Molecular Dynamics Study on the Inhibition Mechanisms of Drugs CQ_1–3 for Alzheimer Amyloid-β₄₀ Aggregation Induced by Cu²⁺

Abstract

The aggregation of amyloid-β (Aβ) peptide induced by Cu(2+) is a key factor in development of Alzheimer's disease (AD), and metal ion chelation therapy enables treatment of AD. Three CQi (i = 1, 2, and 3 with R = H, Cl, and NO2, respectively) drugs had been verified experimentally to be much stronger inhibitors than the pioneer clioquinol (CQ) in both disaggregation of Aβ40 aggregate and reduction of toxicity induced by Cu(2+) binding at low pH. Due to the multiple morphologies of Cu(2+)-Aβ40 complexes produced at different pH states, we performed a series of molecular dynamics simulations to explain the structural changes and morphology characteristics as well as intrinsic disaggregation mechanisms of three Cu(2+)-Aβ40 models in the presence of any of the three CQi drugs at both low and high pH states. Three inhibition mechanisms for CQi were proposed as "insertion", "semi-insertion", and "surface" mechanisms, based on the morphologies of CQi-model x (CQi-x, x = 1, 2, and 3) and the strengths of binding between CQi and the corresponding model x. The insertion mechanism was characterized by the morphology with binding strength of more than 100 kJ/mol and by CQi being inserted or embedded into the hydrophobic cavity of model x. In those CQi-x morphologies with lower binding strength, CQi only attaches on the surface or inserts partly into Aβ peptide. Given the evidence that the binding strength is correlated positively with the effectiveness of drug to inhibit Aβ aggregation and thus to reduce toxicity, the data of binding strength presented here can provide a reference for one to screen drugs. From the point of view of binding strength, CQ2 is the best drug. Because of the special role of Asp23 in both Aβ aggregation and stabilizing the Aβ fibril, the generation of a H-bond between CQ3 and Asp23 of the Aβ40 peptide is believed to be responsible for CQ3 having the strongest disaggregation capacity. Therefore, besides strong binding, stronger propensity to H-bond with Asp23 would be another key factor to be taken seriously into account in drug screens. Meanwhile, the structural characteristics of drug CQi itself are also worthy of attention. First, the increasing polarity from CQ1 and CQ2 to CQ3 in turn results in increasing probability and strength of the interaction between the drug and the N-terminal (NT) region of Aβ40, which obviously inhibits Aβ peptide aggregation induced by Cu(2+) binding. Second, both the benzothiazole ring and phenol ring of CQi can overcome the activation energy barrier (∼16 kJ/mol) to rotate flexibly around the intramolecular C7-N14 bond to achieve the maximum match and interaction with the ambient Aβ40 residues. Such a structural feature of CQi paves the new way for ones in selection and modification of a drug.

Revisiting Cu(II) Bound Amyloid-β40 and Amyloid-β42 Peptides: Varying Coordination Chemistries

“…Our results for apo Aβ42 are in accord with the REMD studies by Yang and Teplow (135). The structuring of the Cterminal region of apo Aβ42 including β-sheet structure adaptation with high probability have been investigated by few additional research groups (130)(131)(132)(133)(134)(135)(136)(137). These results agree with our findings.…”

Alzheimer’s disease: How metal ions define β-amyloid function

“…These compounds are well-known metal chelators with good metal-binding affinities but also with known historic side effects that reflect the narrow Kd window in vivo [580]. Derivatives of clioquinol can be tailored for higher affinity to remedy Cu(II)-induced toxicity, interestingly at the same time reducing Aβ aggregation [581].…”

Sulfonated Compounds Bind with Prostatic Acid Phosphatase (PAP248–286) to Inhibit the Formation of Amyloid Fibrils

“…The root‐mean‐square deviations (RMSDs) evaluate the deviation of the backbone of the peptide. Molecular mechanics/Poisson–Boltzmann surface area (MM/PBSA), which was previously employed in many protein–ligand systems, was utilized to study the binding free energy …”