Expert opinion on drug discovery · 2025
In silico structural analysis of carbapenemase variants in Klebsiella pneumoniae: insights for precision drug discovery against multidrug-resistant strains.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Abada Emad, Mashraqi Abdullah, Alothman Norah S, Alharbi Asmaa A, Alhejely Amani
Аннотация
BACKGROUND: Carbapenemase-producing Klebsiella pneumoniae severely limits treatment options by inactivating carbapenem and other β-lactam antibiotics. To support precision drug discovery, this study investigates how structural and dynamic differences among major carbapenemase families shape their interaction with carbapenem drugs.
RESEARCH DESIGN AND METHODS: The authors performed an in-silico analysis of five key Klebsiella pneumoniae carbapenemases (KPC, NDM, VIM, IMP, OXA-48) using multiple sequence alignment, homology modeling, molecular docking, and 50-ns molecular dynamics simulations.
RESULTS: Sequence identity between variants was low (33.8-48.5%), indicating deep evolutionary divergence. SWISS-MODEL homology models showed high stereochemical quality, supporting reliable active-site interpretation. Docking suggested stronger binding of meropenem and imipenem to KPC and NDM, mediated by conserved catalytic residues in class A (Ser70, Lys73, Glu166) and class B (His120, His122, Asp124). MD simulations indicated more rigid, compact complexes for KPC and NDM, contrasted with higher flexibility in OXA-48.
CONCLUSIONS: These results reinforce that Klebsiella pneumoniae carbapenemases are not interchangeable targets and that inhibitor design must account for family-specific active-site geometries and dynamics. Integrating such structural insight with future virtual screening and experimental validation could enable variant-tailored inhibitors rather than relying on a single broad-spectrum carbapenemase blocker.
RESEARCH DESIGN AND METHODS: The authors performed an in-silico analysis of five key Klebsiella pneumoniae carbapenemases (KPC, NDM, VIM, IMP, OXA-48) using multiple sequence alignment, homology modeling, molecular docking, and 50-ns molecular dynamics simulations.
RESULTS: Sequence identity between variants was low (33.8-48.5%), indicating deep evolutionary divergence. SWISS-MODEL homology models showed high stereochemical quality, supporting reliable active-site interpretation. Docking suggested stronger binding of meropenem and imipenem to KPC and NDM, mediated by conserved catalytic residues in class A (Ser70, Lys73, Glu166) and class B (His120, His122, Asp124). MD simulations indicated more rigid, compact complexes for KPC and NDM, contrasted with higher flexibility in OXA-48.
CONCLUSIONS: These results reinforce that Klebsiella pneumoniae carbapenemases are not interchangeable targets and that inhibitor design must account for family-specific active-site geometries and dynamics. Integrating such structural insight with future virtual screening and experimental validation could enable variant-tailored inhibitors rather than relying on a single broad-spectrum carbapenemase blocker.