Discovery of Retinoic Acid-Related Orphan Receptor γt Inverse Agonists via Docking and Negative Image-Based Screening

Retinoic acid-related
orphan receptor γt (RORγt) has
a vital role in the differentiation of T-helper 17 (TH17) cells. Potent
and specific RORγt inverse agonists are sought for treating
TH17-related diseases such as psoriasis, rheumatoid arthritis, and
type 1 diabetes. Here, the aim was to discover novel RORγt ligands
using both standard molecular docking and negative image-based screening.
Interestingly, both of these in silico techniques put forward mostly
the same compounds for experimental testing. In total, 11 of the 34
molecules purchased for testing were verified as RORγt inverse
agonists, thus making the effective hit rate 32%. The pIC50 values for the compounds varied from 4.9 (11 μM) to 6.2 (590
nM). Importantly, the fact that the verified hits represent four different
cores highlights the structural diversity of the RORγt inverse
agonism and the ability of the applied screening methodologies to
facilitate much-desired scaffold hopping for drug design.