Exploring Aspartic Protease Inhibitor Binding to Design Selective Antimalarials.

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Computational Biology

Background:

• Drug selectivity against pathogen aspartic proteases remains a significant challenge.
• Developing targeted therapies requires understanding enzyme-inhibitor interactions at an atomic level.

Purpose of the Study:

• To investigate factors determining selectivity in drugs targeting malaria aspartic proteases (plasmepsins).
• To explore the binding and unbinding pathways of specifically designed plasmepsin inhibitors using advanced computational methods.

Main Methods:

• Utilized advanced metadynamics simulations to analyze inhibitor binding/unbinding pathways.
• Characterized critical transition states in atomistic detail.
• Correlated simulation findings with experimental enzymatic activity data.

Main Results:

• Identified hydrophobic substituents targeting the flap loop as key to achieving plasmepsin inhibitor selectivity.
• Observed unique ligand binding behavior under the flap loop in plasmepsins, distinct from other aspartic proteases.
• Validated simulation predictions against experimental enzymatic activity measurements.

Conclusions:

• Selective inhibition of plasmepsins can be achieved by designing inhibitors that bind under the flap loop.
• The developed computational approach can predict inhibitor selectivity early in the drug design process.
• This methodology holds promise for designing selective inhibitors against various enzyme classes, including aspartic proteases.