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Rationally Designed Dual Kinase Inhibitors for Management of Obstructive Sleep Apnea-A Computational Study

Kosi Gramatikoff1, Miroslav Stoykov2, Mario Milkov2

  • 1Research Institute, Medical University "Prof. Dr. Paraskev Stoyanov", 55 Marin Drinov Str., 9002 Varna, Bulgaria.

Biomedicines
|January 28, 2026
PubMed

Insights

This study identifies the CK1δ-PINK1 signaling pathway as a key target for obstructive sleep apnea (OSA) drug discovery. Novel dual kinase inhibitors were rationally designed, offering a new precision therapeutic approach for OSA management.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Computational Biology

Background:

  • Obstructive sleep apnea (OSA) affects over a billion adults globally, presenting significant comorbidities like cardiovascular disease and cognitive decline.
  • Current pharmacological treatments for OSA are limited, and traditional omics approaches face challenges in therapeutic translation due to gene overlap with other diseases.
  • A novel top-down, comorbidity-driven strategy is proposed to identify actionable molecular targets for OSA.

Purpose of the Study:

  • To identify molecular targets for OSA management using a comorbidity-driven approach.
  • To develop rational dual kinase inhibitors for OSA by targeting the CK1δ-PINK1 signaling cascade.
  • To establish a generalizable workflow for drug discovery in complex, multimorbid diseases.

Main Methods:

  • A five-tier modeling workflow including comorbidity network analysis and disease module identification.
  • Mechanistic pathway reconstruction of the CK1δ-(HIF1A)-PINK1 signaling cascade.
  • Molecular docking of *Nigella sativa* alkaloids and reference inhibitors against CK1δ and PINK1, followed by rational design and computational validation of novel dual inhibitors.

Main Results:

  • Network analysis identified a discrete OSA disease module involving CK1δ and PINK1, linking circadian disruption and neurodegeneration.
  • Specific *Nigella sativa* alkaloids showed potent binding to CK1δ and PINK1.
  • Rationally designed dual inhibitors (ICL, PFL) exhibited superior binding affinities compared to reference compounds, indicating enhanced therapeutic potential.

Conclusions:

  • The CK1δ-PINK1 axis is validated as a therapeutic target for OSA through a comorbidity-driven translational framework.
  • Rationally designed dual inhibitors represent advanced precision therapeutics for OSA's complex pathophysiology.
  • The developed five-tier workflow offers a scalable template for discovering drugs targeting complex, multimorbid conditions.
Keywords:
Nigella sativaPINK1casein kinase 1 delta (CK1δ)comorbiditiesdual kinase inhibitorsnetwork pharmacologyneurodegenerationobstructive sleep apneaplant alkaloidsprecision therapeuticsrational drug design

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