Discovery and biological evaluation of an adamantyl-amide derivative with likely MmpL3 inhibitory activity - 20/07/23
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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.
Le texte complet de cet article est disponible en PDF.Highlights |
• | A new MmpL3 inhibitor with intracellular antimycobacterial activity was identified. |
• | The compound has a good selectivity index and low mutation frequency. |
• | In vitro mutagenesis identified resistance-associated mutations. |
• | Molecular modelling suggested how an observed mutation causes drug resistance. |
• | MmpL3 inhibitors that remain effective despite resistance mutations can be designed. |
Keywords : Mycobacterium tuberculosis, MmpL3, Drug resistance, Mutation
Plan
Vol 141
Article 102350- juillet 2023 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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