Identification of human tau-tubulin kinase 1 inhibitors: an integrated e-pharmacophore-based virtual screening and molecular dynamics simulation.
Srabanti JanaSushil Kumar SinghPublished in: Journal of biomolecular structure & dynamics (2019)
Tau-tubulin kinase 1 inhibitors inhibit tau protein phosphorylation on Ser198, Ser199, Ser202, Ser422, and also in paired helical filaments. We developed receptor-based pharmacophore models by exploiting three TTBK1 protein structures, i.e., 4NFN, 4BTM, and 4BTK. The integrated e-pharmacophore based virtual screening and molecular dynamics simulation recognized four hits viz. ZINC14644839, ZINC00012956, ZINC91332506, and ZINC69775110 as TTBK1 inhibitors. The Glide XP docking energies (-8.48 to -10.71 kcal.mol-1) of hits were better than cocrystal ligand of 4NFN protein structure (-8.37 kcal.mol-1). Among the hits, ZINC14644839 possessed best binding energy with four hydrogen bonding interactions. The inhibitors showed acceptable calculated ADME and blood-brain barrier permeability properties and could be potential TTBK1 inhibitors for neurodegenerative diseases.Communicated by Ramaswamy H. Sarma.
Keyphrases
- molecular dynamics simulations
- molecular docking
- blood brain barrier
- oxide nanoparticles
- molecular dynamics
- protein protein
- endothelial cells
- binding protein
- cerebrospinal fluid
- amino acid
- high resolution
- small molecule
- density functional theory
- tyrosine kinase
- brain injury
- subarachnoid hemorrhage
- induced pluripotent stem cells
- cerebral ischemia
- dna binding