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European Pharmaceutical Students’ Association
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.
