Virtual screening of ligands with high binding affinity to the multi-drug resistant Candida auris lanosterol demethylase enzyme Y132 F and K143R mutants.

Abstract

With the emergence of the multi-drug resistant Candida auris, there is a need to find ligands that can successfully bind to the lanosterol demethylase of the mutated Candida auris Y132F and K143R. In this study, we used Saccharomyces cerevisiae 4LXJ as the template for modeling the 3D structure of the lanosterol demethylase enzyme of Candida auris. The structure was modeled using Swissmodel. The Y132F and K143R models were almost identical to the 4LXJ lanosterol demethylase with RSMDs of 0.105 and 0.999 Angstroms, respectively. Amino acid sequence alignments of 4LXJ and nine other organisms which include different Candida spp. and Homo sapiens were performed. It was found that the ERG11 enzyme is highly-conserved in fungi and in humans. This implies that there is a need to design highly specific ligands to Candida auris. The ligands were generated from the Traditional Chinese Medicine Systems Pharmacology database and were docked to the mutant Candida auris spp. Y132F and K143R and binding energies were obtained both using Autodock Vina. All ligands with a binding energy below -6kcal/mol are considered to be good binders and those with less than -8.5 kcal/mol are considered to be strong binders for both of the mutants K143R and Y132F. There were 34 good binders to the mutant Y132F and 28 good binders to K143R. Among those 34 good binders, 12 are top binders for Y132F. There are 10 top binders, among 28 good binders, for K143R. The top binders passed the criteria of Lipinski’s rule of five indicating good potential absorption, and bioavailability, as well as sufficiency for IV dosing. Cross-docking results with the human ERG11 lanosterol demethylase showed an average of only -6kcal/mol binding, indicating that there is very weak to no cross-binding and a higher specificity for the fungal enzyme. It is also important to note that the important amino acids in the active site that interact with the ligands the most were found to be: Tyr64, Met87, Tyr118, Pro230, Phe233, Leu376, His377, Ser378, Ser503 and Met504. These are important to note to guide further drug design as well as to be aware of enzyme mutations that can weaken drug binding and affinity. Keywords: Candida auris, Multi-drug resistance, Lanosterol 14α-demethylase, ERG11, Molecular docking, Traditional Chinese Medicine