Targeting human inosine 5’ monophosphate dehydrogenase type 2 for anti-dengue lead identification – a computational approach

Abstract

Dengue is a rapidly evolving arboviral disease that mainly affects tropical and subtropical regions of the world. The lack of therapeutic drugs and effective vaccines suggests that further resources need to be investigated. The effectiveness of the existing dengue vaccine is improbable as its efficacy depends on prior exposure to the dengue virus(DENV). Although the mechanism underlying the action of bioactive compounds to limit viral replication is less studied and still needs to be further explored, medicinal plants are excellent alternatives to combat DENV infection. In the current study, an in silico screening of phytochemicals from Annona reticulata Linn. against human Impdh2 was performed using Autodock Vina. Daucosterol (−9.0 kcal/mol) and Kaurenoic acid (−8.5 kcal/mol) were chosen as the top hits based on molecular interaction analysis. The hits were further exposed to pharmacokinetics and toxicity properties to determine their drug-like parameters. Molecular dynamics simulation studies of the Impdh2-top hits were carried out to investigate their kinetic behaviour and structural stabilities. The binding free energies of the Impdh2-hit complexes were determined using MM-PBSA analysis. According to the overall conclusions of the study, Daucosterol showed good binding affinity and high structural stability to the binding site residues of the target, therefore it is recommended as a lead compound against dengue.

Communicated by Ramaswamy H. Sarma

Keywords:

• Dengue
• Impdh2
• virtual screening
• Annona
• phytochemicals

Acknowledgements

The authors are grateful to the KSCSTE, Government of Kerala, for the generous financial support. Also, we extend our gratitude to the Director, JNTBGRI for invaluable assistance, continuous encouragement, and provision of necessary facilities that enabled the successful execution of this work.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

The MD simulation run was performed on resources funded by the Gujarat State Biotechnology Mission, and the authors gratefully acknowledge the AMR grant (GSBTM/JD(R&D)/626/22-23/00018348).