AChE bivalent inhibitors (Part II)
From Proteopedia
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 (1e3q) 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.
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Among the most interesting drugs that have been designed to inhibit acetylcholinesterase are those that have two binding sites that bind both the peripheral and catatylic sites simultaneously. Such drugs bind highly specificly and strongly. A good example is .
It appears that the principal interaction between the aceylcholine and the enzyme is relatively newly discovered cation-pi interactions between the cationic moiety of the substrate and the many aromatic residues lining the catalytic gorge. Unlike most interatomic interactions in chemistry, cation-pi interactions are unusual in that their energy hardly changes as the cationic and aromatic ring centers vary between 4 and 7 Angstroms apart, and for a wide variety of relative orientations of the aromatic rings. This gives the substrate an energetically smooth ride down the gorge with few bumps or barriers to impede passage down the gorge.
Most acetylcholinesterases have a net negative charge and a large patch of negative potential around the entrance to the active site gorge, which may be useful to attract the positively charged acetycholine substrate to the site. As one travels down the gorge, this potential becomes increasingly more and more negative, reaching a peak at the active site at the base. Because of this potential, the peripherial site is thought to act like a substrate trap, that forces practically molecule of substrate that reaches the peripheral site to travel down the gorge to the active site, that probably contributes greatly to the extremely rapid rate of degrading the substrate. This whole enzyme therefore acts like a brilliantly designed natural vacuum cleaner that clears the neurotransmitter out of the synapse extremely quickly. Yet to be solved, however, is how the products clear the active site rapidly, whether back through the gorge, or out a back door on the other side of the protein that quickly opens each catalytic cycle (Trp 84 is actually near the surface of the 'underside' of the protein.)
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 Structure of acetylcholinesterase complexed with E2020 (Aricept): implications for the design of new anti-Alzheimer drugs., Kryger G, Silman I, Sussman JL, Structure. 1999 Mar 15;7(3):297-307. PMID:10368299
