AChE inhibitors and substrates (Part III)

Galanthamine iminium derivative

The X-ray structure of TcAChE in complex with galanthamine iminium derivative (compound 5) was determined at 2.05 Å resolution (1w6r). The of this compound (cyan) with TcAChE is virtually identical to that of galanthamine (red) itself (1dx6). The TcAChE residues which interact with galanthamine in the galanthamine/TcAChE complex are colored pink, while those of compound 5/TcAChE are in lime. The main structural change is the side-chain movement of Phe330 in compound 5/TcAChE complex, in comparison to that of galanthamine. Compound 5 differs from galanthamine by the presence of (N⁺; blue) instead N of galanthamine. This chemical difference causes the structural change in TcAChE and the slight decrease in affinity of compound 5 to TcAChE in comparison to galanthamine ^[1].

Rivastigmine

Rivastigmine (Exelon) is a carbamate inhibitor of AChE, and it is currenly used in therapy of Alzheimer's disease. Rivastigmine (Exelon) (colored yellow) interacts with TcAChE (colored lime) at the (1gqr). The carbamyl moiety of rivastigmine is to the active-site S200 Oγ. The second part of rivastigmine (the leaving group), NAP ((−)-S-3-[1-(dimethylamino)ethyl]phenol) is also held in the active-site gorge, but it is from the carbamyl moiety, hence, carbamylation took place. The of TcAChE/NAP (colored magenta) is known (1gqs). The TcAChE active-site residues which are interacting with NAP are colored violet. NAP is located in a similar region of TcAChE active site, but with different orientation than that of the NAP part (colored yellow) in the TcAChE/rivastigmine complex. Only H440 and F330 significantly change their side-chain conformations. of the TcAChE active sites in 4 different structures (TcAChE/rivastigmine (1gqr), TcAChE/NAP (1gqs), native TcAChE (2ace), and TcAChE/VX (1vxr, TcAChE colored white and VX black) reveals that the conformation of H440 in the TcAChE/NAP structure is very similar its conformation in the native TcAChE (2ace), but the distance between H440 Nδ and E327 Oε is significantly longer in the TcAChE/rivastigmine and the TcAChE/VX complexes. This structural change disrupts the catalytic triad consisting of S200, E327, H440. This could explain the very slow kinetics of AChE reactivation after its inhibition by rivastigmine ^[2].

Thioflavin T

The TcAChE active site consists of two binding subsites. One of them is the "catalytic anionic site" (CAS), which involves the catalytic triad (colored orange) and the conserved residues which also participate in ligand recognition. Another conserved residue (colored cyan) is situated at the second binding subsite, termed the "peripheral anionic site" (PAS), ~14 Å from CAS. is a good example of the PAS-binding AChE inhibitors. of the crystal structure of the edrophonium/TcAChE (mentioned above as a CAS-binding inhibitor) (2ack) on the thioflavin T/TcAChE complex structure (2j3q) shows that these ligands' positions do not overlap. Of note is that Phe330, which is part of the CAS, is the single residue interacting with thioflavin T. This residue is the only one which significantly to avoid clashes in comparison to other CAS residues of the edrophonium/TcAChE complex ^{[3] [4]}.

OTMA

OTMA is a nonhydrolyzable substrate analogue of AChE. Its hydrolysis is impossible as possesses atom instead of the in the AChE natural substrate ACh. Similarly to ACh, OTMA covalently binds to the TcAChE (2vja) Oγ at the CAS. At this subsite OTMA also interacts with (cation-π interactions); (electrostatic interaction); (hydrogen bonds). OTMA binds not only at CAS, but also at PAS. A second OTMA molecule interacts with (cation-π interactions), and (weak hydrogen bond) ^[5]. Thus, this dual binding mode of OTMA with TcAChE (to CAS and PAS) could be prototypical for AChE bivalent inhibitors.