Virtual screening by 2-D fingerprints, shape and docking for discovering new chemotypes of activator protein-1 inhibitors.
Activator protein-1 Fos/Jun proteins bind to cognate DNA and regulate gene expression. Small-molecule inhibitors targeting activator protein-1 DNA binding have been developed in the past decades for therapeutic applications. Recent structural and in silico studies suggest a putative inhibitor binding pocket on the activator protein-1 structure, and computational modeling suggests a consensus binding mode of three classes of known small-molecule inhibitors. Here, virtual screening of two-dimensional fingerprints, shape, and docking was performed in search of novel chemotypes of activator protein-1 inhibitors. A standard score (Z3-score) coalescing top-ranked ligands from the three methods was used and the top-scoring ligands were clustered by similarity. A representative ligand from each large cluster was evaluated using metadynamics simulations and molecular mechanics calculations. Representative hits showed diverse chemotypes and their modeled binding pose on activator protein-1 reproduced key interactions with binding site residues.Communicated by Ramaswamy H. Sarma.
['Yin|Zhou|Z|https://orcid.org/0000-0002-9750-7312']
D001665:Binding Sites D008024:Ligands D062105:Molecular Docking Simulation D056004:Molecular Dynamics Simulation D011485:Protein Binding D018808:Transcription Factor AP-1
virtual screening fingerprints docking Activator protein-1 metadynamics simulation data fusion