Elucidation of furanone as ergosterol pathway inhibitor in Cryptococcus neoformans

Abstract

In the era of antiretroviral therapy, the prevalence of Cryptococcal infection among HIV patients in developed countries has decreased considerably. However, C. neoformans ranks top among the critical priority pathogen that affects a wide range of immunocompromised individuals. The threat of C. neoformans is because of its incredibly multifaceted intracellular survival capabilities. Cell membrane sterols especially ergosterol and enzymes of its biosynthetic pathway are considered fascinating drug targets because of their structural stability. In this study, the ergosterol biosynthetic enzymes were modeled and docked with furanone derivatives. Among the tested ligands Compound 6 has shown a potential interaction with Lanosterol 14 α-demethylase. This best-docked protein-ligand complex was taken further to molecular dynamics simulation. In addition, Compound 6 was synthesized and an in vitro study was conducted to quantify the ergosterol in Compound 6 treated cells. Altogether the computational and in vitro study demonstrates that Compound 6 has anticryptococcal activity by targeting the biosynthetic pathway of ergosterol.

Communicated by Ramaswamy H. Sarma

Keywords:

• Cryptococcus neoformans
• antifungal agents
• ergosterol
• docking
• MD simulation

Acknowledgments

The authors are grateful to SASTRA Deemed University for their kind support to obtain patent for Compound 6. We acknowledge DBT, GoI (Grant number: BT/PR40144/BTIS/137/46/2022) and SASTRA Deemed University for the financial support towards the purchase of Schrodinger software suite.

Disclosure statement

No potential conflict of interest was reported by the authors.

Author’s contributions

JS performed the Insilco, in vitro tests and wrote the manuscript. SSR trained JS to perform HPLC and Chemical Synthesis. SM guided the in silico work. UM guided the Chemical synthesis part. Compound 6 discovery, Idea, work design, and manuscript verification was done by JR.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.