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6) Edrophonium (EDR) (2ack) is stacked between the aromatic rings of , near TcAChE which consists of S200, E327, and H440.
7) Rivastigmine (Exelon) is a carbamate inhibitor of AChE, and it is currenly used in therapy of Alzheimer's disease. The of TcAChE complexed with rivastigmine (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 was from the carbamyl moiety, so the carbamylation took place. The of TcAChE with NAP alone (colored magenta) (without carbamyl moiety) also was determined (1gqs). The TcAChE active-site residues which are important in interaction with NAP are colored violet. NAP alone is located in the relatively similar region of TcAChE active site, but with unliked orientation in comparison to NAP part of rivastigmine. Only H440 and F330 significantly changed their side-chain conformations. of the TcAChE active sites in 4 different complexes (with rivastigmine, NAP alone, ACh (2ace), and the additional AChE inhibitor VX (1vxr) revealed that the conformation of H440 in the NAP alone/TcAChE is very similar to that of native TcAChE (2ace), but the distance between H440 Nδ and E327 Oε is significantly increased in rivastigmine/TcAChE and VX/TcAChE complexes. This structural change disrupts the catalytic triad consisting of E327, H440, and S200. This could explain for the very slow kinetics of AChE reactivation after its inhibition by rivastigmine.
8) The TcAChE active site consists of two binding subsites. First of them is the "catalytic anionic site" (CAS), which involves catalytic triad (colored orange) and the conserved residues which also participate in ligands 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 (mentioned above CAS-binding inhibitor) in complex with TcAChE (2ack) on thioflavin T/TcAChE structure demonstrates that these ligands do not overlapped. Of note, that Phe330, which is part of the CAS, is a single residue interacting with thioflavin T. Only this residue significantly to avoid clashes in comparison to other CAS residues of the edrophonium/TcAChE complex.
9) is a nonhydrolyzable substrate analogue of AChE. The hydrolyze is impossible since OTMA possesses instead of 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). Of note, OTMA binds not only at CAS, but also at PAS. The second OTMA molecule interacts with (cation-π interactions), and (weak hydrogen bond) at this subsite. Thus, this dual binding mode of OTMA with TcAChE (to CAS and PAS) could be prototypical for AChE bivalent inhibitors.
