Dual Inhibitors of AChE and BACE-1 for Reducing Aβ in Alzheimer’s Disease: From In Silico to In Vivo

Abstract

Alzheimer’s disease (AD) is a complex and widespread condition, still not fully understood and with no cure yet. Amyloid beta (Aβ) peptide is suspected to be a major cause of AD, and therefore, simultaneously blocking its formation and aggregation by inhibition of the enzymes BACE-1 (β-secretase) and AChE (acetylcholinesterase) by a single inhibitor may be an effective therapeutic approach, as compared to blocking one of these targets or by combining two drugs, one for each of these targets. We used our ISE algorithm to model each of the AChE peripheral site inhibitors and BACE-1 inhibitors, on the basis of published data, and constructed classification models for each. Subsequently, we screened large molecular databases with both models. Top scored molecules were docked into AChE and BACE-1 crystal structures, and 36 Molecules with the best weighted scores (based on ISE indexes and docking results) were sent for inhibition studies on the two enzymes. Two of them inhibited both AChE (IC50 between 4–7 μM) and BACE-1 (IC50 between 50–65 μM). Two additional molecules inhibited only AChE, and another two molecules inhibited only BACE-1. Preliminary testing of inhibition by F681-0222 (molecule 2) on APPswe/PS1dE9 transgenic mice shows a reduction in brain tissue of soluble Aβ42.

Explaining Multiclass Compound Activity Predictions Using Counterfactuals and Shapley Values

“…Interestingly, a recent investigation a empted the design of dual inhibitors for TP2 [15]. The active compounds reported in this study contained a similar benzyl-piperidine substructure [15], consistent with the results of our analysis. In the Base-CPD active against target B, an amide bond and adjacent hydroxyl groups strongly opposed the DT-CPD prediction, while the tricyclic system on the left and the trifluorobutane and phenyl groups on the right made modest negative and positive contributions to the prediction of DT activity, respectively.…”

Pregnenolone derivatives for the treatment of Alzheimer's disease: synthesis, and in vitro inhibition of amyloid β1–42 peptide aggregation, acetylcholinesterase and carbonic anhydrase-II

“…To a solution of a-brominated 16 (5 mmol) in DMF, 5.25 mmol of trimethylamine (Et 3 N) and 7.5 mmol of amines (17)(18)(19)(20)(21)(22) were added. The mixture was reuxed overnight.…”

“…The 42-mer peptide, Ab 1-42 , is the more toxic among these two (i.e., Ab 1-42 and Ab 1-40 ). [18][19][20] Therefore, blocking the PAS could serve to reduce Ab aggregation in order to increase the chance to prevent harmful effects. Moreover, a number of authors studied the effect of AChE PAS inhibitors (propidium and fasciculin) and active site inhibitor (edrophonium) on Ab aggregation process experimentally.…”

Activity Models of Key GPCR Families in the Central Nervous System: A Tool for Many Purposes

“…Our ISE is a unique and unprecedented generic classification algorithm for finding reasonable solutions to highly complex combinatorial problems . For drug classifications, ,− a learning set comprises molecules known to have an activity (i.e., agonists, antagonists, or inhibitors) on a specific target, diluted by a considerable number (100- or 1000-fold) of assumed inactive molecules. The algorithm randomly picks five property filters out of ∼200 physicochemical properties of each molecule to distinguish between the active (“positive”) and the inactive compounds.…”

“…Most GPCR structures still need to be elucidated because detailed structure information requires large-scale expression and purification due to their highly dynamic nature. , Structures are currently reported for ∼120 members of class A GPCRs . This gap may be partially filled by computational modeling − and by improvements in the quality of cryo-EM of GPCR structures . On the other hand, much data about ligand binding and action has been accumulated, including GPCR activation and blocking of GPCR activity.…”