Epigenetic mechanisms include a plethora of modifications that influence gene expression without altering the DNA sequence. Histone posttranslational modifications (PTMs) play crucial roles in cellular biology, fate, and survival. Histone modifications have been linked to several diseases including cancer, metabolic syndromes, and neurological disorders. Histones are targets of several PTMs, including methylation, acetylation, and phosphorylation, which can modify chromatin structure and accessibility. Methylation is pivotal in many processes involved in cell differentiation, homeostasis, and disease. Methylation occurs mainly on arginine/lysine residues and is mediated by numerous enzymes sharing common domains. More than 20 human histone Ne-methylated lysine residue demethylases (KDMs) have been identified to date. Many exhibit deregulated expression patterns in cancer as well as in neurological and immunological diseases. As with lysine methyltransferases, a growing evidence suggests that KDMs are involved in disease initiation and progression. KDMs have thus emerged as new potential therapeutic targets .
The receptor-based library of potential Lysine-specific demethylase 4A (KDM4A) inhibitors has been designed by Life Chemicals based on known X-ray data for complex with pyrido[3,4-d]pyrimidin-4(3H)-one derivative. Compounds from the Life Chemicals Stock Screening Collection have been initially processed with medicinal chemistry filters that included PAINS and toxicophore filters and Rule of Five restrictions. At the next step, a receptor-based virtual screening workflow has been set up using Schrödinger software. The bound ligand has been extracted from the KDM4A crystal structure, and the pre-filtered compounds from the Life Chemicals Stock Screening Collection were docked in the active site (Fig.1). The docking procedure implied constraining the two key features contributing to the ligand binding - ligand-metal (Zn2+) coordination and presence of a ligand’s hydrophobic moiety between side chains of Ty177 and Phe185 (Fig. 2).
The screening resulted in around 4,000 compounds which were further narrowed down to 2,003 with manual evaluation of the receptor-ligand complexes. The Library comprises drug-like compounds selected with computational chemistry and virtual screening techniques and is intended for screening in KDM-related drug discovery projects.
Fig. 1. Docked compound F2949-0036 from the KDM4A Receptor Based Focused Library in the KDM4A active site. Intermolecular hydrogen bonds and Pi-Pi interactions are indicated.
Fig. 2. Metal coordination and hydrophobic positional constraints (2.8 Å radius) in the KDM4A active site
1. Franci G, Sarno F, Nebbioso A, Altucci L. Identification and characterization of PKF118-310 as a KDM4A inhibitor. Epigenetics. 2017, 12(3):198-205