Role of death-associated protein kinase 1 (DAPK1) in retinal degenerative diseases: an in-silico approach towards therapeutic intervention

Abstract

The Death-associated protein kinase 1 (DAPK1) has emerged as a crucial player in the pathogenesis of degenerative diseases. As a serine/threonine kinase family member, DAPK1 regulates critical signaling pathways, such as apoptosis and autophagy. In this study, we comprehensively analyzed DAPK1 interactors and enriched molecular functions, biological processes, phenotypic expression, disease associations, and aging signatures to elucidate the molecular networks of DAPK1. Furthermore, we employed a structure-based virtual screening approach using the PubChem database, which enabled the identification of potential bioactive compounds capable of inhibiting DAPK1, including caspase inhibitors and synthetic analogs. Three selected compounds, CID24602687, CID8843795, and CID110869998, exhibited high docking affinity and selectivity towards DAPK1, which were further investigated using molecular dynamics simulations to understand their binding patterns. Our findings establish a connection between DAPK1 and retinal degenerative diseases and highlight the potential of these selected compounds for the development of novel therapeutic strategies. This study provides valuable insights into the molecular mechanisms underlying DAPK1-related diseases, and offers new opportunities for the discovery of effective treatments for retinal degeneration.

Communicated by Ramaswamy H. Sarma

Keywords:

• Retinal degeneration
• cell death
• DAPK1
• docking
• MD simulation

Acknowledgements

The authors gratefully acknowledge Dr. Ravanan P, Associate Professor and Head, Department of Microbiology, School of Life Sciences, Central University of Tamil Nadu, India, for his valuable suggestions and insights throughout this work . The authors sincerely thank Mr. Aman Firoz, Technology Consultant, IT Department, Vox Populi Solutions LLC, Dubai, and Mr. Adhish Mazumder, TRA, School of Bio-Sciences and Technology for their generous contributions, which were instrumental in completing the molecular dynamic simulations presented in this manuscript.

CRediT authorship contribution statement

Each author sufficiently contributed to the project to accept public accountability for the relevant parts of the article’s content. (1) Authors who conceived and designed the study: PT (2) Authors who performed the computational and experimental work: AF, PT (3) Analyzed and interpreted the data and wrote the article: AF, PT.

Disclosure statement

The authors report that there are no competing interests to declare.

Table 1. Direct interactors of DAPK1 implicated in ophthalmic disorders: Unveiling insights from the human non redundant protein interactome.

Table 2. List of potential compounds and their fundamental properties, including synthetic accessibility, PAIN alerts, bioavailability, drug properties (zero violation based on lipinski, ghose, veber, egan, muegge rule), and docking score. Considering all these properties, the compounds are ranked based on their suitability as drug candidates.

Additional information

Funding

PT greatly acknowledge the financial support from the Science and Engineering Research Board (YSS/2014/000915). Additionally, PT gratefully acknowledges the Vellore Institute of Technology, Vellore, for their support through the Seed Grant for Research (file no. SG20220051).