“In silico identification of ethoxy phthalimide pyrazole derivatives as IL-17A and IL-18 targeted gouty arthritis agents”

Abstract

Two proinflammatory cytokines, IL17A and IL18, are observed to be elevated in the serum of gout patients and they play a crucial role in the development and worsening of inflammation, which has severe effects. In present study, we have combined molecular docking, molecular dynamics studies and MM-PBSA analysis to study the effectiveness of ethoxy phthalimide pyrazole derivatives (series 3a to 3e) as potential inhibitors against cytokines IL17A and IL18 as a druggable targets. The binding energy of the docked series ranges from −13.5 to −10.0 kcal/mol and extensively interacts with the amino acids in the active pocket of IL17A and IL18. Compound 3e had the lowest binding energy with IL17A at −12.6 kcal/mol compared to control allopurinol (3.32 kcal/mol). With IL18, compound 3a seems to have the lowest binding energy of −9.6 kcal/mol compared to control allopurinol (3.18 kcal/mol). In MD simulation studies, compound 3a forms a stable and energetically stabilized complex with the target protein. Depending on properties of the bound IL17A-3a and IL18-3a complexes was compared by means of MM-PBSA analysis. These derivatives can be used as a scaffold to develop promising IL17A and IL18 inhibitors to assess their potential for gouty arthritis and other related diseases.

Communicated by Ramaswamy H. Sarma

Highlights

• Ethyl phthalimide pyrazole derivatives (series 3a to 3e) bind to the IL17 and IL18 protein.

• The RMSD, RMSF, Radius of gyration, Residual correlative motion (RCM), No. of hydrogen bonds, Protein secondary structure content, Per-residue protein secondary structure, Dynamic Cross Correlation Matrix, and MM/PBSA energy calculated for selected compound (3a) with IL17 and IL18 through MD simulation studies for 100ns.

Keywords:

• Molecular docking
• MD simulation
• polymer compounds
• chronic arthritis
• IL17
• IL18

Acknowledgement

The authors are thankful to Dr. Ashok kumar Gadiya, Chairman, Mewar University, Gangrar, Rajasthan for his continued support and assistance throughout the work. Department of Life Sciences and Chemistry, Faculty of Science & Technology, and Mewar University for providing necessary infrastructure facilities. SKS acknowledges the Department of Biotechnology and Genetic Engineering, Noakhali Science and Technology University for MD Simulation experiment. AKV acknowledges Dr. Ramdas Pai PhD scholarship from MUJ.

Disclosure statement

The authors declare no competing interests

Data availability statement

All data generated or analyzed during this study are included in this published article.

Consent for publication

All the authors have made a significant contribution to the manuscript and agree with its contents and give consent for the article to be published in Journal of Biomolecular Structure and Dynamics.

Additional information

Funding

This work was supported by Science and Engineering Research Board (SERB), India grant CRG/2020/002008 to SKS.