Exploring the role of TLK2 mutation in tropical calcific pancreatitis: an in silico and molecular dynamics simulation study

Abstract

Tropical calcific pancreatitis (TCP) is a juvenile form of non-alcoholic chronic pancreatitis seen exclusively in tropical countries. The disease poses a high risk of complications, including pancreatic diabetes and cancer, leading to significant mortality due to poor diagnosis and ineffective treatments. This study employed whole exome sequencing (WES) of 5 TCP patient samples to identify genetic variants associated with TCP. Advanced computational techniques were used to gain atomic-level insights into disease progression, including microsecond-scale long MD simulations and essential dynamics. In silico virtual screening was performed to identify potential therapeutic compounds targeting the mutant protein using the Asinex and DrugBank compound library. WES analysis predicted several single nucleotide variants (SNVs) associated with TCP, including a novel missense variant (c.T1802A or p.V601E) in the TLK2 gene. Computational analysis revealed that the p.V601E mutation significantly affected the structure of the TLK2 kinase domain and its conformational dynamics, altering the interaction profile between ATP and the binding pocket. These changes could impact TLK2's kinase activity and functions, potentially correlating with TCP progression. Promising lead compounds that selectively bind to the TLK2 mutant protein were identified, offering potential for therapeutic interventions in TCP. These findings hold great potential for future research.

Communicated by Ramaswamy H. Sarma

Keywords:

• Tropical calcific pancreatitis (TCP;), tousled-like kinase
• TLK2
• whole exome sequencing
• molecular docking
• and dynamics simulation

Acknowledgments

We thank Shiv Nadar Institution of Eminence, Delhi-NCR, India, for providing the research infrastructure required for this study. We also acknowledge the Indian Council of Medical Research (ICMR), New Delhi, India, for providing a Senior Research Fellowship (Project ID: 2021‐14351; File No.: BMI/11(100)/2022) awarded to Mr. Ashish Shrivastava.

Authors’ Contributions

Ashish Shrivastava: Investigation, Visualization, Writing—original draft, Writing—review & editing. Sri Krishna Jayadev Magani: Investigation, Validation, Writing—review & editing. Kiran Bharat Lokhande: Visualization Writing—review & editing. Madhusudan Chintakhindi: Conceptualization, Resources, Validation, Writing—review & editing. Ashutosh Singh: Conceptualization, Data curation, Formal analysis, Funding acquisition, Methodology, Project administration, Resources, Supervision, Validation, Writing—original draft, Writing—review & editing.

Disclosure statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Data availability statement

The original contributions made in the study are included in the article/supplementary material. For further inquiries, it is advisable to contact the corresponding authors.

Ethics statement

Shiv Nadar University’s Institutional Ethics Committee (IEC) for Human Research approved the study protocol.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.