Structure-Based Virtual Screening and Discovery of New Bi-functional DAPK1 Inhibitors.

Area of Science:

• Neuroscience
• Molecular Biology
• Pharmacology

Background:

• A signaling complex involving Death-Associated Protein Kinase 1 (DAPK1) and N-methyl D-aspartate receptor subtype 2B (NR2B) is implicated in neuronal death.
• Following stroke, N-methyl-D-aspartate (NMDA) receptors interact with DAPK1 via the NR2B subunit, causing excitotoxicity due to receptor overactivation.

Purpose of the Study:

• To identify potential inhibitors of DAPK1 using computational screening.
• To explore natural compounds that can modulate DAPK1 activity and mitigate excitotoxicity.

Main Methods:

• Utilized the ZINC-12 database for virtual screening of compounds.
• Assessed binding affinity of natural compounds to DAPK1.
• Analyzed interactions with key DAPK1 sites, including the ATP-binding site and substrate-recognition motifs.

Main Results:

• Identified several natural compounds exhibiting significant binding affinity to DAPK1.
• Observed that these compounds interact with both the ATP-binding site and substrate-recognition motifs of DAPK1.
• These interactions suggest a mechanism for inhibiting DAPK1 activity.

Conclusions:

• Natural compounds interacting with both the ATP-binding site and substrate-recognition motifs are potential DAPK1 inhibitors.
• These findings offer a basis for developing novel therapeutic agents targeting DAPK1 for stroke and related neurological conditions.
• Further investigation into these compounds could lead to treatments for excitotoxicity-induced neuronal damage.