Epigenetic mechanisms include a plethora of modifications that influence gene expression without altering the DNA sequence. Histones are targets of several posttranslational modifications (PTMs), including methylation, acetylation, and phosphorylation, which can modify chromatin structure and accessibility, playing a crucial role in epigenetic regulation and cell survival. Histone PTMs have been linked to several diseases including cancer, metabolic syndromes, and neurological disorders.
Methylation is pivotal in many processes involved in cell differentiation, homeostasis and disease. It mainly occurs on arginine/lysine residues and is mediated by numerous enzymes sharing common domains. More than 20 human histone N-methylated lysine residue demethylases (KDMs) have been identified to date. Many of them exhibit deregulated expression patterns in cancer as well as in neurological and immunological diseases. As with lysine methyltransferases, growing evidence suggests that KDMs are involved in disease initiation and progression, thus emerging as new highly-promising therapeutic targets .
The Life Chemicals Receptor-based Screening Library contains over 2,000 potential lysine-specific demethylase 4A (KDM4A) inhibitors selected with computational chemistry and virtual screening techniques. The Library presented is a rich source of inhibitors for screening projects in KDM-related drug discovery.
A receptor-based virtual screening workflow based on known X-ray data for the complex with a pyrido[3,4-d]pyrimidin-4(3H)-one derivative has been set up using Schrödinger software. The bound ligand has been extracted from the KDM4A crystal structure. Compounds from the Life Chemicals HTS Compound Collection have been pre-filtered with in house MedChem filters, including PAINS and toxicophore filters and the Rule of Five restrictions, and then 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 the presence of a ligand’s hydrophobic moiety between side chains of Ty177 and Phe185 (Fig. 2).
The screening resulted in identifying around 4,000 molecules which were further narrowed down to 2,000 drug-like screening compounds with manual evaluation of receptor-ligand complexes.
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