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

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Abstract

Recently, a new signaling complex Death-Associated Protein Kinase 1 (DAPK1)—N-methyl D-aspartate receptor subtype 2B (NR2B) engaged in the neuronal death cascade was identified where it was found that after stroke injury, N-methyl-D-aspartate glutamate (NMDA) receptors interact with DAPK1 through NR2B subunit and lead to excitotoxicity via overactivation of NMDA receptors. In this study, we used ZINC-12 database to find out potential inhibitor of DAPK1 and found some natural compounds showing good binding affinity towards DAPK1. These natural compounds showed interactions with ATP-binding site residues as well as substrate-recognition motifs. Thus, it has been concluded that the ligands those are showing interactions with both the sites could be considered as potential inhibitors for DAPK1.

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Abbreviations

DAPK1:

Death-associated protein kinase 1

Ser/Thr:

Serine/Threonine

Ca2+/CaM:

Ca2+/calmodulin

NMDARs:

N-Methyl-D-aspartate receptors

AD:

Alzheimer’s disease

NR2B-CT:

N-Methyl D-aspartate receptor subtype 2B (NR2B) carboxyl terminus

GEL:

Gly-Glu-Leu

PEN:

Pro-Glu-Asn

PEF/Y:

Pro-Glu-Phe/Tyr

VS:

Virtual screening

MD:

Molecular dynamics

SPC:

Simple point charge

RMSD:

Root-mean-square deviation

RMSF:

Root-mean-square fluctuation

SASA:

Solvent accessible surface area

Rg:

Radius of gyration

MMGBSA:

Molecular mechanics-generalized born surface area

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Acknowledgements

The authors in the manuscript thank Prof. Ramanathan Sowdhamini, National Centre for Biological Sciences for contributing in the discussion part of the manuscript. PT and PR greatly acknowledge the financial support from the Science and Engineering Research Board (YSS/2014/000915/EEQ/2021/000061, respectively).

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Authors and Affiliations

  1. Apoptosis and Cell Survival Research Laboratory, Department of Biosciences, School of Biosciences and Technology, Vellore Institute of Technology, 412G Pearl Research Park, Vellore, Tamil Nadu, 632014, India

    Priti Talwar & Pratibha Singh

  2. Functional Genomics Laboratory, Department of Microbiology, Central University of Tamil Nadu, Thiruvarur, Tamil Nadu, 610005, India

    Palaniyandi Ravanan

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  1. Priti Talwar
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  2. Pratibha Singh
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Correspondence to Priti Talwar or Palaniyandi Ravanan.

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Talwar, P., Singh, P. & Ravanan, P. Structure-Based Virtual Screening and Discovery of New Bi-functional DAPK1 Inhibitors. Mol Biotechnol 66, 876–901 (2024). https://doi.org/10.1007/s12033-023-00744-9

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