Pharmacophore-based computational study on inhibitor of TMPRSS6 as hepcidin modulator in an iron overload of beta-thalassaemia

ABSTRACT

TMPRSS6 (transmembrane protease, serine 6) plays an important role in the cleavage of hemojuvelin (HJV), a key protein involved in the regulation of hepcidin metabolism. TMPRSS6 cleaves HJV at specific sites, leading to the activation of the bone morphogenetic protein (BMP6-SMAD) pathway. This pathway further leads to the production of hepcidin (a liver peptide enzyme), which promotes iron absorption and removal from the bloodstream. In-silico pharmacophore analysis is used in this study to identify potential small therapeutic compounds that inhibit TMPRSS6 activity. Pharmacophore investigations of known inhibitors (peptidomimetic benzothiazole) were carried out to identify the molecules’ important properties for interacting with the target. The pharmacophore model of the TMPRSS6 (PDB ID: 6N4T) inhibitor (KD7) pharmacophore features were used to screen the small molecules library that binds to the target and modulates its activity. The docking parameters of the top 5 hit molecules had lower binding energy in comparative analysis to reference molecule. The best-fit pharmacophore feature ligands were docked at the binding site of the target protein. This study demonstrates that knocking out the enzyme reduces the effects of iron overload in conditions like hemochromatosis and beta-thalassemia. In-silico investigation discovered significant evidence of catalytic activity.

KEYWORDS:

• Hepcidin
• TMPRSS6
• pharmacophore study
• molecular docking
• MD simulation

Acknowledgements

Author(s) would like to acknowledge the Department of Bioinformatics, Central University of South Bihar, Gaya Bihar and the Indian Council of Medical Research, New Delhi India for all technical and financial support. The authors also acknowledge the National Supercomputing Mission (NSM) for providing computing resources for PARAM Ananta at IIT Gandhinagar, which is implemented by C-DAC and supported by the Ministry of Electronics and Information Technology (MeitY) and the Department of Science and Technology (DST), Government of India.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

This study was completed with teamwork. Every author has made a substantial contribution to the study.

Ethical approval

This article does not contain any studies with animals and humans performed by any of the authors.

Additional information

Funding

This work was supported by the Indian Council of Medical Research, New Delhi India under the ICMR Grant (ISRM/12(22)/2019, ID No. 2019-0370) for this manuscript.