4D-QSAR, ADMET properties, and molecular dynamics simulations for designing N-substituted urea/thioureas as human glutaminyl cyclase inhibitors.
Comput Biol Chem
; 112: 108131, 2024 Oct.
Article
en En
| MEDLINE
| ID: mdl-38968781
ABSTRACT
Human glutaminyl cyclase (hQC) inhibitors have great potential to be used as anti- Alzheimer's disease (AD) agents by reducing the toxic pyroform of ß-amyloid in the brains of AD patients. The four-dimensional quantitative structure activity relationship (4D-QSAR) model of N-substituted urea/thioureas was established with satisfying predictive ability and statistical reliability (Q2 = 0.521, R2 = 0.933, R2prep = 0.619). By utilizing the developed 4D-QSAR model, a set of new N-substituted urea/thioureas was designed and evaluated for their Absorption Distribution Metabolism Excretion and Toxicity (ADMET) properties. The results of molecular dynamics (MD) simulations, Principal component analysis (PCA), free energy landscape (FEL), dynamic cross-correlation matrix (DCCM) and molecular mechanics generalized Born Poisson-Boltzmann surface area (MM-PBSA) free energy calculations, revealed that the designed compounds were remained stable in protein binding pocket and compounds b â¼ f (-35.1 to -44.55 kcal/mol) showed higher binding free energy than that of compound 14 (-33.51 kcal/mol). The findings of this work will be a theoretical foundation for further research and experimental validation of urea/thiourea derivatives as hQC inhibitors.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Tiourea
/
Urea
/
Aminoaciltransferasas
/
Relación Estructura-Actividad Cuantitativa
/
Inhibidores Enzimáticos
/
Simulación de Dinámica Molecular
Límite:
Humans
Idioma:
En
Revista:
Comput Biol Chem
Asunto de la revista:
BIOLOGIA
/
INFORMATICA MEDICA
/
QUIMICA
Año:
2024
Tipo del documento:
Article
Pais de publicación:
Reino Unido