Identification and In Silico Characterization of Novel Helicobacter pylori Glucose-6-Phosphate Dehydrogenase Inhibitors

Molecules

Abigail González-Valdez¹  Rodrigo Aguayo-Ortiz²  Gabriel Navarrete-Vázquez³  Carlos Wong-Baeza⁴  Isabel Baeza-Ramírez⁴  Paulina Ortiz-Ramírez⁵  Laura Morales-Luna⁵  Saúl Gómez-Manzo⁵  Sergio Enríquez-Flores⁶  Fernando Gómez-Chávez⁷  Verónica Pérez de la Cruz⁸  Víctor Martínez-Rosas⁹  Beatriz Hernández-Ochoa⁹ 

[1] Departamento de Biología Molecular y Biotecnología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico;Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico;Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Av. Universidad 1001, Chamilpa, Cuernavaca, Morelos 62209, Mexico;Laboratorio de Biomembranas, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Ciudad de México 11340, Mexico;Laboratorio de Bioquímica Genética, Instituto Nacional de Pediatría, Secretaría de Salud, Ciudad de México 04530, Mexico;Laboratorio de EIMyT, Grupo de Investigación en Biomoléculas y Salud Infantil, Instituto Nacional de Pediatría, Secretaría de Salud, Ciudad de México 04530, Mexico;Laboratorio de Inmunología Experimental, Instituto Nacional de Pediatría, Ciudad de México 04530, Mexico;Neurochemistry and Behavior Laboratory, National Institute of Neurology and Neurosurgery “Manuel Velasco Suárez”, Ciudad de México 14269, Mexico;Programa de Posgrado en Biomedicina y Biotecnología Molecular, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Ciudad de México 11340, Mexico;

关键词: Helicobacter pylori;    glucose-6-phosphate dehydrogenase;    inhibitors;    docking;    homology modeling;    drug candidates;   

DOI  :  10.3390/molecules26164955

来源: DOAJ

【 摘 要 】

Helicobacter pylori (H. pylori) is a pathogen that can remain in the stomach of an infected person for their entire life. As a result, this leads to the development of severe gastric diseases such as gastric cancer. In addition, current therapies have several problems including antibiotics resistance. Therefore, new practical options to eliminate this bacterium, and its induced affections, are required to avoid morbidity and mortality worldwide. One strategy in the search for new drugs is to detect compounds that inhibit a limiting step in a central metabolic pathway of the pathogen of interest. In this work, we tested 55 compounds to gain insights into their possible use as new inhibitory drugs of H. pylori glucose-6-phosphate dehydrogenase (HpG6PD) activity. The compounds YGC-1; MGD-1, MGD-2; TDA-1; and JMM-3 with their respective scaffold 1,3-thiazolidine-2,4-dione; 1H-benzimidazole; 1,3-benzoxazole, morpholine, and biphenylcarbonitrile showed the best inhibitory activity (IC₅₀ = 310, 465, 340, 204 and 304 μM, respectively). We then modeled the HpG6PD protein by homology modeling to conduct an in silico study of the chemical compounds and discovers its possible interactions with the HpG6PD enzyme. We found that compounds can be internalized at the NADP⁺ catalytic binding site. Hence, they probably exert a competitive inhibitory effect with NADP⁺ and a non-competitive or uncompetitive effect with G6P, that of the compounds binding far from the enzyme’s active site. Based on these findings, the tested compounds inhibiting HpG6PD represent promising novel drug candidates against H. pylori.

【 授权许可】

Unknown