Network-based drug repositioning of linagliptin as a potential agent for uterine fibroids targeting transforming growth factor-beta mediated fibrosis.

Anusha Shreenidhi Bhat, Amritha Chakkittukandiyil, Santhosh Kumar Muthu, Satvik Kotha, Sudharsan Muruganandham, Kalirajan Rajagopal, Saravanan Jayaram, Ram Kothandan, Divakar Selvaraj

Biochemical and biophysical research communications 2024 Apr 09

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Uterine fibroid is the most common non-cancerous tumor with no satisfactory options for long-term pharmacological treatment. Fibroblast activation protein-α (FAP) is one of the critical enzymes that enhances the fibrosis in uterine fibroids. Through STITCH database mining, we found that dipeptidyl peptidase-4 inhibitors (DPP4i) have the potential to inhibit the activity of FAP. Both DPP4 and FAP belong to the dipeptidyl peptidase family and share a similar catalytic domain. Hence, ligands which have a binding affinity with DPP4 could also bind with FAP. Among the DPP4i, linagliptin exhibited the highest binding affinity (Dock score = -8.562 kcal/mol) with FAP. Our study uncovered that the differences in the S2 extensive-subsite residues between DPP4 and FAP could serve as a basis for designing selective inhibitors specifically targeting FAP. Furthermore, in a dynamic environment, linagliptin was able to destabilize the dimerization interface of FAP, resulting in potential inhibition of its biological activity. True to the in-silico results, linagliptin reduced the fibrotic process in estrogen and progesterone-induced fibrosis in rat uter us. Furthermore, linagliptin reduced the gene expression of transforming growth factor-β (TGF-β), a critical factor in collagen secretion and fibrotic process. Masson trichrome staining confirmed that the anti-fibrotic effects of linagliptin were due to its ability to reduce collagen deposition in rat uterus. Altogether, our research proposes that linagliptin has the potential to be repurposed for the treatment of uterine fibroids. Copyright © 2024 Elsevier Inc. All rights reserved.

Citation

Anusha Shreenidhi Bhat, Amritha Chakkittukandiyil, Santhosh Kumar Muthu, Satvik Kotha, Sudharsan Muruganandham, Kalirajan Rajagopal, Saravanan Jayaram, Ram Kothandan, Divakar Selvaraj. Network-based drug repositioning of linagliptin as a potential agent for uterine fibroids targeting transforming growth factor-beta mediated fibrosis. Biochemical and biophysical research communications. 2024 Apr 09;703:149611