Journal
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
Volume 38, Issue 3, Pages 886-900Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/07391102.2019.1590242
Keywords
e-pharmacophore; molecular docking; molecular dynamics; TTBK1 inhibitor
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Funding
- Ministry of Human Resource Development, New Delhi, India
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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.
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