Identification of Potent ADCK3 Inhibitors through Structure-Based Virtual Screening.

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• ADCK3 is an atypical protein kinase crucial for coenzyme Q10 (CoQ10) biosynthesis.
• Mutations in ADCK3 lead to CoQ10 deficiency and ataxia, highlighting its importance.
• The precise functions of ADCK3 remain elusive, necessitating chemical tools for investigation.

Purpose of the Study:

• To discover novel small-molecule inhibitors of ADCK3 using structure-based virtual screening.
• To identify selective inhibitors that can serve as chemical probes for elucidating ADCK3 function.
• To provide a foundation for developing therapeutic agents targeting ADCK3-related disorders.

Main Methods:

• Structure-based virtual screening (VS) of approximately 170,000 compounds.
• Development of a pharmacophore model based on ADCK3 active-site analysis.
• Biochemical assays for hit validation and selectivity profiling against p38 kinase.
• Molecular dynamics (MD) and metadynamics simulations to predict binding modes.

Main Results:

• Identified a novel series of ADCK3 inhibitors.
• Confirmed 129 compounds as ADCK3 inhibitors, with 114 exhibiting selectivity over p38.
• MD simulations revealed key interactions between inhibitors and ADCK3 active-site residues.

Conclusions:

• The study successfully identified selective small-molecule inhibitors of ADCK3.
• These compounds represent promising starting points for further drug development and mechanistic studies.
• The findings contribute to understanding ADCK3's role in CoQ10 biosynthesis and associated diseases.