AUTHOR=Shityakov Sergey , Skorb Ekaterina V. , Förster Carola Y. , Dandekar Thomas 

TITLE=Scaffold Searching of FDA and EMA-Approved Drugs Identifies Lead Candidates for Drug Repurposing in Alzheimer’s Disease

JOURNAL=Frontiers in Chemistry

VOLUME=9

YEAR=2021

URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2021.736509

DOI=10.3389/fchem.2021.736509

ISSN=2296-2646

ABSTRACT=<p>Clinical trials of novel therapeutics for Alzheimer’s Disease (AD) have consumed a significant amount of time and resources with largely negative results. Repurposing drugs already approved by the Food and Drug Administration (FDA), European Medicines Agency (EMA), or Worldwide for another indication is a more rapid and less expensive option. Therefore, we apply the scaffold searching approach based on known amyloid-beta (Aβ) inhibitor tramiprosate to screen the DrugCentral database (<italic>n</italic> = 4,642) of clinically tested drugs. As a result, menadione bisulfite and camphotamide substances with protrombogenic and neurostimulation/cardioprotection effects were identified as promising Aβ inhibitors with an improved binding affinity (Δ<italic>Gbind</italic>) and blood-brain barrier permeation (logBB). Finally, the data was also confirmed by molecular dynamics simulations using implicit solvation, in particular as Molecular Mechanics Generalized Born Surface Area (MM-GBSA) model. Overall, the proposed <italic>in silico</italic> pipeline can be implemented through the early stage rational drug design to nominate some lead candidates for AD, which will be further validated <italic>in vitro</italic> and <italic>in vivo</italic>, and, finally, in a clinical trial.</p>