Molecular Determinants of Orthosteric-allosteric Dual Inhibition of PfHT1 by Computational Assessment
Journal:
arXiv
Published Date:
Apr 18, 2025
Abstract
To overcome antimalarial drug resistance, carbohydrate derivatives as
selective PfHT1 inhibitor have been suggested in recent experimental work with
orthosteric and allosteric dual binding pockets. Inspired by this promising
therapeutic strategy, herein, molecular dynamics simulations are performed to
investigate the molecular determinants of co-administration on orthosteric and
allosteric inhibitors targeting PfHT1. Our binding free energy analysis capture
the essential trend of inhibitor binding affinity to protein from published
experimental IC50 data in three sets of distinct characteristics. In
particular, we rank the contribution of key residues as binding sites which
categorized into three groups based on linker length, size of tail group, and
sugar moiety of inhibitors. The pivotal roles of these key residues are further
validated by mutant analysis where mutated to nonpolar alanine leading to
reduced affinities to different degrees. The exception was fructose derivative,
which exhibited a significant enhanced affinity to mutation on orthosteric
sites due to strong changed binding poses. This study may provide useful
information for optimized design of precision medicine to circumvent
drug-resistant Plasmodium parasites with high efficacy.
