Combined Structure and Ligand-Based Design of Selective Acetylcholinesterase Inhibitors


Perez-Sanchez H., den Haan H., Perez-Garrido A., Pena-Garcia J., Chakraborty S., ERDOĞAN ORHAN İ., ...Daha Fazla

JOURNAL OF CHEMICAL INFORMATION AND MODELING, cilt.61, sa.1, ss.467-480, 2021 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 61 Sayı: 1
  • Basım Tarihi: 2021
  • Doi Numarası: 10.1021/acs.jcim.0c00463
  • Dergi Adı: JOURNAL OF CHEMICAL INFORMATION AND MODELING
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Applied Science & Technology Source, Compendex, Computer & Applied Sciences, EMBASE, MEDLINE
  • Sayfa Sayıları: ss.467-480
  • Lokman Hekim Üniversitesi Adresli: Hayır

Özet

Acetylcholinesterase is a prime target for therapeutic intervention in Alzheimer's disease. Acetylcholinesterase inhibitors (ACKEIs) are used to improve cognitive abilities, playing therefore an important role in disease management. Drug repurposing screening has been performed on a corporate chemical library containing 11 353 compounds using a target fishing approach comprising three-dimensional (3D) shape similarity and pharmacophore modeling against an approved drug database, Drugbank. This initial screening identified 108 hits. Among them, eight molecules showed structural similarity to the known ACKEI drug, pyridostigmine. Further structure-based screening using a pharmacophore-guided restoring method identifies one more potential hit. Experimental evaluations of the identified hits sieve out a highly selective AChEI scaffold. Further lead optimization using a substructure search approach identifies 24 new potential hits. Three of the 24 compounds (compounds 10b, 10h, and 10i) based on a 6-(2-(pyrrolidin-1-yl)pyrimidin-4-yl)-thiazolo[3,2-alpha]pyrimidine scaffold showed highly promising AChE inhibition ability with IC50 values of 13.10 +/- 0.53, 16.02 +/- 0.46, and 6.22 +/- 0.54 mu M, respectively. Moreover, these compounds are highly selective toward AChE. Compound 10i shows AChE inhibitory activity similar to a known Food and Drug Administration (FDA)-approved drug, galantamine, but with even better selectivity. Interaction analysis reveals that hydrophobic and hydrogen-bonding interactions are the primary driving forces responsible for the observed high affinity of the compound with AChE.