Virtual screening of ligands with high binding affinity to two multidrug- resistant Candida auris lanosterol 14-alpha demethylase L126l and I466m enzyme mutants

Abstract

Antifungal resistance is one of the major global health concerns of today. Among the emerging antifungal drug-resistant species is Candida auris, whose resistance emerges from mutations in its ERG11 (lanosterol 14a-demethylase) gene. The 3D protein structures of two resistant mutants, F126L and I466M, of the C. auris ERG11 gene were successfully modeled using the homologous protein, 4LXJ of Saccharomyces cerevisiae, as the model template. The RMSDs between the mutants, F126L and I466M, and 4LXJ were both 0.099 Å which indicates a very highly similar structure, almost structurally identical. Sequence alignment of the lanosterol 14a-demethylase protein sequences of C. auris, S. cerevisiae, Homo sapiens, and eight other Candida spp. revealed that the ERG11 gene is highly conserved among the 11 species. Conserved regions were also observed in the active site of 4LXJ. Ligands were docked in silico with each mutant structure through molecular docking from which the top 6 ligands were identified according to binding affinity (!Gbinding) and receptor-ligand interactions all of which were found to be in compliance with the Lipinski’s Rule of Five. The top 10 best ligands for the F126L mutant were MOL002966, MOL002398, MOL002508, MOL002510, MOL002554, MOL002560, MOL002563, MOL002861, MOL002865 and MOL002568 with !Gbinding ranging from - 8.9 to -8.5 kcal/mol; MOL001560, MOL001558, MOL000945, MOL000986, MOL001371, and MOL000570, MOL000516, MOL000981, MOL001985 and MOL001516 with !G ranging from -9.6 to -8.2 kcal/mol for I466M mutant. The most commonly bound amino acids to the top ligands of F126L are Phe233, Met87, and His377; Leu376, Phe233, Met87 for I466M. These amino acids are important for ligand interaction and may mutate in response to drug pressure. Cross-docking with human lanosterol demethylase revealed weak binding by the ligands with an average of -6.45 kcal/mol and - 6.63 kcal/mol for F126L and I466M mutants, respectively. The low binding affinity for the human lanosterol demethylase indicates high specificity for the mutants thus decreasing the chances of side effects in humans.