Reappraisal of FDA approved drugs against Alzheimer’s disease based on differential gene expression and protein interaction network analysis: an in silico approach

Abstract

Alzheimer’s disease (AD), a most prevailing neurodegenerative disorder with turbulence in cognitive and behavioural abilities, epitomizes one of the highest unmet medical requirements. The current AD treatment focuses merely on symptomatic relief, this explains a dearth in drug research oriented towards unwinding of disease specific druggable targets. On the other hand, toxicity and poor bioavailability hamper the evolution of novel chemical entities (NCE) in clinical trials. Drug repurposing offers a gateway to rejuvenate new therapeutic applications for existing approved drugs. This study concentrates on the identification of potential druggable AD targets and screening of FDA approved drugs with a concept of drug repurposing. differentially expressed genes (DEGs) were identified in frontal cortex, temporal cortex and hippocampus in AD patients from Gene Expression Omnibus (GEO) dataset GSE36980. Protein-protein interaction (PPI) analysis revealed SERPINA3 and BDNF to possess high node degree interaction with literature derived candidate genes (LDGs) in AD males and females, respectively, thus were selected as potential AD targets. Subsequently, FDA approved drugs were screened through the above shortlisted targets and were ranked based on molecular docking and MM-GBSA energy calculations using Glide and Prime tools, respectively. Drugs possessing best docking score and maximum binding energy were further evaluated through molecular dynamics simulation studies, which revealed the affinity of Tiludronic acid and Olsalazine towards SERPINA3 and BDNF, respectively.

Graphical Abstract

Communicated by Ramaswamy H. Sarma

Keywords:

• Drug repurposing
• Alzheimer’s disease
• SERPINA3
• BDNF
• olsalazine
• tiludronic acid

Acknowledgements

We thank Pharmacological Modelling and Simulation Centre (PMSC) research centre and members of M.S. Ramaiah University of Applied Sciences, Bangalore for their support throughout the work. We are thankful to Vinod Devaraji (Schrödinger, LLC, India) for providing his expertise in Molecular Dynamics studies.

Disclosure statement

Authors acknowledge that there is no conflict to declare.

Additional information

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.