Inhibition of recombinant enzyme 3-hydroxy-3-methylglutaryl-CoA reductase from Candida glabrata by α-asarone-based synthetic compounds as antifungal agents

• Published in: Journal of biotechnology 2019-02, Vol.292, p.64-67
• Main Authors: Andrade-Pavón, Dulce, Ortiz-Álvarez, Jossue, Sánchez-Sandoval, Eugenia, Tamariz, Joaquín, Hernández-Rodríguez, César, Ibarra, J. Antonio, Villa-Tanaca, Lourdes
• Format: Article
• Language: English
• Subjects: Anisoles - pharmacology; Antifungal; Antifungal Agents - pharmacology; Biological Sciences; Biologiska vetenskaper; C. glabrata; Candida glabrata - enzymology; Docking; Ergosterol; Fungal Proteins - antagonists & inhibitors; HMGR; Hydroxymethylglutaryl CoA Reductases - metabolism; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Medical Biotechnology; Medicinsk bioteknologi
• ISSN: 0168-1656; 1873-4863; 1873-4863
• DOI: 10.1016/j.jbiotec.2019.01.008

•The recombinant enzyme CgHMGR was used as a model to test new compounds with possible antifungal activity.•Compounds 3 and 4 inhibited CgHMGR enzyme activity, with an IC50 lower than that for α-asarone.•Molecular docking studies revealed that compounds 3 and 4 bind to CgHMGR active site.•Effect caused by simvastatin and α-asarone-based compounds were reversed with the addition of sterols. Due to increasing resistance of Candida species to antifungal drugs, especially azoles, new drugs are needed. The proposed compounds 3 and 4 are analogous to α-asarone (2), a naturally occurring potent inhibitor of HMGR with hypolipidemic and antifungal activity. We used the recombinant enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase of Candida glabrata (CgHMGR) as a model to test the effectiveness of the test compounds. Compounds 3 and 4 demonstrated inhibitory kinetics, having lower IC50 values (42.65 μM and 28.77 μM, respectively) than compound 2 (>100 μM). The docking studies showed better binding energies for compounds 3 and 4 (−5.35 and −6.1 kcal/mol, respectively) than for compound 2 (−4.53 kcal/mol). These findings suggest that the tested compounds are better than their natural analogue. Plaque assays were performed on the C. glabrata strain CBS138 by applying ergosterol or cholesterol to evaluate the possible reversal of the inhibition induced by compounds 2, 3 and 4. Inhibition was easily suppressed in all three cases, recovering the viability of C. glabrata. These results reveal that the CgHMGR model is excellent for testing antifungals. Compound 4 produced the best effect and is herein proposed as a new potent antifungal agent.