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Identification of Mycobacterium tuberculosis CtpF as a target for designing new antituberculous compounds
dc.contributor.author | Santos P. | |
dc.contributor.author | Lopez-Vallejo F. | |
dc.contributor.author | Ramírez D. | |
dc.contributor.author | Caballero J. | |
dc.contributor.author | Mata Espinosa D. | |
dc.contributor.author | Hernández-Pando R. | |
dc.contributor.author | Soto C.Y. | |
dc.date.accessioned | 2020-09-02T22:28:05Z | |
dc.date.available | 2020-09-02T22:28:05Z | |
dc.date.issued | 2020 | |
dc.identifier | 10.1016/j.bmc.2019.115256 | |
dc.identifier.citation | 28, 3, - | |
dc.identifier.issn | 09680896 | |
dc.identifier.uri | https://hdl.handle.net/20.500.12728/6192 | |
dc.description | The emergence of tuberculosis (TB) produced by multi-drug resistance (MDR) and extensively-drug resistance (XDR) Mycobacterium tuberculosis (Mtb), encourages the development of new antituberculous compounds, as well as the identification of novel drug targets. In this regard, plasma membrane P-type ATPases are interesting targets because they play a crucial role in ion homeostasis and mycobacterial survival. We focused on Mtb CtpF, a calcium P-type ATPase that responds to a broad number of intraphagosomal conditions, as a novel target. In this study, we evaluated the capacity of cyclopiazonic acid (CPA), a well-known inhibitor of the sarco-endoplasmic reticulum Ca2+-ATPase (SERCA), to inhibit the ATPase activity of CtpF and the Mtb growth demonstrating that CtpF is a druggable target. A homology modeling of CtpF was generated for molecular docking studies of CtpF with CPA and key pharmacophoric features were identified, which were used to perform a pharmacophore-based virtual screening of the ZINC database, and to identify CtpF inhibitor candidates. Molecular docking-based virtual screening and MM-BGSA calculations of candidates allowed identifying six compounds with the best binding energies. The compounds displayed in vitro minimum inhibitory concentrations (MIC) ranging from 50 to 100 μg/mL, growth inhibitions from 29.5 to 64.0% on Mtb, and inhibitions of Ca2+-dependent ATPase activity in Mtb membrane vesicles (IC50) ranging from 4.1 to 35.8 μM. The compound ZINC63908257 was the best candidate by displaying a MIC of 50 μg/mL and a Ca2+ P-type ATPase inhibition of 45% with IC50 = 4.4 μM. Overall, the results indicate that CtpF is a druggable target for designing new antituberculous compounds. © 2019 Elsevier Ltd | |
dc.language.iso | en | |
dc.publisher | Elsevier Ltd | |
dc.subject | Antimycobacterial therapeutics | |
dc.subject | Cyclopiazonic acid | |
dc.subject | Molecular docking | |
dc.subject | P-type ATPases | |
dc.subject | Tuberculosis | |
dc.subject | cyclopiazonic acid | |
dc.subject | dimethyl sulfoxide | |
dc.subject | plasma membrane calcium transporting adenosine triphosphatase | |
dc.subject | rifampicin | |
dc.subject | sarcoplasmic reticulum calcium transporting adenosine triphosphatase | |
dc.subject | tuberculostatic agent | |
dc.subject | unclassified drug | |
dc.subject | zinc 09787234 | |
dc.subject | zinc 12584082 | |
dc.subject | zinc 14541509 | |
dc.subject | zinc 45605493 | |
dc.subject | zinc 55090623 | |
dc.subject | zinc 63908257 | |
dc.subject | animal cell | |
dc.subject | Article | |
dc.subject | bacteriostatic activity | |
dc.subject | controlled study | |
dc.subject | drug design | |
dc.subject | drug screening | |
dc.subject | drug targeting | |
dc.subject | enzyme inhibition | |
dc.subject | IC50 | |
dc.subject | minimum inhibitory concentration | |
dc.subject | molecular docking | |
dc.subject | Mycobacterium tuberculosis | |
dc.subject | nonhuman | |
dc.subject | pharmacophore | |
dc.title | Identification of Mycobacterium tuberculosis CtpF as a target for designing new antituberculous compounds | |
dc.type | Article |