Molecular modeling and in vitro study on pyrocatechol as potential pharmacophore of CD151 inhibitor

• Published in: Journal of molecular graphics & modelling 2020-11, Vol.100, p.107681, Article 107681
• Main Authors: Akella, Manasa, Malla, RamaRao
• Format: Article
• Language: English
• Subjects: Antiproliferative; Breast cancer; CD151; Pharmacophore; Pyrocatechol
• ISSN: 1093-3263; 1873-4243
• DOI: 10.1016/j.jmgm.2020.107681

CD151 has been recognized as a prognostic marker, the therapeutic target of breast cancers, but less explored for small molecule inhibitors due to lack of a validated model. The 3-D structure of CD151 large extracellular loop (LEL) was modeled using the LOMETS server and validated by the Ramachandran plot. The validated structure was employed for molecular docking and structure-based pharmacophore analysis. Druglikeness was evaluated by the ADMET description protocol. Antiproliferative activity was evaluated by MTT, BrdU incorporation, flow cytometry, and cell death ELISAPLUS assay. This study predicted the best model for CD151-LEL with 94.1% residues in favored regions and Z score −2.79 kcal/mol using the threading method. The web-based receptor cavity method identified one functional target site, which was suitable for the binding of aromatic and heterocyclic compounds. Molecular docking study identified pyrocatechol (PCL) and 5-fluorouracil (FU) as potential leads of CD151-LEL. The pharmacophore model identified interaction points of modeled CD151-LEL with PCL and FU. Also, the analysis of ADMET properties revealed the drug-likeness of PCL and FU. The viability of MDA-MB 231 cells was significantly reduced with PCL and FU but less affected MCF-12A, normal healthy breast epithelial cell line. With 50% toxic concentration, both PCL and FU significantly inhibited 82.46 and 87.12% proliferation, respectively, of MDA-MB 231 cells by altering morphology and inducing G1 cell cycle arrest and apoptosis. In addition, PCL and FU inhibited the CD151 expression by 4.5-and 4.8-folds, respectively. This study suggests the further assessment of pyrocatechol as a potential lead of CD151 in breast cancer at the molecular level. [Display omitted] •Pyrocatechol was predicted as a druggable candidate by Lipinski’s rule of five.•Docked to the binding site of CD151-LEL with docking score similar to 5-fluorouracil.•Exhibited pharmacophore features in structure-and ligand-based pharmacophore analysis.•Inhibited MDA-MB 231 cell viability but not normal breast epithelial cell line.•Reduced proliferation and CD151 expression, induced cell cycle arrest and apoptosis.