Computational Insights into Novel Inhibitor N-(3-(tert-Butylcarbamoyl)-4-methoxyphenyl)-indole and Ingliforib Specific against GP Isoenzyme Dimers Interaction Mechanism
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Published:2023-06-22
Issue:13
Volume:28
Page:4909
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ISSN:1420-3049
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Container-title:Molecules
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language:en
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Short-container-title:Molecules
Author:
Wang Youde1ORCID, Li Shuai1, Yan Zhiwei1, Zhang Liying1
Affiliation:
1. Laboratory of Traditional Chinese Medicine Research and Development of Hebei Province, Institute of Traditional Chinese Medicine, Chengde Medical University, Chengde 067000, China
Abstract
The high conservation of the three subtypes of glycogen phosphorylase (GP) presents significant challenges for specific inhibitor studies targeting GP. Our prior screening revealed that compound 1 exhibited unequal inhibitory activity against the three GP subtypes, with a noticeable effect against brain GP (PYGB). The commercially available ingliforib demonstrated potent inhibitory activity specifically against liver GP (PYGL). To guide the further design and screening of high-specificity inhibitors, the possible reasons for the differential inhibitory activity of two compounds against different GP subtypes were analyzed, with ingliforib as a reference, through molecular docking and molecular dynamics simulations. Initially, the study predicted the binding modes of ligands with the three GP receptor subtypes using molecular docking. Subsequently, this was validated by molecular dynamics experiments, and possible amino acid residues that had important interactions were explored. The strong correlation between the calculated interaction free energies and experimental inhibitory activity implied the reasonable binding conformations of the compounds. These findings offer insight into the different inhibitory activity of compound 1 and ingliforib against all three GP subtypes and provide guidance for the design of specific target molecules that regulate subtype selectivity.
Funder
Natural Science Foundation of Hebei Province Hebei Provincial Department of Science and Technology
Subject
Chemistry (miscellaneous),Analytical Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Molecular Medicine,Drug Discovery,Pharmaceutical Science
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