Computational Tool to Design Small Synthetic Inhibitors Selective for XIAP-BIR3 Domain - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Molecules Année : 2023

Computational Tool to Design Small Synthetic Inhibitors Selective for XIAP-BIR3 Domain

Résumé

X-linked inhibitor of apoptosis protein (XIAP) exercises its biological function by locking up and inhibiting essential caspase-3,-7 and-9 toward apoptosis execution. It is overexpressed in multiple human cancers, and it plays an important role in cancer cells' death skipping. Inhibition of XIAP-BIR3 domain and caspase-9 interaction was raised as a promising strategy to restore apoptosis in malignancy treatment. However, XIAP-BIR3 antagonists also inhibit cIAP1-2 BIR3 domains, leading to serious side effects. In this study, we worked on a theoretical model that allowed us to design and optimize selective synthetic XIAP-BIR3 antagonists. Firstly, we assessed various MM-PBSA strategies to predict the XIAP-BIR3 binding affinities of synthetic ligands. Molecular dynamics simulations using hydrogen mass repartition as an additional parametrization with and without entropic term computed by the interaction entropy approach produced the best correlations. These simulations were then exploited to generate 3D pharmacophores. Following an optimization with a training dataset, five features were enough to model XIAP-BIR3 synthetic ligands binding to two hydrogen bond donors, one hydrogen bond acceptor and two hydrophobic groups. The correlation between pharmacophoric features and computed MM-PBSA free energy revealed nine residues as crucial for synthetic ligand binding:
Fichier principal
Vignette du fichier
molecules-28-05155.pdf (2.05 Mo) Télécharger le fichier
Origine : Fichiers éditeurs autorisés sur une archive ouverte

Dates et versions

hal-04148037 , version 1 (01-07-2023)

Identifiants

Citer

Marc Farag, Charline Kieffer, Nicolas Guedeney, Anne Sophie, Jana Sopkova-de Oliveira Santos. Computational Tool to Design Small Synthetic Inhibitors Selective for XIAP-BIR3 Domain. Molecules, 2023, ⟨10.3390/molecules28135155⟩. ⟨hal-04148037⟩
5 Consultations
20 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More