RT Journal Article
T1 Discovery of 3H-pyrrolo[2,3-c]quinolines with activity against Mycobacterium tuberculosis by allosteric inhibition of the glutamate-5-kinase enzyme
A1 Panciera, Michele
A1 Lence Quintana, Emilio José
A1 Rodríguez-Costa, Ángela
A1 Gracia Díaz, Begoña
A1 Aínsa Claver, José Antonio
A1 Marco-Marin, Clara
A1 Rubio, Vicente
A1 Correia, Carlos Roque Duarte
A1 González Bello, Concepción
K1 Allosteric inhibition
K1 Target shape-motionGlutamate-5-kinaseMolecular dynamics simulation studiesPyrroloquinoline
K1 Tuberculosis
K1 Target shape-motion
K1 Glutamate-5-kinase
K1 Molecular dynamics simulation studies
K1 Pyrroloquinoline
AB 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 drugsG
PB Elsevier
YR 2022
FD 2022
LK http://hdl.handle.net/10347/29032
UL http://hdl.handle.net/10347/29032
LA spa
NO European Journal of Medicinal Chemistry 232 (2022) 114206
NO Financial support from the Spanish Ministry of Science and Innovation (PID2019-105512RB-I00, CG-B), Axencia Galega de Innovación (2020-PG067, CG-B), the Xunta de Galicia [ED431C 2021/29 and the Centro singular de investigación de Galicia accreditation 2019–2022 (ED431G 2019/03), CG-B], and the European Regional Development Fund (ERDF) is gratefully acknowledged. MP and CRDC thank the Fundação de Amparo à Pesquisa do estado de São 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 Fundación Ramón Areces (Ciencias de la Vida, XX National call). All authors are grateful to the Centro de Supercomputación de Galicia (CESGA) for use of the Finis Terrae computer
DS Minerva
RD 23 abr 2026