Identification of small molecules against cyclin dependent kinase-5 using chemoinformatics approach for Alzheimer’s disease and other tauopathies

Abstract

Alzheimer’s disease (AD) is a multifactorial complex and wide spreading global disease. It is a chronic neurodegenerative disorder characterized by amyloid beta (Aβ) and neurofibrillary tangles (NFTs). Several enzymes are involved in which CDK5 is a major tau phosphorylation enzyme. We have screened (n = 5,36,801) compounds against CDK5 and 392 compounds were selected for pharmacokinetics analysis. In the pharmacokinetics analysis, various descriptors were used for filtering the compounds. After that 16 compounds with the control compound Z3R were employed for the redocking using Autodock Vina and Autodock. Lastly, four compounds were selected and employed for 100 ns MDS studies. On the basis of various MD analysis like RMSD, RMSF, Rg, SASA, Number of hydrogen bonds, Principal component analysis and binding free energy (CDK5-ZINC6261568: −129.50 kJ.mol⁻¹ and CDK5-ZINC14168360: −191.16 kJ.mol⁻¹), we have found that ZINC6261568 and ZINC14168360 can act as a lead compound against the CDK5.

Communicated by Ramaswamy H. Sarma

Keywords:

• Alzheimer’s disease
• neurofibrillary tangles
• CDK5
• virtual screening
• molecular docking
• molecular dynamics simulation
• principal component analysis
• MM-PBSA

Disclosure statement

The authors declare that there are no competing interests.

Additional information

Funding

RS wants to thanks the ICMR (ISRM/11(53)/2019) for providing the Senior Research Fellowship.