br Experimental section br Biological activity protocol br M

Experimental section
Biological activity protocol
Molecular docking simulation Molecular docking experiments were performed using Glide software package [46] implemented in Schrodinger Suite (2017–2) (Schrödinger, Inc., USA) [47] running on Intel CORE i7 based hpZ230 workstation with the Microsoft Windows 10 OS. In this protocol, the protein was kept rigid, while the ligands were allowed to be flexible throughout the docking simulation.
Conflicts of interest
Acknowledgments Authors are thankful to the Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu-Natal (UKZN), South Africa, for their constant support, encouragement and financial assistance. The corresponding author RK is also thankful to National Research Foundation- South Africa (NRF-SA) for funding this project (Grant No. 103728; 112079). Authors wish to thank Dr Vladimir Krystof (Palacký University Olomouc, Czech Republic) for performing biochemical and cellular assays () and Director, Indian Institute of Chemical Technology (IICT-Hyderabad) for cytotoxicity studies. One of the authors (CB) gratefully acknowledges the National Research Foundation (DST-NRF), South Africa for research funding in the form of an Innovation Post-Doctoral Research Fellowship (UID: 99546). Authors also sincerely thank the Centre for High Performance Computing (CHPC), Cape Town, South Africa for computational resources. Authors express heartfelt thanks to Mr Dilip Jagjivan and Dr Caryl Janse Van Rensburg (UKZN, South Africa) for their assistance in the NMR and HRMS experiments.
Introduction Alzheimer’s disease (AD) is the progressive version of mild cognitive impairment and usually met by the elderly population. It falls into the class of neurodegenerative disorders that attacks the bwx synthesis nerves cells, or neurons, resulting in loss of memory, impairment of thinking and language skills, and causes behavioral changes. It is a progressive disorder which develops slowly and gets worse as the brain function declines. The brain cells eventually wither and die. Although 90% of cases of AD are sporadic, 5–10% are of familial AD (FAD) which has an early onset in an autosomal dominant pattern (Liu et al., 2016). The sporadic late onset AD (LOAD) on other hand commences in the age of 70s or 80s (Onos et al., 2016). Worldwide nearly 44 million people have Alzheimer’s disease. From the 5.1 million people of age 65 and older affected in 2015, the number is estimated to reach 7.1 million by 2025. Every 1 in 8 people over the age of 65 while, nearly half over the age of 85 have Alzheimer’s disease.
Pathophysiology of AD
Different protein kinase signalling pathways involved in AD
Cdk5 as a therapeutic target Cyclin dependent kinase 5 (Cdk5) is a proline directed serine/threonine kinase. Functionally, Cdk5 plays an important role in neuron development, neuronal survival, phosphorylation of cytoskeletal proteins and synaptic plasticity (Mushtaq et al., 2016). Activation of Cdk5 requires regulatory proteins. In mammals, p35 and p39 are the two known proteins to activate Cdk5. These are specifically expressed in neuronal cells (Li et al., 2016). Increase in calcium concentration results in their calpain mediated cleavage into truncated products p25 and p29 respectively. Out of these, p35 is been extensively studied (Shukla et al., 2012). It can be split into 2 parts: p10 and p25 (Shukla et al., 2012). The N-terminal p10 region consists of the myristoylated region important for membrane targeting of p35 and the signal for degradation via ubiquitin-proteosome pathway (Wilkaniec et al., 2016). p25 has the Cdk5 binding as well as activation domain.