AChE bivalent inhibitors (Part II)

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Similarly to the other AChE bivalent inhibitors, BW284C51 (BW) also binds the TcAChE at its . At the CAS there is a cation-aromatic interaction between BW quaternary group and (colored orange), an aromatic-aromatic interaction between BW and His440, and an electrostatic interaction between the proximal quaternary group and Glu199. Near the PAS the distal quaternary group of BW makes a quaternary interaction with (colored cyan) and an aromatic interaction with Tyr334. In the middle of the active-site gorge there is a hydrogen bond of 3.53 Å between the BW carbonyl and Tyr121 OH, as well as alkyl interactions with Phe331. The superposition of BW with other AChE bivalent inhibitors (decamethonium, colored gray, 1acl) and (Aricept, colored blueviolet, 1eve) within the active-site gorge of TcAChE reveals similar interactions in their mode of binding. All these 3 inhibitors form cation-π and π-π interactions with active-site gorge aromatic residues (colored yellow). These interactions might be most important in the binding affinity of these 3 inhibitors. have a similar trajectory along the active-site gorge, while traces a different route, especially near the CAS at its bottom. This causes the , which interacts strongly with BW, in comparison to DECA and E2020. The experimental inhibition constants K_i for TcAChE range from 2.0 to 64 nM for BW and E2020, but from 0.34 to 7.0 µM for DECA, corresponding to 100-fold weaker binding. E2020 and BW are i) conformationally less flexible than DECA; ii) they have aromatic groups (in contrast to DECA) making favourable π-π interactions with TcAChE aromatic residues in iii) addition to cation-π interactions with their quaternary amino groups; and iv) their greater bulk (especially of that of E2020), which produces a tighter fit inside the binding site. All the above causes the stronger binding of BW and E2020 over DECA to the TcAChE. Mutations at the mouse or chicken AChE residues, corresponding to the TcAChE (colored red), cause significant increase of K_i 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