In Silico Identification of Novel Natural Anti-Cancer Compounds Targeting ITGAV Protein

The alpha-V (ITGAV) integrins regulate localization and activity of proteolytic enzymes that remodel the extracellular matrix during tumorigenesis and metastasis. ITGAV has been identified to have central role in promoting many cancers; such as Breast cancer, Glioblastoma and Pancreatic adenocarcinoma. Yet no chemically synthesizable drug that specifically target ITGAV protein is on the market. This study aims to identify novel natural Anti-Cancer compounds targeting ITGAV Protein. To start with, a pharmacophore model was built utilizing PharmaGist web server using a database containing eight (۸) highly potent ITGAV inhibitors that were collected from ChEMBL. Different pharmacophore models were generated and best model was selected based on the high score of ۲۸.۱۹۱ and maximum number of aligned compounds of eight. Selected model was screened against the ZINC natural database using ZINCPHARMER to find potential drug candidates and resulted in ۲۱۸ compounds. Retrieved database from ZINCPHARMER further evaluated by docking studies and top ۲% compounds (eight compounds) showing highest binding a nity were chosen. In order to select compounds structurally di↵erent, an attempt to cluster molecules based on their origin compound was done using ZINC database. Four clusters were identified eventually, from each cluster the compound that showed the highest binding a nity was selected for proceeding the study. Later on, ADMET studies were done on selected compounds and ZINC۳۱۱۶۴۹۷۹ was identified to be closest to drug-like molecules than other three compounds due to its high oral bioavailability in comparison with ZINC۶۸۶۰۱۲۳۲ and ZINC۰۲۱۲۱۰۱۰; meanwhile it’s oral administration wouldn’t be toxic in despite of compounds ZINC۱۱۸۶۵۵۷۳ and ZINC۰۲۱۲۱۰۱۰. To confirm stability of the selected drug candidate to the target protein; the MD simulation approach were employed, which confirmed stability of the selected compound in complex with ITGAV protein. Therefore, newly obtained molecule (ZINC۳۱۱۶۴۹۷۹) may serve as lead compound for treatment of ITGAV related cancers

کلیدواژه ها:

Pharmacophore modeling ، Docking ، Molecular Dynamics Simulation ، ADMET ، Integrin Subunit Alpha V