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

Autor: Jokinen EM; MedChem.fi, Institute of Biomedicine, Integrative Physiology and Pharmacology, University of Turku, FI-20014 Turku, Finland.; InFLAMES Research Flagship Center, University of Turku, FI-20014 Turku, Finland., Niemeläinen M; MedChem.fi, Institute of Biomedicine, Integrative Physiology and Pharmacology, University of Turku, FI-20014 Turku, Finland., Kurkinen ST; MedChem.fi, Institute of Biomedicine, Integrative Physiology and Pharmacology, University of Turku, FI-20014 Turku, Finland.; InFLAMES Research Flagship Center, University of Turku, FI-20014 Turku, Finland., Lehtonen JV; Structural Bioinformatics Laboratory, Biochemistry, Faculty of Science and Engineering, Åbo Akademi University, FI-20500 Turku, Finland.; InFLAMES Research Flagship Center, Åbo Akademi University, FI-20500 Turku, Finland., Lätti S; MedChem.fi, Institute of Biomedicine, Integrative Physiology and Pharmacology, University of Turku, FI-20014 Turku, Finland.; InFLAMES Research Flagship Center, University of Turku, FI-20014 Turku, Finland., Postila PA; MedChem.fi, Institute of Biomedicine, Integrative Physiology and Pharmacology, University of Turku, FI-20014 Turku, Finland.; InFLAMES Research Flagship Center, University of Turku, FI-20014 Turku, Finland., Pentikäinen OT; MedChem.fi, Institute of Biomedicine, Integrative Physiology and Pharmacology, University of Turku, FI-20014 Turku, Finland.; InFLAMES Research Flagship Center, University of Turku, FI-20014 Turku, Finland., Niinivehmas SP; MedChem.fi, Institute of Biomedicine, Integrative Physiology and Pharmacology, University of Turku, FI-20014 Turku, Finland.; InFLAMES Research Flagship Center, University of Turku, FI-20014 Turku, Finland.
Jazyk: angličtina
Zdroj: Molecules (Basel, Switzerland) [Molecules] 2023 Apr 13; Vol. 28 (8). Date of Electronic Publication: 2023 Apr 13.
DOI: 10.3390/molecules28083420
Abstrakt: 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%.
Databáze: MEDLINE
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