AChE bivalent inhibitors (Part II)

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This page is a continuation of the page AChE bivalent inhibitors

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Similarly to the other AChE bivalent inhibitors, BW284C51 (BW) also binds the TcAChE at the both subsites: CAS and PAS of its . At the CAS, BW makes a cation-aromatic interaction via quaternary group with (colored orange), BW phenyl ring forms an aromatic-aromatic interaction with His440, there is also an electrostatic interaction between the BW proximal quaternary group and Glu199. Near the PAS, BW via its distal quaternary group interacts with (colored cyan) and forms an aromatic interaction with Tyr334. BW forms hydrogen bond with Tyr121 OH, and makes alkyl interactions with Phe331. The superposition of BW with two other AChE bivalent inhibitors (decamethonium, colored gray, 1acl) and (Aricept, colored blueviolet, 1eve) at the TcAChE active site reveals similar mode of binding. All these 3 inhibitors form cation-π and π-π interactions with active-site gorge aromatic residues (colored yellow). The superposition of reveals their similar position at the active site, but has a different trajectory from them. This causes the , which interacts stronger with BW than with DECA and E2020. However, the conformations of the other important residues at the active site are similar in all these inhibitor-TcAChE complexes. It has been shown experimentally that BW and E2020 bind to TcAChE approximately 100-fold stronger than DECA. These findings could be explained by several reasons: i) E2020 and BW are less flexible than DECA; ii) the aromatic groups of E2020 and BW form favourable π-π interactions with TcAChE aromatic residues, in contrast to DECA; and iii) and have aromatic groups and, therefore, occupy more volume and better fit the active-site gorge, than . Mutations at the mouse or chicken AChE residues, corresponding to the TcAChE (colored red), cause significant increase of inhibition constant values for all these 3 inhibitors, supporting the notion that these residues are critical for inhibitor-AChE binding.

Reference

Structure of a complex of the potent and specific inhibitor BW284C51 with Torpedo californica acetylcholinesterase., Felder CE, Harel M, Silman I, Sussman JL, Acta Crystallogr D Biol Crystallogr. 2002 Oct;58(Pt 10 Pt 2):1765-71. Epub, 2002 Sep 28. PMID:12351819