Discovery of new PKN2 inhibitory chemotypes via QSAR-guided selection of docking-based pharmacophores.
Mahmoud A Al-Sha'erHaneen A BasheerMutasem Omar TahaPublished in: Molecular diversity (2022)
Serine/threonine-protein kinase N2 (PKN2) plays an important role in cell cycle progression, cell migration, cell adhesion and transcription activation signaling processes. In cancer, however, it plays important roles in tumor cell migration, invasion and apoptosis. PKN2 inhibitors have been shown to be promising in treating cancer. This prompted us to model this interesting target using our QSAR-guided selection of docking-based pharmacophores approach where numerous pharmacophores are extracted from docked ligand poses and allowed to compete within the context of QSAR. The optimal pharmacophore was sterically-refined, validated by receiver operating characteristic (ROC) curve analysis and used as virtual search query to screen the National Cancer Institute (NCI) database for new promising anti-PKN2 leads of novel chemotypes. Three low micromolar hits were identified with IC 50 values ranging between 9.9 and 18.6 µM. Pharmacological assays showed promising cytotoxic properties for active hits in MTT and wound healing assays against MCF-7 and PANC-1 cancer cells.
Keyphrases
- cell migration
- molecular dynamics
- molecular docking
- cell cycle
- protein kinase
- high throughput
- papillary thyroid
- molecular dynamics simulations
- cell adhesion
- squamous cell
- cell proliferation
- wound healing
- small molecule
- protein protein
- oxidative stress
- squamous cell carcinoma
- lymph node metastasis
- structure activity relationship
- emergency department
- transcription factor
- young adults
- adverse drug