Publication
Title
Discovery and biological evaluation of an adamantyl-amide derivative with likely MmpL3 inhibitory activity
Author
Abstract
A series of molecules containing bulky lipophilic scaffolds was screened for activity against Mycobacterium tuberculosis and a number of compounds with antimycobacterial activity were identified. The most active compound, (2E)-N-(adamantan-1-yl)-3-phenylprop-2-enamide (C1), has a low micromolar minimum inhibitory concentration, low cytotoxicity (therapeutic index = 32.26), low mutation frequency and is active against intracellular Mycobacterium tuberculosis. Whole genome sequencing of mutants resistant to C1 showed a mutation in mmpL3 which may point to the involvement of MmpL3 in the antimycobacterial activity of the compound. In silico mutagenesis and molecular modelling studies were performed to better understand the binding of C1 within MmpL3 and the role that the specific mutation may play in the interaction at protein level. These analyses revealed that the mutation increases the energy required for binding of C1 within the protein translocation channel of MmpL3. The mutation also decreases the solvation energy of the protein, suggesting that the mutant protein might be more solvent-accessible, thereby restricting its interaction with other molecules. The results reported here describe a new molecule that may interact with the MmpL3 protein, providing insights into the effect of mutations on protein-ligand interactions and enhancing our understanding of this essential protein as a priority drug target.
Language
English
Source (journal)
Tuberculosis / International Union against Tuberculosis and Lung Disease. - Edinburgh, 2001, currens
Publication
Edinburgh : 2023
ISSN
1472-9792
DOI
10.1016/J.TUBE.2023.102350
Volume/pages
141 (2023) , p. 1-9
Article Reference
102350
ISI
001053546500001
Pubmed ID
37244249
Medium
E-only publicatie
Full text (Publisher's DOI)
Full text (publisher's version - intranet only)
UAntwerpen
Faculty/Department
Research group
Project info
Development of a Centre for Whole Genome Sequencing studies of Mycobacterium.
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Web of Science
Record
Identifier
Creation 02.10.2023
Last edited 24.05.2024
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