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Novel Scaffolds for Modulation of NOD2 Identified by Pharmacophore-Based Virtual Screening.

ABSTRACT: 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.

SUBMITTER: Guzelj S

PROVIDER: S-EPMC9405794 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Novel Scaffolds for Modulation of NOD2 Identified by Pharmacophore-Based Virtual Screening.

Guzelj Samo S Tomašič Tihomir T Jakopin Žiga Ž

Biomolecules 20220729 8

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 p ...[more]

PMID: 36008948

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Novel Scaffolds for Modulation of NOD2 Identified by Pharmacophore-Based Virtual Screening.

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Novel Scaffolds for Modulation of NOD2 Identified by Pharmacophore-Based Virtual Screening.

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