“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.