Targeting the NF-κB/IκBα complex via fragment-based E-Pharmacophore virtual screening and binary QSAR models

Publication date: Available online 5 October 2018Source: Journal of Molecular Graphics and ModellingAuthor(s): Tarek Kanan, Duaa Kanan, Ismail Erol, Samira Yazdi, Matthias Stein, Serdar DurdagiAbstractNuclear factor-κB (NF-κB) transcription factors represent a conserved family of proteins that regulate not only immune cells, but also heart cells, glial cells and neurons, playing a fundamental role in various cellular processes. Due to its dysregulation in certain cancer types as well as in chronic inflammation and autoimmune diseases, it has recently been appreciated as an important therapeutic target. The aim of this study was to investigate the binding pocket of NF-κB (p50/p65) heterodimer complex in association with NF-κB inhibitor IκBα to identify potent ligands via fragment-based e-pharmacophore screening. The ZINC Clean Fragments (∼2 million) and the Schrodinger's medically relevant Glide fragments library (∼670) were used to create the e-pharmacophore models at the potential binding site of the target which was validated by site mapping. Glide/HTVS docking was conducted followed by re-docking of the top 20% fragments by Glide/SP and Glide/XP protocols. The top-85000 Glide XP-docked fragments were used to generate the e-pharmacophore hypotheses. The Otava small molecule library (∼260000 drug-like molecules) and additional 85 known NF-κB inhibitors were screened against the derived e-pharmacophore models. The top-1000 high-scored molecules, which were well a...
Source: Journal of Molecular Graphics and Modelling - Category: Molecular Biology Source Type: research