Deconstructing Best-in-Class Neoglycoclusters as a Tool for Dissecting Key Multivalent Processes in Glycosidase...

Area of Science:

• Enzyme inhibition
• Medicinal chemistry
• Biophysical chemistry

Background:

• Multivalency enhances enzyme inhibitor potency and selectivity.
• Rational design of multivalent inhibitors is complex due to interconnected mechanistic events.
• Cyclopeptoid inhibitors of Jack bean α-mannosidase (JBα-man) show large multivalent effects.

Purpose of the Study:

• To understand the mechanisms behind multivalent binding effects in enzyme inhibition.
• To identify key parameters influencing affinity enhancement in multivalent inhibitors.
• To provide guidelines for designing potent and selective multiheaded inhibitors.

Main Methods:

• Structure-activity relationship (SAR) studies via deconstruction of inhibitors.
• Binding stoichiometry assessments.
• Thermodynamic modeling and atomistic simulations.

Main Results:

• Statistical rebinding mechanisms significantly contribute to affinity enhancement.
• Inhitope accessibility, topological restrictions, and electrostatic interactions are crucial.
• Strong chelate-binding alone does not guarantee high affinity enhancement.

Conclusions:

• Deconstruction of multivalent inhibitors aids understanding of complex binding mechanisms.
• Multivalent binding is influenced by a combination of factors beyond simple chelation.
• Findings offer guidelines for the rational design of novel enzyme inhibitors.