Discovery and characterization of novel FAK inhibitors for breast cancer therapy via hybrid virtual screening, biological evaluation and molecular dynamics simulations.
Journal:
Bioorganic chemistry
Published Date:
Mar 26, 2025
Abstract
Focal adhesion kinase (FAK) is a critical drug target implicated in various disease pathways, including hematological malignancies and breast cancer. Therefore, identifying FAK inhibitors with novel scaffolds could offer new opportunities for developing effective therapeutic compounds. Herein, we disclosed the discovery of a new backbone inhibitor of FAK using an "internal" database, employing a structure-based high-transparency permeability virtual screening (HTVS) and a DeepDock algorithm based on geometric deep learning. Subsequently, molecular docking was conducted at different precisions to identify 10 compounds for further evaluation of biological activity. Ultimately, compound 4, a pyrimidin-4-amine derivative, demonstrated inhibitory activity against FAK and breast cancer cells, further supporting its potential as a FAK inhibitor. Moreover, molecular dynamics simulations were carried out to gain more detailed insights into the binding mechanism between compound 4 and FAK to guide subsequent structural optimization.
Authors
Keywords
Antineoplastic Agents
Breast Neoplasms
Cell Proliferation
Dose-Response Relationship, Drug
Drug Discovery
Drug Evaluation, Preclinical
Drug Screening Assays, Antitumor
Female
Focal Adhesion Kinase 1
Focal Adhesion Protein-Tyrosine Kinases
Humans
Molecular Docking Simulation
Molecular Dynamics Simulation
Molecular Structure
Protein Kinase Inhibitors
Structure-Activity Relationship
