Potential Anti-Alzheimer Agents from Guanidinyl Tryptophan Derivatives with Activities of Membrane Adhesion and Conformational Transition Inhibitions.

Pathomwat Wongrattanakamon,Supat Jiranusornkul,Jutamas Jiaranaikulwanitch,Wipawadee Yooin,Chalermpong Saenjum,Opa Vajragupta

doi:10.3390/molecules26164863

Pathomwat Wongrattanakamon, Supat Jiranusornkul + Show 4 more

Open Access

https://doi.org/10.3390/molecules26164863

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Abstract

Guanidinyl tryptophan derivatives TGN1, TGN2, TGN3, and TGN4 were synthesized, and these compounds were shown to possess in vitro inhibitory activity for amyloid aggregation in a previous study. Nevertheless, the influence of the TGN series of compounds on the binding and permeation behaviors of an Aβ monomer to the cell membranes was not elucidated. In this study, we investigated the effect of compounds in the TGN series on the behavior of an Aβ monomer regarding its toxicity toward the bilayer lipid membrane using molecular dynamics (MD) simulation. MD simulations suggest that TGN4 is a potential agent that can interfere with the movement of the Aβ monomer into the membrane. The MM-GBSA result demonstrated that TGN4 exhibits the highest affinity to the Aβ1–42 monomer but has the lowest affinity to the bilayer. Moreover, TGN4 also contributes to a decrease in the binding affinity between the Aβ1–42 monomer and the POPC membrane. Regarding the results of the binding mode and conformational analyses, a high number of amino-acid residues were shown to provide the binding interactions between TGN4 and the Aβ1–42 monomer. TGN4 also reduces the conformational transition of the Aβ1–42 monomer by means of interacting with the monomer. The present study presents molecular-level insights into how the TGN series of compounds affect the membrane adsorption and the conformational transition of the Aβ1–42 monomer, which could be valuable for the further development of new anti-Alzheimer agents.

Highlights

Alzheimer’s disease (AD) is a progressive degenerative brain disease and the most common cause of dementia [1,2]
The results of the present study provide a rational basis for understanding the influence of guanidinyl tryptophan compounds on the membrane surface binding of the Aβ1–42 monomer, which can explain the anti-amyloid aggregation effect
Exhibited a disruptive effect on Aβ42 protofibril by destabilizing the two hydrophobic core regions and disrupting the intrachain salt bridges. In this molecular dynamics (MD) simulation study, TGN4 was selected as a candidate lead compound on the basis of several findings

Summary

Introduction

Alzheimer’s disease (AD) is a progressive degenerative brain disease and the most common cause of dementia [1,2]. Regarding the pathological features of AD, the disease is characterized by the accumulation of neurofibrillary tangles and senile plaques inside and outside brain cells, respectively In these plaques, amyloid-β protein (Aβ) aggregations are observed in a variety of types. The in vitro study by Mrdenovic et al [4] showed that the aggregation of the Aβ monomers can result in the formation of Aβ oligomers, which is the neurotoxic form. This neurotoxic protein is able to permeate the cell membrane. The formation of a molecular interaction between Aβ and the membrane surface is a conceptually physiological mechanism due to the amphipathic properties of the amyloid protein and lipid structures. The inhibition of the Aβ monomer’s conformational transition behaviors may lead to a decrease in the ability of the Aβ monomer to bind to cell membranes

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