Insights on in-silico approaches for identifying potential bioactive inhibitors for TNF-α and IL-6 proteins associated with rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic immunocompromised disorder that primarily affects joints thereby leading to synovial inflammation, pain, stiffness, stress, and affecting the quality of life. The present study aimed to determine and identify bioactive compounds that can be developed as potential inhibitors to target human TNF-α and IL-6 proteins associated with RA. The present study also aimed to determine physiochemical properties and toxicity of compounds by ADMET, identify binding pockets via CASTp server, stereochemical quality of protein by PROCHECK, MMGB/SA analysis by fastDRH and molecular dynamics (WebGro). The findings of the present study revealed staurosporine was the most effective compound against TNF-α with the highest binding affinity of −10.8 kcal/mol. Similarly, withanoside L showed the highest binding affinity of −8.2 kcal/mol when docked against IL-6. In the present study, rutin, withanoside II, and withanoside IV did not follow Lipinski’s rule of five whereas staurosporine, somnifericin, and withanolide L followed RO5. In the present study, the top binding pocket of TNF-α had highest area (SA) of 2743.25 Å2 and volume (SA) 4514.06 Å3 whereas IL-6 had highest area (SA) of 63.54 Å2 and volume (SA) of 38.58 Å3 respectively. In this study, Ramachandran plot analysis revealed that 90.2% and 95.2% residues for TNF-α and IL-6 proteins occupied the most favored region. In the present study, TNF-α rutin complex and IL-6 rutin complex showed the highest PB1 score of 13.69 kcal/mol and 12.30 kcal/mol respectively. WebGro server estimated molecular dynamic properties (RMSD, Rg, SASA, RMSF and hydrogen bonds) of the proteins. Bio2Byte tools predicted the biophysical behaviour of the proteins. The findings of the present study revealed that staurosporine and withanolide L could be developed as potential inhibitors of TNF- α and IL-6, however further in-vitro and in-vivo studies are required to validate these results.

Keywords

• Rheumatoid arthritis
• TNF-α
• IL-6
• Molecular Docking
• MM/PB(GB) SA
• Molecular dynamics simulation