Mechanism of Small Molecules Inhibiting Activator Protein‑1 DNA Binding Probed with Induced Fit Docking and Metadynamics Simulations

Transcription factor activator protein-1 (AP-1) binds to cognate DNA and regulates gene expression. In recent decades, small-molecule inhibitors have been developed for therapeutic applications that block AP-1 binding to DNA. However, the mechanism by which small molecules inhibit AP-1-DNA binding remains elusive. Here, computational studies identified a drug-binding site on the AP-1 Fos/Jun apo structure. Induced fit docking of known inhibitors, together with metadynamics simulations to identify the most plausible binding pose, showed a consensus mode of AP-1/inhibitor interaction. The in silico binding mode of the inhibitors suggests a mechanism of AP-1-DNA binding inhibition, where the inhibitors block the base-contacting residues, preclude access of DNA, and prohibit conformational changes of AP-1 upon DNA binding.