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Published on: December 28, 2017
Azole resistance: insights from Y132 substitutions in Candida sterol 14α-demethylase utilizing molecular dynamics
R Shyama Prasad Rao1,2, Larina Pinto1, Renuka Suravajhala3
1Center for Bioinformatics, NITTE deemed to be University, Mangaluru, India.
Abstract:
Azole-resistant Candida infections are on the rise. Resistant substitutions at Y132 in sterol 14α-demethylase, the key target of azole drugs, are frequent. However, it is unclear why only some Y132 substitutions are favoured or how they exert differential effects on different azoles. Reported instances of Y132 substitutions were collected from the literature. Extensive molecular dynamics simulations of sterol 14α-demethylase bound to fluconazole or VT1161 (VT1) were performed using GROMACS, and the ligand-binding free energies were computed to quantify the effects of various Y132 substitutions on azole binding/interactions. Three azole-resistant substitutions, Y to C/F/H, were reported at residue position 132 in sterol 14α-demethylase. The Y132H was the most common substitution in C. albicans, while it was Y132F in other species. Ligand-binding free energies were -13.97 kcal/mol and -35.30 kcal/mol for fluconazole and VT1, respectively. There were differences in the ligand-binding free energies after substitutions compared to the wild type protein. Y132F and Y132H were the most frequent substitutions in Candida sterol 14α-demethylase. Far higher binding free energy of fluconazole in comparison with VT1 might partly explain its susceptibility to azole-resistant substitutions. The results give key insights into azole resistance, and antifungal drug discovery and optimization.
Insights
Azole-resistant Candida infections are increasing due to mutations like Y132F/H in sterol 14α-demethylase. Molecular simulations reveal differential azole binding, explaining resistance patterns and aiding antifungal drug design.
Area of Science:
- Mycology
- Biochemistry
- Computational Biology
Background:
- Azole antifungal drugs target sterol 14α-demethylase in Candida species.
- Emerging azole resistance is often linked to substitutions at the Y132 residue of sterol 14α-demethylase.
- The specific mechanisms driving differential resistance to various azoles remain incompletely understood.
Purpose of the Study:
- To investigate the impact of Y132 substitutions in sterol 14α-demethylase on the binding affinity of different azole antifungal agents.
- To elucidate the molecular basis for differential azole resistance in Candida infections.
- To provide insights for the development of novel antifungal therapies.
Main Methods:
- Literature review to collect reported Y132 substitutions in Candida sterol 14α-demethylase.
- Extensive molecular dynamics simulations using GROMACS to model protein-ligand interactions.
- Computation of ligand-binding free energies to quantify the effects of Y132 substitutions on azole binding.
Main Results:
- Three frequent azole-resistant substitutions (Y132C, Y132F, Y132H) were identified.
- Y132H was most common in Candida albicans, while Y132F predominated in other species.
- VT1161 exhibited significantly higher binding free energy (-35.30 kcal/mol) compared to fluconazole (-13.97 kcal/mol), suggesting greater stability against resistance mutations.
Conclusions:
- The differential binding free energies of fluconazole and VT1161 correlate with observed resistance patterns.
- Y132F and Y132H substitutions are key drivers of azole resistance in Candida.
- Understanding these molecular interactions is crucial for optimizing existing antifungals and designing new drugs to combat resistant infections.
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