Identification of Mycobacterium tuberculosis CtpF as a target for designing new antituberculous compounds. Issue 3 (1st February 2020)

• Record Type: Journal Article
• Authors: Santos, Paola; Lopez-Vallejo, Fabian; Ramírez, David; Caballero, Julio; Mata Espinosa, Dulce; Hernández-Pando, Rogelio; Soto, Carlos Y.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 28:Issue 3(2020)
• Publication Date: 2020-02-01
• Subjects: Tuberculosis -- Antimycobacterial therapeutics -- Cyclopiazonic acid -- P-type ATPases -- Molecular docking; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2019.115256
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: 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 Ca 2+ -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 Ca 2+ -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 Ca 2+ 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.