Virtual screening and molecular dynamics identify sulfonamide indole analogs as candidate CBP bromodomain binders

Abstract Epigenetic dysregulation, particularly via bromodomain-mediated recognition of histone acetylation, drives oncogenic gene expression in cancers, including prostate and acute myeloid leukemia, positioning the CREB-binding protein (CBP) bromodomain as a key therapeutic target for disrupting pro-proliferative programs without genetic alteration. While inhibitors like CCS1477 advance clinically, challenges in selectivity over BET paralogs and ligand efficiency persist (Conery et al., 2023; Urano et al., 2020). Here, we employed a computational pipeline starting from the YF2-23 co-crystal (PDB: 7JUO) to derive a sulfonamide-indole pharmacophore for PubChem screening, retrieving 392 analogs rescored by molecular docking simulation in the hinge pocket (Asp1116-Tyr1125). Top hits from this virtual screening campaign advanced to 1 µs MD simulations (duplicate replicates), revealing CID135236309's exceptional stability versus CID135236185 and CID66966190's steric issues. MM-GBSA on final 10 ns trajectories yielded binding free energy values of -34.98, -32.97, and − 25.60 kcal/mol, respectively, against YF2-23's -37.26 kcal/mol, with electrostatics underscoring the lead's hinge triad potency (Genheden and Ryde, 2015). This workflow nominates CID135236309 as a selective CBP lead for synthesis and validation, advancing epigenetic drug design.