Novel scaffolds for modulation of NOD2 identified by pharmacophore-based virtual screening

Guzelj, Samo (author), Tomašič, Tihomir (author), Jakopin, Žiga (author)

Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) is an innate immune pattern recognition receptor responsible for the recognition of bacterial peptidoglycan fragments. Given its central role in the formation of innate and adaptive immune responses, NOD2 represents a valuable target for modulation with agonists and antagonists. A major challenge in the discovery of novel small-molecule NOD2 modulators is the lack of a co-crystallized complex with a ligand, which has limited previous progress to ligand-based design approaches and high-throughput screening campaigns. To that end, a hybrid docking and pharmacophore modeling approach was used to identify key interactions between NOD2 ligands and residues in the putative ligand-binding site. Following docking of previously reported NOD2 ligands to a homology model of human NOD2, a structure-based pharmacophore model was created and used to virtually screen a library of commercially available compounds. Two compounds, 1 and 3, identified as hits by the pharmacophore model, exhibited NOD2 antagonist activity and are the first small-molecule NOD2 modulators identified by virtual screening to date. The newly identified NOD2 antagonist scaffolds represent valuable starting points for further optimization.

• Language: English
• Keywords: antagonist, homology modeling, NOD2, Nucleotide-binding oligomerization, pharmacophore modeling, virtual screening
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication date: 01.01.2022
• Year: 2022
• Number of pages: 17 str.
• Numbering: Vol. 12, iss. 8, art. 1054
• PID: 20.500.12556/RUL-138680-86544121-2823-7222-34ef-8017072a3c05
• UDC: 615.4:54:616-006
• ISSN on article: 2218-273X
• DOI: 10.3390/biom12081054
• COBISS.SI-ID: 117616387
• Publication date in RUL: 09.08.2022

Record is a part of a journal

• Title: Biomolecules
• Shortened title: Biomolecules
• Publisher: MDPI
• ISSN: 2218-273X
• COBISS.SI-ID: 519952921

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.
• Licensing start date: 09.08.2022

Secondary language

• Language: Slovenian
• Keywords: antagonisti, modeliranje homologije, NOD2, oligomerizacija, ki veže nukleotide, modeliranje farmakoforja, virtualno rešetanje