TY  - JOUR
A1  - Spinaci, Andrea
A1  - Lambertucci, Catia
A1  - Buccioni, Michela
A1  - Dal Ben, Diego
A1  - Graiff, Claudia
A1  - Barbalace, Maria Cristina
A1  - Hrelia, Silvana
A1  - Angeloni, Cristina
A1  - Tayebati, Seyed Khosrow
A1  - Ubaldi, Massimo
A1  - Masi, Alessio
A1  - Klotz, Karl-Norbert
A1  - Volpini, Rosaria
A1  - Marucci, Gabriella
T1  - A\(_{2A}\) adenosine receptor antagonists: are triazolotriazine and purine scaffolds interchangeable?
JF  - Molecules
N2  - The A\(_{2A}\) adenosine receptor (A\(_{2A}\)AR) is one of the four subtypes activated by nucleoside adenosine, and the molecules able to selectively counteract its action are attractive tools for neurodegenerative disorders. In order to find novel A\(_{2A}\)AR ligands, two series of compounds based on purine and triazolotriazine scaffolds were synthesized and tested at ARs. Compound 13 was also tested in an in vitro model of neuroinflammation. Some compounds were found to possess high affinity for A\(_{2A}\)AR, and it was observed that compound 13 exerted anti-inflammatory properties in microglial cells. Molecular modeling studies results were in good agreement with the binding affinity data and underlined that triazolotriazine and purine scaffolds are interchangeable only when 5- and 2-positions of the triazolotriazine moiety (corresponding to the purine 2- and 8-positions) are substituted.
KW  - A\(_{2A}\) adenosine receptor antagonist
KW  - purine derivatives
KW  - triazolotriazine derivatives
KW  - anti-Parkinson agents
KW  - anti-inflammatory agents
KW  - molecular modeling
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-270618
SN  - 1420-3049
VL  - 27
IS  - 8
ER  - 
TY  - JOUR
A1  - Shityakov, Sergey
A1  - Skorb, Ekaterina V.
A1  - Förster, Carola Y.
A1  - Dandekar, Thomas
T1  - Scaffold Searching of FDA and EMA-Approved Drugs Identifies Lead Candidates for Drug Repurposing in Alzheimer’s Disease
JF  - Frontiers in Chemistry
N2  - 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 (n = 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 (ΔGbind) 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 in silico pipeline can be implemented through the early stage rational drug design to nominate some lead candidates for AD, which will be further validated in vitro and in vivo, and, finally, in a clinical trial.
KW  - scaffold search
KW  - approved drugs
KW  - drug repurposing
KW  - alzheimer's disease
KW  - chemical similarity
KW  - molecular modeling
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-248703
SN  - 2296-2646
VL  - 9
ER  -