Structure of acetylcholinesterase complexed with E2020 (Aricept®): implications for the design of new anti-Alzheimer drugs

Abstract

Our study shows, a posteriori, that the design of E2020 took advantage of several important features of the active-site gorge of AChE to produce a drug with both high affinity for AChE and a high degree of selectivity for AChE versus butyrylcholinesterase (BChE). It also delineates voids within the gorge that are not occupied by E2020 and could provide sites for potential modification of E2020 to produce drugs with improved pharmacological profiles.

Synthesis and in silico evaluation of 1N-methyl-1S-methyl-2-nitroethylene (NMSM) derivatives against Alzheimer disease: to understand their interacting mechanism with acetylcholinesterase

“…The methylsulfanyl group establishes the HB between S7 and O of Trp86 with a distance of 3.29 Å. The benzyl ring (Cg: C11, C12, C13, C14, C15, and C16) of this ligand faces the six-membered ring of the Trp86 indole by the strong π-π stacking interaction with the distance of 3.47 Å so as observed in Donepezil-tAChE complex [8] (Fig. 3b).…”

“…The PAS, CAS, oxyanion hole (Gly120 and Gly121), CT, acyl binding pocket (Phe297 and Phe338), and other residues Leu76, Trp117, Tyr119, Leu130, Ser293, Val294, Arg296, and Ile451 of hAChE were involved in van der Waals (VdW) contacts. In close assessment of this binding mode, the Trp86 and Trp286 were found to make overlap of two adjacent site stacked [55] interactions with benzyl ring and dimethoxyindanone ring, respectively, instead of making π-π stacked interaction as compared with crystal structure of Donepezil-tAChE complex [8]. The GOLD score, external H bond (E-HB) and external van der Waals (E-VdW) scores for Donepezil were 51.2624, 0.3207, and 45.4531, respectively.…”

“…Abnormal activity of human acetylcholinesterase (hAChE), the enzyme responsible for hydrolysis of ACh, was attributed to the reduced level of ACh. Treating AD was achieved through inhibiting the anomalous action of AChE [3][4][5][6] by various specific AChE inhibitors [7] such as Donepezil (Aricept®) [8], Tacrine (COGNEX®) [9], and Rivastigmine (EXELON®) [10].…”

“…Donepezil, a cholinesterase inhibitor, is one such drug candidate with high specificity for AChE [36] and was designed to interact exclusively with CAS (π-π stacking with Trp86; cation-π interaction with Phe330) and PAS (Tyr124) site residues [8]. Besides the strong interacting abilities of Donepezil, its administration as drug was also associated with several undesirable effects [37,38].…”

Inhibition, ADME and structure based modification of IAA and IBA against acetylcholinesterase: an attempt towards new drug development for Alzheimer's disease

“…The active site gorge of AChE resembles a finger shaped void (Kryger et al 1999). The bottom of the void is the catalytic site, located at the deepest part of the cleft.…”