Molecular Determinants of Orthosteric-allosteric Dual Inhibition of PfHT1 by Computational Assessment
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| Main Authors: | , , , , , , , |
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| Format: | Preprint |
| Published: |
2025
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| _version_ | 1866915259583823872 |
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| author | Kong, Decheng Ren, Jinlong Li, Zhuang Shan, Guangcun Wang, Zhongjian Zhang, Ruiqin Huang, Wei Dou, Kunpeng |
| author_facet | Kong, Decheng Ren, Jinlong Li, Zhuang Shan, Guangcun Wang, Zhongjian Zhang, Ruiqin Huang, Wei Dou, Kunpeng |
| contents | 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. |
| format | Preprint |
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arxiv_https___arxiv_org_abs_2504_18559 |
| institution | arXiv |
| publishDate | 2025 |
| record_format | arxiv |
| spellingShingle | Molecular Determinants of Orthosteric-allosteric Dual Inhibition of PfHT1 by Computational Assessment Kong, Decheng Ren, Jinlong Li, Zhuang Shan, Guangcun Wang, Zhongjian Zhang, Ruiqin Huang, Wei Dou, Kunpeng Biological Physics Soft Condensed Matter Chemical Physics Biomolecules 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. |
| title | Molecular Determinants of Orthosteric-allosteric Dual Inhibition of PfHT1 by Computational Assessment |
| topic | Biological Physics Soft Condensed Matter Chemical Physics Biomolecules |
| url | https://arxiv.org/abs/2504.18559 |