Nuclear receptors are a class of proteins that are responsible for sensing steroid and thyroid hormones and some other molecules. In response, these receptors work with other proteins to regulate the expression of specific genes, thereby controlling the development, homeostasis, and metabolism of the organism. Nuclear hormone receptors are important drug targets for treatment of inflammatory diseases, cancer and diabetes.
Life Chemicals has developed two dedicated Nuclear Receptor Screening Libraries for drug discovery screening projects in nuclear receptor research.
Nuclear Receptor Docking Library
Nuclear Receptor Targeted Library by Life Chemicals comprises screening compounds selected by protein-ligand docking method. For this purpose, we have applied Glide software from Schrödinger. Using available crystal structures of nuclear receptors (Estrogen, Androgen, Progesterone, Glucocorticoid, Mineralcorticoid, RAR, RXR, PXR, ROR (-α/γ), LXR, PPAR, Thyroid hormone receptors), a number of H-bond and hydrophobic constraints were assigned, that in combination with electrostatic maps of the binding sites have been used as docking/screening models (Fig. 1). To estimate the efficiency of the docking procedure, each model was validated, using a reference set (50 to 1,107 compounds, depending on the target) with known nuclear receptor antagonist activity (IC50 lower than 1 µM), as well as a random set of inactive compounds, both extracted from the ChEMBL database.
In-silico screening of all compounds from the Life Chemicals HTS Compound Collection resulted in selection of about 5,000 potential nuclear receptor modulators. Molecules with unwanted structures were filtered off using the PAINS filters. The compounds are ranked based on docking score values obtained from a docking reference set.
Nuclear Receptor Ligand-Based Library by 2D Similarity
This ligand-based Library has been selected by 2D fingerprint similarity search against nuclear receptor bioactivities recorded in ChEMBL database. Minimum Tanimoto index value has been set to 0.85 that resulted in about 10,000 analogs of nuclear receptor modulators. Further filtering by Lipinski’s Rule of Five, PAINS and toxic/reactive groups criteria has narrowed down the compounds set to the Nuclear Receptor Ligand-Based Library of 6,000 drug-like compounds.
Fig. 1. Ligand positions and conformations generated as based on docking results. For an example, the localization of ligand molecules from the Life Chemicals HTS Compound Collection (F3260-0084 and) are shown in the receptor binding sites (A: compound F3260-0084, estrogen; B: compound F3161-0400, progesterone).