Evaluation of pyrazolopyrimidine derivatives as microtubule affinity regulating kinase 4 inhibitors: Towards therapeutic management of Alzheimer’s disease

Abstract

Microtubule affinity regulating kinase 4 (MARK4) plays essential role in the tau-assisted regulation of microtubule dynamics. Over expression of MARK4 causes early phosphorylation of Ser262 of tau protein which is essential for microtubule binding. Hyperphosphorylation of tau protein causes the formation of paired helical fragments and neurofibrillary tangles, the hallmarks of Alzheimer’s disease. Targeting the modulation of MARK4 activity is an effective strategy for therapeutic intervention of Alzheimer’s and other MARK4 associated neurodegenerative diseases. Having role of pyrazolopyrimidine derivatives in the therapeutic management of neurodegenerative diseases, we have tried to estimate their binding affinity with the MARK4. We performed in silico screening of 59 pyrazolopyrimidine derivatives against MARK4 and obtained a few best possible inhibitors. Molecular docking-based interaction analysis suggested five potential leads that were further analyzed using molecular dynamics simulations, MM/PBSA, principal component analysis and graph theory based dynamic network analysis to observe structural changes caused due to ligand binding. All these computational analyses suggested that compounds with PubChem IDs: 91895678, 91895679, 91895692, 91145515 and 90794095 may be further exploited to address Alzheimer’s and other neurodegenerative diseases.

Communicated by Ramaswamy H. Sarma

Keywords:

• Microtubule affinity regulating kinase 4
• Alzheimer’s disease
• pyrazolopyrimidine derivatives
• drug design and discovery
• molecular docking
• MD simulation and neurodegenerative diseases

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work is supported by the Department of Science and Technology, Government of India (Grant No. EMR/2015/002372). MFA and AH acknowledge the generous support from the Deanship of Scientific Research at King Saud University, Riyadh, Kingdom of Saudi Arabia, for funding this research group under grant No. RGP-150.