Josef Scheiber

Targeting acetylcholinesterase to treat neurodegeneration.

Neurodegenerative disorders, such as Alzheimer’s disease, are often characterised by the degeneration of the cholinergic system. Thus, the aim of many treatment regimens is to support this system either by means of muscarinic agonists or by inhibitors of acetylcholinesterase (AChE), the latter being able to increase the concentration of acetylcholine. However, both pharmacological groups of drugs can only help in the beginning of the progressive disease. The finding that the occupation of the peripheral anionic site of AChE is able to stop the formation of the amyloid plaque led to the development of bivalent ligands that occupy both the active and the peripheral site. This dual action might be more beneficial for treatment of Alzheimer´s disease than simple inhibition of the acetylcholine hydrolysis. Thus, the new bivalent ligands are the focus of this review.

Aziridide-based inhibitors of cathepsin L: synthesis, inhibition activity, and docking studies.

A comprehensive screening of N‐acylated aziridine (aziridide) based cysteine protease inhibitors containing either Boc‐Leu‐Caa (Caa=cyclic amino acid), Boc‐Gly‐Caa, or Boc‐Phe‐Ala attached to the aziridine nitrogen atom revealed Boc‐(S)‐Leu‐(S)‐Azy‐(S,S)‐Azi(OBn)2 (18 a) as a highly potent cathepsin L (CL) inhibitor (Ki=13 nM) (Azy=aziridine‐2‐carboxylate, Azi=aziridine‐2,3‐dicarboxylate). Docking studies, which also accounted for the unusual bonding situations (the flexibility and hybridization of the aziridides) predict that the inhibitor adopts a Y shape and spans across the entire active site cleft, binding into both the nonprimed and primed sites of CL.

Interaction of (benzylidene-hydrazono)-1,4-dihydropyridines with β-amyloid, acetylcholine, and butyrylcholine esterases

Approved drugs for the treatment of Alzheimers disease belong to the group of inhibitors of the acetylcholinesterase (AChE) and NMDA receptor inhibitors. However none of the drugs is able to combat or reverse the progression of the disease. Thus, the recently reported promising multitarget-directed molecule approach was applied here. Using the lead compound DUO3, which was found to be a potent inhibitor of the AChE and butyrylcholinesterase (BuChE) as well as an inhibitor of the formation of the amyloid (Abeta) plaque, new non-permanently positively charged derivatives were synthesized and biologically characterized. In contrast to DUO3 the new bisphenyl-substituted pyridinylidene hydrazones 5 are appropriate to cross the blood-brain barrier due to their pK(a) values and lipophilicity, and to inhibit both the AChE and BuChE. More important some of the pyridinylidene hydrazones inhibit the Abeta fibril formation completely and destruct the already formed fibrils significantly.

Cis-Configured aziridines are new pseudo-irreversible dual-mode inhibitors of Candida albicans secreted aspartic protease 2.

A series of cis‐configured epoxides and aziridines containing hydrophobic moieties and amino acid esters were synthesized as new potential inhibitors of the secreted aspartic protease 2 (SAP2) of Candida albicans. Enzyme assays revealed the N‐benzyl‐3‐phenyl‐substituted aziridines 11 and 17 as the most potent inhibitors, with second‐order inhibition rate constants (k2) between 56 000 and 121 000 M−1 min−1. The compounds were shown to be pseudo‐irreversible dual‐mode inhibitors: the intermediate esterified enzyme resulting from nucleophilic ring opening was hydrolyzed and yielded amino alcohols as transition‐state‐mimetic reversible inhibitors. The results of docking studies with the ring‐closed aziridine forms of the inhibitors suggest binding modes mainly dominated by hydrophobic interactions with the S1, S1′, S2, and S2′ subsites of the protease, and docking studies with the processed amino alcohol forms predict additional hydrogen bonds of the new hydroxy group to the active site Asp residues. C. albicans growth assays showed the compounds to decrease SAP2‐dependent growth while not affecting SAP2‐independent growth.

xMaP—An Interpretable Alignment-Free Four-Dimensional Quantitative Structure–Activity Relationship Technique Based on Molecular Surface Properties and Conformer Ensembles

A novel alignment-free molecular descriptor called xMaP (flexible MaP descriptor) is introduced. The descriptor is the advancement of the previously published translationally and rotationally invariant three-dimensional (3D) descriptor MaP (mapping property distributions onto the molecular surface) to the fourth dimension (4D). In addition to MaP, xMaP is independent of the chosen starting conformation of the encoded molecules and is therefore entirely alignment-free. This is achieved by using ensembles of conformers, which are generated by conformational searches. This step of the procedure is similar to Hopfingers 4D quantitative structure-activity relationship (QSAR). A five-step procedure is used to compute the xMaP descriptor. First, a conformational search for each molecule is carried out. Next, for each of the conformers an approximation to the molecular surface with equally distributed surface points is computed. Third, molecular properties are projected onto this surface. Fourth, areas of identical properties are clustered to so-called patches. Fifth, the spatial distribution of the patches is converted into an alignment-free descriptor that is based on the entire conformer ensemble. The resulting descriptor can be interpreted by superimposing the most important descriptor variables and the molecules of the data set. The most important descriptor variables are identified with chemometric regression tools. The novel descriptor was applied to several benchmark data sets and was compared to other descriptors and QSAR techniques comprising a binary fingerprint, a topological pharmacophore descriptor (Cats2D), and the field-based 3D-QSAR technique GRID/PLS which is alignment-dependent. The use of conformer ensembles renders xMaP very robust. It turns out that xMaP performs very well on (almost) all data sets and that the statistical results are comparable to GRID/PLS. In addition to that, xMaP can also be used to efficiently visualize the derived quantitative structure-activity relationships.