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Updated: Dec 29, 2025
Identification of Kinase-substrate Pairs Using High Throughput Screening
Published on: August 29, 2015
In silico identification of potential inhibitors against human 2'-5'- oligoadenylate synthetase (OAS) proteins
Karen J Gonzalez1, Diego M Moncada-Giraldo1, Juan B Gutierrez2
1Institute of Bioinformatics, University of Georgia, Athens, GA, 30602, USA.
Abstract:
As part of the type I IFN signaling, the 2'-5'- oligoadenylate synthetase (OAS) proteins have been involved in the progression of several non-viral diseases. Notably, OAS has been correlated with immune-modulatory functions that promote chronic inflammatory conditions, autoimmune disorders, cancer, and infectious diseases. In spite of this, OAS enzymes have been ignored as drug targets, and to date, there are no reports of compounds that can inhibit their activity. In this study, we have used homology modeling and virtual high-throughput screening to identify potential inhibitors of the human proteins OAS1, OAS2, and OAS3. Altogether, we have found 37 molecules that could exert a competitive inhibition in the ATP binding sites of OAS proteins, independently of the activation state of the enzyme. This latter characteristic, which might be crucial for a versatile inhibitor, was observed in compounds interacting with the residues Asp75, Asp77, Gln229, and Tyr230 in OAS1, and their equivalents in OAS2 and OAS3. Although there was little correlation between specific chemical fragments and their interactions, intermolecular contacts with OAS catalytic triad and other critical amino acids were mainly promoted by heterocycles with π electrons and hydrogen bond acceptors. In conclusion, this study provides a potential set of OAS inhibitors as well as valuable information for their design, development, and optimization.
Insights
Researchers identified 37 potential drug molecules targeting 2'–5'–oligoadenylate synthetase (OAS) enzymes. These inhibitors show promise for treating non-viral diseases linked to OAS, including inflammatory conditions and cancer.
Area of Science:
- Biochemistry and Molecular Biology
- Drug Discovery and Development
- Immunology
Background:
- 2'-5'-oligoadenylate synthetase (OAS) proteins are implicated in non-viral diseases, including chronic inflammation, autoimmune disorders, cancer, and infections.
- OAS proteins play a role in type I interferon signaling pathways.
- Despite their involvement in disease, OAS enzymes have not been pursued as drug targets, with no known inhibitors.
Purpose of the Study:
- To identify potential small molecule inhibitors for human OAS1, OAS2, and OAS3 proteins.
- To explore novel therapeutic strategies for diseases associated with OAS activity.
Main Methods:
- Utilized homology modeling to create structural models of OAS proteins.
- Performed virtual high-throughput screening to identify potential inhibitor compounds.
- Analyzed molecular interactions between identified compounds and OAS active sites.
Main Results:
- Discovered 37 molecules capable of competitive inhibition at the ATP binding sites of OAS1, OAS2, and OAS3.
- Identified key amino acid residues (Asp75, Asp77, Gln229, Tyr230 in OAS1) crucial for inhibitor binding, suggesting potential for versatile inhibitors.
- Observed that heterocycles with π electrons and hydrogen bond acceptors were key in forming interactions with the OAS catalytic triad and other critical residues.
Conclusions:
- This study presents a promising set of 37 potential OAS inhibitors.
- Provides valuable insights into the design and development of novel OAS-targeting therapeutics.
- Highlights the potential of OAS enzymes as drug targets for various non-viral diseases.
