Repurposing drugs to treat neurological/neurodegenerative diseases

Author: Darina Lyaeva (darinalyaeva1@icloud.com) Scientific Coordinator: Dr Patrick McHugh Institution: School of Applied Sciences, Department of Pharmacy, University of Huddersfield, Queensgate, Huddersfield, West Yorkshire, England, HD1 3DH

INTRODUCTION: Drug repurposing and in silico experimentations provide an exciting alternative to conventional drug discovery methods, which are expensive, time-consuming and often result in the rejection of potentially promising compounds. Alzheimer’s disease (AD) and Multiple Sclerosis (MS) are a leading cause of mental and physical disability worldwide. The limited effectiveness of treatments for these disorders reflects the unmet medical need for new pharmacological therapies.

AIM: The aim of this research project was to explore the role of human sphingosine kinase 1 (SPHK1) in the context of AD and MS and consequently repurpose regulatory approved drugs for their treatment. Additionally, it aimed to explore the effect of point mutations on SPHK1 functioning and their implications in disease pathology.

MATERIAL AND METHODS: In silico methods including molecular dynamics simulations and virtual screening by Molsoft ICM-Pro were used to produce a homology model of SPHK1, investigate two mutations in SPHK1 protein structure and dock the LOPAC chemical library to identify five SPHK1 ligands according to their binding affinity.

RESULTS: The findings revealed a dual nature for the protein. Evidence from the literature proposed a reduction of SPHK1 in AD patients’ brains and an upregulation in lesions of MS patients. Moreover, two mutations associated with SPHK1 functioning were explored. Gly82Asp was proposed as a pathogenic mutation with a ∆∆G value of -0.63, whereas Phe197Ala, carrying a ∆∆G value of 1.02, was thought not to have a major influence on protein structure. This was contrary to the computational stability predictions which indicate positive values have a destabilising effect on proteins. Docking scores (kcal/mol) were ranked most to least negative (highest to lowest binding affinity) in the following order: oxiracetam (-35.25), benzamil hydrochloride (-32.84), Ro 90-7501 (-31.67), piceatannol (-31.08) and SKF 89626 (-30.65).

CONCLUSION: From examining the findings, nootropic oxiracetam, and neurodegeneration inhibitor Ro 90-7501 were proposed to dampen Aβ toxicity in AD through enhancing SPHK1 activity. In contrast, sodium channel blocker benzamil hydrochloride and naturally derived piceatannol were suggested to prevent T cell egression from lymph nodes in MS by antagonising SPHK1. Finally, it was concluded that oxiracetam and Ro 90-7501 carry a repurposing potential for targeting disease progression in AD, whereas benzamil hydrochloride and piceatannol could modify the disease course in MS.

Questions & answers

Please, tell us a little bit more about yourself. My name is Darina, and I am a final-year pharmacy student at the University of Huddersfield. I work part-time as a pharmacy assistant. After graduation, I will commence my foundation training year at Leeds Teaching Hospitals as a trainee pharmacist. Upon qualifying as a pharmacist, I plan to explore the hospital sector by completing a clinical diploma and becoming an independent prescriber. Then, I hope to continue my journey on research by doing a postgraduate degree.

Tell us a bit more about your research and its significance. The focus of this research was sphingosinekinase 1 (SPHK1), a protein kinase implicated in the pathophysiology of neurodegenerative diseases such as Alzheimer’s disease (AD) and multiple sclerosis (MS). Additionally, the repurposing potential of five regulatoryapproved drugs was investigated with respect to their affinity for SPHK1. The findings revealed a dual role of the protein. This pointed to a novel strategy in treating two of the most devastating neurological disorders by stimulation and inhibition of the SPHK1 pathway in AD and MS, respectively. Current pharmacological therapies for AD do not slow down or prevent disease progression, and MS treatment requires better disease-modifying agents. This poses a barrier in treating patients living with these conditions, which impacts their quality of life. The results of our research represent an exciting addition to the investigation of SPHK1 agonists for treating AD and inhibitors for treating MS. Ultimately, this could mean positive patient outcomes by maintaining comfort and independence.

What was the biggest challenge while carrying out the research and how did you overcome that? The biggest challenge was using a software system I was completely unfamiliar with for carrying out the computational simulations for our results. The set-up was complex and hard to comprehend, and it was important to save each result separately. Otherwise, interpreting all results on the same file would become difficult. This is because amino acid interactions and protein-compound interactions would sometimes overlap. I had to take extra time to get comfortable with using the system.

In your opinion, what is the benefit of joining ESSP and what advice do you have for students undertaking research in the future? I believe joining the ESSP can open the door to great research opportunities. It allows you to share your research with people with similar interests and perhaps fill the gaps in knowledge of their future research! After all the time and effort invested, it is extremely fulfilling to be able to achieve recognition on a higher level. My advice for students who are about to dive into their research journey is not to get discouraged if their results differ from the set expectations, as research is not black and white, and their work and contribution is valuable.