Therapeutic Targeting of Cathetpsin K in Osteoporosis: Analysis of Polyphenolic Inhibitors In Silico and ADMET

İbrahim Bektaş; Şükrü Akmeşe

doi:10.5281/zenodo.18103680

Authors

İbrahim Bektaş Harran Üniversitesi https://orcid.org/0000-0001-9430-9735
Şükrü Akmeşe Harran Üniversitesi https://orcid.org/0000-0003-4992-0281

DOI:

https://doi.org/10.5281/zenodo.18103680

Abstract

Objective: Increased bone resorption in osteoporosis is primarily associated with the significant role of the Cathepsin K (CatK) enzyme, secreted by osteoclasts, in collagen degradation. Due to safety concerns encountered with synthetic CatK inhibitors, natural compounds offer promising therapeutic alternatives. The aim of this study is to identify potential inhibitor candidates by evaluating the interactions of selected polyphenols with the CatK enzyme using in silico methods.

Materials and Methods: The crystal structure of CatK (PDB ID: 4X6H) was prepared, and molecular docking analyses were performed using AutoDock Vina software. The binding modes of the ligands were investigated using Discovery Studio Visualizer; interactions such as hydrophobic and hydrogen bonding were evaluated. The pharmacokinetic and toxicological profiles of the compounds were estimated using ADMETlab 3.0, and Lipinski’s rules, absorption, distribution, metabolism, and toxicity parameters were analyzed.

Results: Docking analyses revealed that EGCG, Naringenin, and Genistein exhibited higher binding affinity than the reference inhibitor. These compounds were found to have significant interactions with CatK's catalytic binary and S1–S3 pockets. ADMET results showed that all compounds possessed drug-like properties, had a low risk of toxicity, and exhibited varying metabolic profiles.

Discussion and Conclusion: Consistent interactions with CatK's catalytic binary and selectivity pockets are key determinants in identifying strong inhibitor candidates. The direct contact of the prominent compounds in this study with these regions structurally explains their high affinity. While ADMET data offer general agreement, potential interactions with CYP enzymes in some compounds highlight the need for metabolic optimization. The findings demonstrate that some naturally occurring polyphenols are strong candidates for CatK inhibition, and their structural interactions and pharmacokinetic profiles form the basis for future drug design studies.

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