Dissecting Key Multivalent Processes in Glycosidase Inhibition: Insights from Thermodynamic Modelling and Atomistic Simulations

Multivalency represents a powerful approach to increase the inhibition potency of moderate glycosidase inhibitors. Regarding the key role of catalytic glycoside hydrolysis in biology, understanding the molecular mechanisms and origin of the multivalent inhibitory effect is of great interest and presents a fascinating playground for theoretical studies. Our teams have recently dissected key processes of multivalent glycosidase inhibition through the use of different neoglycoclusters based on deoxynojirimycin (DNJ) inhitopes and a cyclopeptoid scaffold. This companion article details the theoretical aspects of this former study. A thermodynamic model is developed and validated, compared to literature, and extended to account for particularities of the charged DNJ inhitopes.