Perez-Sanchez_2021_J.Chem.Inf.Model_61_467

Reference

Title : Combined Structure and Ligand-Based Design of Selective Acetylcholinesterase Inhibitors - Perez-Sanchez_2021_J.Chem.Inf.Model_61_467
Author(s) : Perez-Sanchez H , den Haan H , Perez-Garrido A , Pena-Garcia J , Chakraborty S , Erdogan Orhan I , Senol Deniz FS , Villalgordo JM
Ref : J Chem Inf Model , 61 :467 , 2021
Abstract :

Acetylcholinesterase is a prime target for therapeutic intervention in Alzheimer's disease. Acetylcholinesterase inhibitors (AChEIs) 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 AChEI drug, pyridostigmine. Further structure-based screening using a pharmacophore-guided rescoring 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-a]pyrimidine scaffold showed highly promising AChE inhibition ability with IC(50) values of 13.10 +/- 0.53, 16.02 +/- 0.46, and 6.22 +/- 0.54 microM, 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.

PubMedSearch : Perez-Sanchez_2021_J.Chem.Inf.Model_61_467
PubMedID: 33320652

Related information

Citations formats

Perez-Sanchez H, den Haan H, Perez-Garrido A, Pena-Garcia J, Chakraborty S, Erdogan Orhan I, Senol Deniz FS, Villalgordo JM (2021)
Combined Structure and Ligand-Based Design of Selective Acetylcholinesterase Inhibitors
J Chem Inf Model 61 :467

Perez-Sanchez H, den Haan H, Perez-Garrido A, Pena-Garcia J, Chakraborty S, Erdogan Orhan I, Senol Deniz FS, Villalgordo JM (2021)
J Chem Inf Model 61 :467