Computational analysis of drug resistant mutations in lanosterol 14and#945; demethylase Erg11p and repurposing vilanterol as a new possible anti Candida albicans drug

Abstract

The human pathogen Candida albicans usually infects people with impaired immune newlinesystems. Azoles are the main antifungals, whereas fluconazole is the first-line azole drug newlineused in treating C.albicans infections. Lanosterol 14and#945;-demethylase (Erg11p) is the target newlineenzyme for azole drugs. Fluconazole inhibits Erg11p by binding to its active site. Erg11p newlineis responsible for producing ergosterol, a important component of the fungal cell newlinemembrane. Erg11p inhibition causes ergosterol depletion in the cell membrane and a newlinetoxic sterol accumulation, which leads to cell growth arrest. newlineClinical isolates of C. albicans frequently acquire azole resistance due to mutations in newlinethe ergosterol biosynthesis gene (ERG11), causing a serious threat to healthcare. Many newlinestudies showed that mutations in the lanosterol 14and#945;-demethylase (Erg11p) lead to newlinereduced azole binding. Approximately 160 residue mutations have been reported in newlineErg11p; Out of 160, only ten were confirmed with fluconazole resistance. Among the ten, newlineonly six were from clinical isolates, and the remaining four were from the laboratory. newlineStill, many Erg11p polymorphisms associated with fluconazole resistance need to be newlinestudied. newlineErg11p is a vital for invasive growth, hyphae development, and pathogenicity of newlineC.albicans. Erg11p mutations hinder the activity of fluconazole. Exploring the Erg11p newlinemutations and their effect on drug binding could provide new insights into overcoming newlinefluconazole resistance. Moreover, finding new inhibitors targeting Erg11p will be newlinebeneficial in developing novel antifungals for drug-resistant C.albicans strains. newlineTherefore, it urges the search for new drugs with fewer side effects and less resistance in newlinetreating C.albicans infectionsThree Erg11p suspected mutations, Threonine285Alanine (THR285ALA), newlineLeucine321Phenylalanine (LEU321PHE), and Serine457Proline (SER457PRO), were newlinecreated using Schrodinger mutation tools. Glide molecular docking was used to study the newlineErg11p-fluconazole binding.