Identification of human tau-tubulin kinase 1 inhibitors: an integrated e-pharmacophore-based virtual screening and molecular dynamics simulation

Abstract

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

Keywords:

• e-pharmacophore
• molecular docking
• molecular dynamics
• TTBK1 inhibitor

Acknowledgments

Authors would like to thank Dr. Ozair Alam, Department of Pharmaceutical Chemistry, School of Pharmaceutical Education & Research, Jamia Hamdard, Hamdard Nagar, New Delhi, India, for his assistance and support. SJ is grateful to Ministry of Human Resource Development, New Delhi, India, for the award of Teaching Assistantship to her.

Disclosure statement

The authors declare no potential conflict of interest concerning the research, authorship, and/or publication of this article.