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Drug Repurposing to Discover Novel Anti-Inflammatory Agents Inhibiting JAK3/STAT Signaling

Abstract

Among the JAKs, JAK3 is the most important target for the treatment of inflammatory diseases because its inhibition showed the utmost immunosuppression. Many JAK3 inhibitors are already available but most of them showed acquired drug resistance or objectionable side effects. To prevent inflammatory diseases, novel and superior drugs are needed. The drug repositioning is an alternate process that can be used as a fast-track approach. Drugs already approved by regulatory agencies have well-known pharmacokinetics and safety profile. When a new therapeutic activity has been identified, the entities can be rapidly advanced into clinical trials. To identify new promising lead molecules, we have selected 1150 approved drugs for their potential to be repurposed for inflammatory diseases. The library of approved drugs was obtained from zinc data base and JAK3 (PDB ID: 3LXK) was retrieved from protein data bank and used for molecular docking simulation and protein-ligand interaction analysis. The virtual screening of full library of drugs by AutoDock Vina version PyRx 0.8 and selected 100 drug molecules and further filtered through click-1 docking software. The binding affinity of top 8 drugs ranges between –10.3 to –7.8 kcal/mole. The threshold binding affinity of fluspirilene for JAK3 was –10.3 kcal/mole was repurposed to be promising drug candidate for inflammatory diseases. The results showed that fluspirilene has best docking interaction with JAK3 (PDB ID: 3LXK) and molecular dynamics simulation was also carried out to investigate structural conformations and to explore the key amino acids in the interaction between target and ligands. In conclusion, fluspirilene could be one of the alternative drugs for the treatment of inflammatory diseases.

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ACKNOWLEDGMENTS

The authors gratefully acknowledge the R&D wing of Integral University, Lucknow, for providing necessary facilities and communication number IU/R&D/2021-MCN0001128.

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Correspondence to M. Nasibullah.

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Sheikh, S.Y., Hassan, F., Khan, M.F. et al. Drug Repurposing to Discover Novel Anti-Inflammatory Agents Inhibiting JAK3/STAT Signaling. Russ J Bioorg Chem 48, 958–975 (2022). https://doi.org/10.1134/S106816202205020X

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  • DOI: https://doi.org/10.1134/S106816202205020X

Keywords:

  • drug repurposing
  • JAK-STAT pathway
  • JAK3
  • virtual screening
  • docking
  • MD simulation