Crystal structures of human cholinesterases in complex with huprine W and tacrine: elements of specificity for anti-Alzheimer's drugs targeting acetyl- and butyryl-cholinesterase

Abstract

The multifunctional nature of Alzheimer's disease calls for MTDLs (multitarget-directed ligands) to act on different components of the pathology, like the cholinergic dysfunction and amyloid aggregation. Such MTDLs are usually on the basis of cholinesterase inhibitors (e.g. tacrine or huprine) coupled with another active molecule aimed at a different target. To aid in the design of these MTDLs, we report the crystal structures of hAChE (human acetylcholinesterase) in complex with FAS-2 (fasciculin 2) and a hydroxylated derivative of huprine (huprine W), and of hBChE (human butyrylcholinesterase) in complex with tacrine. Huprine W in hAChE and tacrine in hBChE reside in strikingly similar positions highlighting the conservation of key interactions, namely, π-π/cation-π interactions with Trp86 (Trp82), and hydrogen bonding with the main chain carbonyl of the catalytic histidine residue. Huprine W forms additional interactions with hAChE, which explains its superior affinity: the isoquinoline moiety is associated with a group of aromatic residues (Tyr337, Phe338 and Phe295 not present in hBChE) in addition to Trp86; the hydroxyl group is hydrogen bonded to both the catalytic serine residue and residues in the oxyanion hole; and the chlorine substituent is nested in a hydrophobic pocket interacting strongly with Trp439. There is no pocket in hBChE that is able to accommodate the chlorine substituent.

1,2,3,4-Tetrahydrobenzo[h][1,6]naphthyridines as a new family of potent peripheral-to-midgorge-site inhibitors of acetylcholinesterase: Synthesis, pharmacological evaluation and mechanistic studies

“…Furthermore, the missing loop that comprises residues 259-263 (PGGTG) was modeled from the X-ray structure of hAChE complexed with huprine W (PDB ID: 4BDT) [31].…”

Shogaol–huprine hybrids: Dual antioxidant and anticholinesterase agents with β-amyloid and tau anti-aggregating properties

“…In fact, the binding mode reproduces the main features of the arrangement found for (-)-huprine X, the 9-ethylanalogue of huprine Y, bound to the Torpedo californica AChE (PDB entry 1E66), 28 and for (-)-huprine W, which bears a hydroxyethyl group at position 9, bound to the human enzyme (PDB entry 4BDT). 29 On the other hand, the phenolic ring stacked against Trp286 in the PAS (Fig. 2).…”

“…29 The structure was refined by removal of N-acetyl-D-glucosamine and sulphate anions and addition of missing hydrogen atoms. Three disulfide bridges were defined between Cys residues 257-272, 409-529, and 69-96, respectively.…”

Crystal Structure of Snake Venom Acetylcholinesterase in Complex with Inhibitory Antibody Fragment Fab410 Bound at the Peripheral Site

“…As a result, the ⍀ loop tip, whose conformation is already constrained by Pro 76 , is further rigidified within the Fab410 combining site. In fact, comparison of the Fab410-bound BfAChE and apo-mAChE structures points to a slightly more open (by as much as 2 Å) Ser 74 -Gln 79 segment at the loop tip, suggesting the occurrence of a rigid body movement upon Fab410 binding.…”

“…Compared with the various Fas2-AChE complexes, which show tightly bound Fas2 at the PAS with a fully occluded gorge entrance and no back door channel in the crystal state (14,23,(71)(72)(73)(74) and display residual activities not exceeding a few percent in solution (15,(75)(76)(77), the semi-occluding Fab410 position at the BfAChE PAS and presumed higher opening frequency of the back door channel in the complex are likely to account for the greater residual activity of the Fab410-BfAChE complex (Table 1). However, the presence of bound Fab410 at the BfAChE PAS raises a question as to whether both conformations of Tyr 442 preexist in unliganded BfAChE or whether one of them is correlated with (i.e.…”