Integrative Ligand-Based Pharmacophore Modeling, Virtual Screening, and Molecular Docking Simulation Approaches Identified Potential Lead Compounds against Pancreatic Cancer by Targeting FAK1

Abstract

Pancreatic cancer is a very deadly disease with a 5-year survival rate, making it one of the leading causes of cancer-related deaths globally. Focal adhesion kinase 1 (FAK1) is a ubiquitously expressed protein in pancreatic cancer. FAK, a tyrosine kinase that is overexpressed in cancer cells, is crucial for the development of tumors into malignant phenotypes. FAK functions in response to extracellular signals by triggering transmembrane receptor signaling, which enhances focal adhesion turnover, cell adhesion, cell migration, and gene expression. The ligand-based drug design approach was used to identify potential compounds against the target protein, which included molecular docking: ADME (absorption, distribution, metabolism, and excretion), toxicity, molecular dynamics (MD) simulation, and molecular mechanics generalized born surface area (MM-GBSA). Following the retrieval of twenty hits, four compounds were selected for further evaluation based on a molecular docking approach. Three newly discovered compounds, including PubChem CID24601203, CID1893370, and CID16355541, with binding scores of −10.4, −10.1, and −9.7 kcal/mol, respectively, may serve as lead compounds for the treatment of pancreatic cancer associated with FAK1. The ADME (absorption, distribution, metabolism, and excretion) and toxicity analyses demonstrated that the compounds were effective and nontoxic. However, further wet laboratory investigations are required to evaluate the activity of the drugs against the cancer.