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dc.contributor.authorSantos P.
dc.contributor.authorLopez-Vallejo F.
dc.contributor.authorRamírez D.
dc.contributor.authorCaballero J.
dc.contributor.authorMata Espinosa D.
dc.contributor.authorHernández-Pando R.
dc.contributor.authorSoto C.Y.
dc.date.accessioned2020-09-02T22:28:05Z
dc.date.available2020-09-02T22:28:05Z
dc.date.issued2020
dc.identifier10.1016/j.bmc.2019.115256
dc.identifier.citation28, 3, -
dc.identifier.issn09680896
dc.identifier.urihttps://hdl.handle.net/20.500.12728/6192
dc.descriptionThe 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.isoen
dc.publisherElsevier Ltd
dc.subjectAntimycobacterial therapeutics
dc.subjectCyclopiazonic acid
dc.subjectMolecular docking
dc.subjectP-type ATPases
dc.subjectTuberculosis
dc.subjectcyclopiazonic acid
dc.subjectdimethyl sulfoxide
dc.subjectplasma membrane calcium transporting adenosine triphosphatase
dc.subjectrifampicin
dc.subjectsarcoplasmic reticulum calcium transporting adenosine triphosphatase
dc.subjecttuberculostatic agent
dc.subjectunclassified drug
dc.subjectzinc 09787234
dc.subjectzinc 12584082
dc.subjectzinc 14541509
dc.subjectzinc 45605493
dc.subjectzinc 55090623
dc.subjectzinc 63908257
dc.subjectanimal cell
dc.subjectArticle
dc.subjectbacteriostatic activity
dc.subjectcontrolled study
dc.subjectdrug design
dc.subjectdrug screening
dc.subjectdrug targeting
dc.subjectenzyme inhibition
dc.subjectIC50
dc.subjectminimum inhibitory concentration
dc.subjectmolecular docking
dc.subjectMycobacterium tuberculosis
dc.subjectnonhuman
dc.subjectpharmacophore
dc.titleIdentification of Mycobacterium tuberculosis CtpF as a target for designing new antituberculous compounds
dc.typeArticle


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