Decoding molecular mechanism of species-selective targeting of fungal versus human HSP90 using multiple replica...

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Heat shock protein 90 (HSP90) is a crucial molecular chaperone involved in fungal virulence.
• Targeting fungal HSP90 offers a therapeutic strategy for antifungal drug development.
• Developing selective inhibitors against fungal HSP90, while sparing human HSP90, is challenging due to evolutionary conservation.

Purpose of the Study:

• To elucidate the molecular mechanism behind the species-selective targeting of fungal versus human HSP90 by compound A11.
• To identify key interactions and residues responsible for the differential binding of compound A11.
• To provide a basis for designing more effective and selective antifungal agents.

Main Methods:

• Molecular docking simulations to predict binding modes.
• Multiple replica microsecond-based molecular dynamics (MD) simulations to analyze conformational changes.
• Binding free energy calculations to quantify binding affinities.
• Per-residue free energy decomposition analysis to identify key interactions.

Main Results:

• Compound A11 binding induces distinct conformational changes in human HSP90 nucleotide-binding domain (NBD) compared to fungal HSP90 NBD.
• Binding free energy calculations reveal stronger binding of compound A11 to fungal HSP90 NBD than to human HSP90 NBD.
• Identification of specific 'hot spot' residues in fungal HSP90 NBD crucial for favorable compound A11 binding.

Conclusions:

• Compound A11 exhibits selectivity for fungal HSP90 over human HSP90.
• The study reveals the molecular basis for this selectivity, highlighting specific residue interactions.
• Findings offer valuable insights for the rational design of selective fungal HSP90 inhibitors for antifungal therapies.