Identification of potential death-associated protein kinase-1 (DAPK1) inhibitors by an integrated ligand-based and structure-based computational drug design approach

Abstract

Death-associated protein kinase 1 (DAPK1) is a calcium/calmodulin (Ca²⁺/CaM)-dependent serine/threonine kinase that is abundantly expressed in the memory- and cognition-related brain areas. DAPK1 is associated with several pathological hallmarks of Alzheimer’s disease (AD); it is an attractive target for designing a novel DAPK1 inhibitor as an effective therapeutic treatment for AD. In the present study, we have used an integrated ligand-based and structure-based drug design method to identify DAPK1 inhibitors. The pharmacophoric features of compound 38 G (PDB ID 4TXC) were mapped, and the models were evaluated using enrichment factor (EF) and goodness of hit (GH) score. The selected models were used to screen Zinc 15 compounds library. The identified hits were passed through drug-likeliness and PAINS filtering. The docking study was performed in three steps to yield molecules with good binding energy and ligand-target interactions. Finally, three hits were obtained, that is, ZINC000020648330, ZINC000006755051 and ZINC000020650468, which were subjected to rigorous molecular dynamics simulation. All three hits exhibited optimal stability under simulated conditions and low predicted toxicity.

Communicated by Ramaswamy H. Sarma

Keywords:

• DAPK1
• Alzheimer’s disease
• drug discovery
• molecular modelling
• autodock

Acknowledgement

The authors would like to extend their gratitude toward Professor David A. Case, Department of Chemistry & Chemical Biology, Rutgers University, New Jersey, USA for providing support granting a license for Amber 20.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The authors would like to acknowledge the financial support from the Ministry of Education (MoE), New Delhi, India in the form of teaching assistantships to PG, RS and SR.