REPUBLIC OF SERBIA

MINISTRY OF DEFENCE

www.mod.gov.rs

MINISTRY OF DEFENCE

Material Resources Sector

Defensive Technologies Department

Military Technical Institute

www.vti.mod.gov.rs

COMPLETE KINETIC PROFILING OF THE THREE NANOMOLAR ACETYLCHOLINESTERASE INHIBITORS

mAJA vITOROVIĆ-TODOROVIĆ

Military Technical Institute, Belgrade, mvitod@chem.bg.ac.rs

MIRJANA JAKIŠIĆ

Military Technical Institute, Belgrade, jakisicmirjana@gmail.com

SONJA bAUK

Military Technical Institute, Belgrade, bauk.sonja@gmail.com

BRANKO DRAKULIĆ

Center for Chemistry, IChTM, Belgrade, bdarkuli@chem.bg.ac.rs

Abstract: Acetylcholinesterase (EC 3.1.1.7) is an enzyme which terminates cholinergic neurotransmission, by hydrolyzing acetylcholine at nerve and nerve-muscle junctions. It is well known target for the treatment of Alzheimer’s disease and for the pretreatment of nerve agents intoxications. Recently, we developed 3D-QSAR model using an alignment-independent descriptors based on the molecular interaction fields for the estimation of reversible inhibition potency (IC₅₀) for possible dual binding site ligands. Based on this model, three reversible ligands were designed and synthesized, comprising tacrine unit and aroylacrylic acid amid scaffold, mutually linked by eight polymethylene units linker. Their inhibition potency was determined by Ellman assay. Along with this, we estimated inhibition type and corresponding inhibition constants (K_i1 and K_i2) for the three compounds. Putative noncovalent interactions of the lingands with aminoacid residues in acetylcholinesterase active site gorge were estimated by docking calculations.

Keywords: acetylcholinesterase, reversible inhibition, dual-binding site ligands, inhibition type, inhibition constants, docking calculations.