, Xunta de Galicia, European Commission, Fundação de Amparo à Pesquisa do Estado de São Paulo, Conselho Nacional de Desenvolvimento Científico e Tecnológico (Brasil), Ministerio de Economía, Industria y Competitividad (España), Fundación Ramón Areces, Universidade de Santiago de Compostela. Departamento de Química Orgánica |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Pharmacology
Binding Sites Proline Organic Chemistry Antitubercular Agents Glutamic Acid General Medicine Mycobacterium tuberculosis Glutamate-5-kinase Allosteric inhibition Pyrroloquinoline Target shape-motionGlutamate-5-kinaseMolecular dynamics simulation studiesPyrroloquinoline Drug Discovery Quinolines Tuberculosis Target shape-motion Molecular dynamics simulation studies |
| Zdroj: | Minerva. Repositorio Institucional de la Universidad de Santiago de Compostela instname Digital.CSIC. Repositorio Institucional del CSIC |
| Popis: | 21 páginas, 9 figuras, 3 tablas The therapeutic potential of 3H-pyrrolo[2,3-c]quinolines-the main core of Marinoquinoline natural products-has been explored for the development of new anti-TB agents. The chemical modification of various positions in this scaffold has led to the discovery of two pyrroloquinolines (compounds 50 and 54) with good in vitro activity against virulent strains of Mycobacterium tuberculosis (H37Rv, MIC = 4.1 μM and 4.2 μM, respectively). Enzymatic assays showed that both derivatives are inhibitors of glutamate-5-kinase (G5K, encoded by proB gene), an essential enzyme for this pathogen involved in the first step of the proline biosynthesis pathway. G5K catalyzes the phosphoryl-transference of the γ-phosphate group of ATP to L-glutamate to provide L-glutamyl-5-phosphate and ADP, and also regulates the synthesis of L-proline. The results of various molecular dynamics simulation studies revealed that the inhibition of G5K would be caused by allosteric interaction of these compounds with the interface between enzyme domains, against different pockets and with distinct recognition patterns. The binding of compound 54 promotes long-distance conformational changes at the L-glutamate binding site that would prevent it from anchoring for catalysis, while compound 50 alters the ATP binding site architecture for recognition. Enzyme assays revealed that compound 50 caused a substancial increase in the Kmapp for ATP, while no significant effect was observed for derivative 54. This work also demonstrates the potential of the G5K enzyme as a biological target for the development of new anti-TB drugs. Financial support from the Spanish Ministry of Science and Innovation (PID2019-105512RB-I00, CG-B), Axencia Galega de Innovacion (2020-PG067, CG-B), the Xunta de Galicia [ED431C 2021/ 29 and the Centro singular de investigacion de Galicia accreditation 2019e2022 (ED431G 2019/03), CG-B], and the European Regional Development Fund (ERDF) is gratefully acknowledged. MP and CRDC thank the Fundaçao de Amparo ~ a Pesquisa do estado de S ao Paulo ~ (FAPESP) for a postdoctoral fellowship (2016/23055-3), and research grants (2014/25770-6, 2013/07600-3). CRDC also thanks the Brazilian National Research Council (CNPq) (grants 406642/2018-0, 306773/ 2018-0). AR thanks the Spanish Ministry of Economy, Industry and Competitiveness for her FPI fellowship (BES-2017-080946). VR thanks the Fundacion Ram on Areces (Ciencias de la Vida, XX National call). All authors are grateful to the Centro de Supercomputacion de Galicia (CESGA) for use of the Finis Terrae computer |
| Databáze: | OpenAIRE |
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