Virtual Screening Strategy to Identify Retinoic Acid-Related Orphan Receptor γt Modulators

Elmeri Jokinen, Miika Niemeläinen, Sami Kurkinen, Jukka Lehtonen, Sakari Lätti, Pekka Postila, Olli Pentikäinen, Sanna Niinivehmas*

*Corresponding author for this work

Research output: Contribution to journalArticleScientificpeer-review

4 Citations (Scopus)
15 Downloads (Pure)

Abstract

Molecular docking is a key method used in virtual screening (VS) campaigns to identify small-molecule ligands for drug discovery targets. While docking provides a tangible way to understand and predict the protein-ligand complex formation, the docking algorithms are often unable to separate active ligands from inactive molecules in practical VS usage. Here, a novel docking and shape-focused pharmacophore VS protocol is demonstrated for facilitating effective hit discovery using retinoic acid receptor-related orphan receptor gamma t (RORγt) as a case study. RORγt is a prospective target for treating inflammatory diseases such as psoriasis and multiple sclerosis. First, a commercial molecular database was flexibly docked. Second, the alternative docking poses were rescored against the shape/electrostatic potential of negative image-based (NIB) models that mirror the target’s binding cavity. The compositions of the NIB models were optimized via iterative trimming and benchmarking using a greedy search-driven algorithm or brute force NIB optimization. Third, a pharmacophore point-based filtering was performed to focus the hit identification on the known RORγt activity hotspots. Fourth, free energy binding affinity evaluation was performed on the remaining molecules. Finally, twenty-eight compounds were selected for in vitro testing and eight compounds were determined to be low μM range RORγt inhibitors, thereby showing that the introduced VS protocol generated an effective hit rate of ~29%.
Original languageEnglish
Article number3420
Number of pages20
JournalMolecules
Volume28
Issue number8
DOIs
Publication statusPublished - 13 Apr 2023
MoE publication typeA1 Journal article-refereed

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