Identification of novel JMJD2A inhibitor scaffold using shape and electrostatic similarity search combined with docking method and MM-GBSA approach

We present a hierarchical workflow combining shape- and electrostatic-based virtual screening for the identification of novel Jumonji domain-containing protein 2A (JMJD2A) inhibitors. Our virtual screening protocol initially involved the identification of small molecules, which had similar shape and electrostatic properties to 5-carboxy-8-hydroxyquinoline (5-carboxy-8-HQ, IOX-1). Molecular docking and Molecular Mechanics/Generalized Born Surface Area (MM-GBSA) rescoring were then used to prioritize these small molecules for Amplified Luminescent Proximity Homogeneous Assay Screen (AlphaScreen) assay. Compounds contained a catechol scaffold displayed inhibition activity against JMJD2A. They also exhibited competitive inhibition with respect to 2-oxoglutaric acid (2OG). Our study suggested that the novel structure discovered in the present study may serve as a starting point for developing JMJD2A inhibitors.