Identification of human tau-tubulin kinase 1 inhibitors: an integrated e-pharmacophore-based virtual screening and molecular dynamics simulation
| Autor: | Sushil Kumar Singh, Srabanti Jana |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
030303 biophysics
Tau protein Drug Evaluation Preclinical Quantitative Structure-Activity Relationship macromolecular substances Molecular Dynamics Simulation Protein Serine-Threonine Kinases Ligands Permeability 03 medical and health sciences Molecular dynamics Structural Biology mental disorders Humans Databases Protein Receptor Protein Kinase Inhibitors Molecular Biology 0303 health sciences Virtual screening biology Chemistry Kinase Reproducibility of Results Hydrogen Bonding General Medicine Molecular Docking Simulation Biochemistry biology.protein Phosphorylation Identification (biology) Pharmacophore |
| DOI: | 10.6084/m9.figshare.7938242.v1 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|