Virtual screening and structure–activity relationship study of novel BTK inhibitors in Traditional Chinese Medicine for the treatment of rheumatoid arthritis

Abstract

Bruton tyrosine kinase (BTK) is a known drug target for the treatment of autoimmune diseases, including rheumatoid arthritis (RA). In this study, a series of 1-amino-1H-imidazole-5-carboxamide derivatives with good inhibitory activity against BTK were selected to explore the structure-activity relationships of these BTK inhibitors (BTKIs). Furthermore, we concentrated on 182 prescriptions of Traditional Chinese Medicine with therapeutic effects on RA. 54 herbs with a frequency of ≥10 were counted to establish a database containing 4027 ingredients for virtual screening. Five compounds with relatively higher docking scores and better absorption, distribution, metabolism, elimination and toxicity (ADMET) parameters were then selected for higher precision docking. The results demonstrated that the potentially active molecules form hydrogen bond interactions with the hinge region residues Met477, Glu475, glycine-rich P-loop residue Val416, Lys430 and DFG motif Asp539. In particular, they also interact with the key residues Thr474 and Cys481 of BTK. The molecular dynamics (MD) results demonstrated that all five compounds above could bind with BTK stably as its cognate ligand in dynamic conditions. This work identified several potential BTKIs using a computer-aided drug design approach and may provide crucial information for developing novel BTKIs.

Communicated by Ramaswamy H. Sarma

Keywords:

• Rheumatoid arthritis
• Bruton’s tyrosine kinase inhibitors
• three-dimensional quantitative structure–activity relationship (3D-QSAR)
• virtual screening
• molecular dynamics simulations

Acknowledgements

The authors gratefully acknowledge the supports by Dr. Bi and the Program of Beijing Medical and Health Foundation (No. FY2204), the Medical Science Research and Development Funds of Beijing Health Alliance Charitable Foundation (No. B21114FN, No. B21115FN).

Authors’ Contributions

L.S.: Conceptualization, methodology, data curation, and writing the original draft. Z.W.: Methodology, Software, validation, and data curation. Z.Y.: Funding acquisition and supervision. X.L.: Supervision and Software. H.D.: Funding acquisition, supervision, writing and review. All authors have read and agreed to the submission of the manuscript.

Disclosure statement

The authors declare no conflicts of interest.

Data availability statement

Data is contained within the article and Supplementary Materials.

Additional information

Funding

This work was supported by the Program for Xi’an Science and Technology Bureau (No. 20YXYJ0001(5)), the Fundamental Research Funds for the Central Universities (lzujbky-2022-sp09).