Recently tetraspanin CD151 has been identified as an important biological target involved in metastatic processes which include cell adhesion, tumor progression processes, and so forth in different types of cancers, such as breast cancer and glioblastoma. This in Silico study considered 1603 compounds from the Food and Drug Administration database, after performing an ADMET analysis; we selected 853 ligands, which were used for docking analysis. The most promising ligands were selected from docking studies, based on two criteria: (a) showed lowest affinity to the CD151 protein and (b) they interact with the QRD motif, located in the second extracellular loop. Furthermore, we investigate the stability of the protein-ligand complexes through MD simulations as well as free energy MM-PBSA calculations. From these results, loperamide and glipizide were identified as the best evaluated drugs. We suggest an in vitro analysis is needed to confirm our in silico prediction studies.

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.