Unravelling the Relacatib activity against the CTSK proteins causing pycnodysostosis: a molecular docking and dynamics approach

Abstract

Pycnodysostosis is an atypical autosomal recessive condition of Lysosomal storage disorder that originated due to the deficit of the enzyme Cathepsin K which is vital for normal osteoclast action in bone resorption. Abnormal degradation of type 1 collagen and accumulation of toxic undigested collagen fibers in lysosomes of the osteoclast cells resulting in high bone density, brittle bones, and a short stature is caused in CTSK protein-carrying individuals. The broad aim of this study is to identify the most significant variant through various computational pipelines. This study was initiated by retrieving a total number of thirty-six variants from NCBI, HGMD, and UniProt databases, and the Y283C variant was found to be more significant by various standard computational tools. A structural investigation was performed to understand and gain a better knowledge about the interaction profile for the native (1BY8) and variant (Y283C) with Relacatib (a small-molecule drug that blocks the function of Cathepsin K, an enzyme that has been linked to osteoporosis, osteoarthritis, and other bone-degrading diseases). The interaction profile was analyzed using molecular docking. Relacatib (ligand) had an average binding affinity for both native (-7.16 kcal/mol) and Y283C (-6.76 kcal/mol). Finally, Molecular dynamics simulations were done in duplicates to recognize the variant (Y283C) activity of the protein structure against Relacatib for 100 ns. This study assists in comprehending the most pathogenic amino-acid variant, the ligand interaction with the protein structure, and paves the way for understanding the steadiness of the ligand with the native and selected significant amino-acid variant.

Communicated by Ramaswamy H. Sarma

Keywords:

• Pycnodysostosis: CTSK protein: Relacatib: molecular docking: molecular dynamics: MMPBSA

Acknowledgments

The authors like to acknowledge Sri Ramachandra Institute of Higher Education and Research (DU) for their constant support. Author MPN acknowledges Indian Council of Medical Research for supporting the work with Senior Research Fellowship [BMI/11(42)/2022]

Author contribution

The author PK was involved in overall work design and data collection. PK and HBA were involved in manuscript writing, mutational analysis, molecular docking, and dynamic simulation. PK and MPN were involved in drafting the manuscript. RM was involved in making the study design and supervising the work. Author RE was involved in identifying the pharmacophore features in the study. RM, TKD, RE and GSR critically examined the manuscript for submission. The authors approve the manuscript in its correct form.

Compliance with ethical standards

This article does not contain any studies with human or animal subjects performed by the any of the authors.

Data availability statement

All data generated or analyzed during this study are included in this published article (and its supplementary information files).

Disclosure statement

No potential conflict of interest was reported by the authors.