A1 Refereed original research article in a scientific journal
Virtual Screening Strategy to Identify Retinoic Acid-Related Orphan Receptor γt Modulators
Authors: Jokinen Elmeri M, Niemeläinen Miika, Kurkinen Sami T, Lehtonen Jukka V, Lätti Sakari, Postila Pekka A, Pentikäinen Olli T, Niinivehmas Sanna P
Publisher: MDPI
Publication year: 2023
Journal: Molecules
Journal name in source: Molecules (Basel, Switzerland)
Journal acronym: Molecules
Article number: 3420
Volume: 28
Issue: 8
ISSN: 1420-3049
eISSN: 1420-3049
DOI: https://doi.org/10.3390/molecules28083420
Web address : https://doi.org/10.3390/molecules28083420
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/179841704
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%.
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