Exploring the Mechanism of Inhibition of Au Nanoparticles on the Aggregation of Amyloid-β(16-22) Peptides at the Atom Level by All-Atom Molecular Dynamics

Song, Menghua; Sun, Yunxiang; Luo, Yin; Zhu, Yanyan; Liu, Yongsheng; Li, Huiyu

doi:10.3390/ijms19061815

Cited by 43 publications

(18 citation statements)

References 49 publications

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“…MD simulations have also been used to investigate the inhibition process of amyloid β (Aβ) fibrillation by using Au-NPs [546]. The simulations showed that Au-NPs can influence the conformational change of the peptides and reduce inter-peptide interactions which can in turn prevent the β-Sheet formation of Aβ peptides and prolong the progress of Aβ aggregation.…”

Section: Interactions With Viruses and Biomacromoleculesmentioning

confidence: 99%

Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development

et al. 2020

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Molecular dynamics (MD) simulations have become increasingly useful in the modern drug development process. In this review, we give a broad overview of the current application possibilities of MD in drug discovery and pharmaceutical development. Starting from the target validation step of the drug development process, we give several examples of how MD studies can give important insights into the dynamics and function of identified drug targets such as sirtuins, RAS proteins, or intrinsically disordered proteins. The role of MD in antibody design is also reviewed. In the lead discovery and lead optimization phases, MD facilitates the evaluation of the binding energetics and kinetics of the ligand-receptor interactions, therefore guiding the choice of the best candidate molecules for further development. The importance of considering the biological lipid bilayer environment in the MD simulations of membrane proteins is also discussed, using G-protein coupled receptors and ion channels as well as the drug-metabolizing cytochrome P450 enzymes as relevant examples. Lastly, we discuss the emerging role of MD simulations in facilitating the pharmaceutical formulation development of drugs and candidate drugs. Specifically, we look at how MD can be used in studying the crystalline and amorphous solids, the stability of amorphous drug or drug-polymer formulations, and drug solubility. Moreover, since nanoparticle drug formulations are of great interest in the field of drug delivery research, different applications of nano-particle simulations are also briefly summarized using multiple recent studies as examples. In the future, the role of MD simulations in facilitating the drug development process is likely to grow substantially with the increasing computer power and advancements in the development of force fields and enhanced MD methodologies.

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Section: Interactions With Viruses and Biomacromoleculesmentioning

confidence: 99%

Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development

et al. 2020

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“…Hydrophobic interactions play important roles between the inhibitors and the residues of SIRT6. In previous computer simulation studies, hydrophobic interactions between small molecules and proteins have also been reported [44][45][46][47][48].…”

Section: Resultsmentioning

confidence: 88%

“…∆G polar is calculated by the GB model [64] and ∆G suf is estimated by the solvent accessible surface area (SASA). As the binding energy (∆G binding ) reported here is the relative binding free energy, the contribution of conformational entropy of the small molecule was ignored in accordance with a number of previous computational studies [45,46,66,67]. Therefore, in this study, we use the formula ∆G binding = ∆E MM + ∆G solv [61] to calculate the binding free energy.…”

Section: Analysis Methodsmentioning

confidence: 99%

Structural Insight into the Interactions between Structurally Similar Inhibitors and SIRT6

Zhao

Zhu

Wang

et al. 2020

IJMS

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Sirtuin 6 (SIRT6) is an NAD+-dependent deacetylase with a significant role in 20% of all cancers, such as colon cancers and rectal adenocarcinoma. However, there is currently no effective drug for cancers related to SIRT6. To explore potential inhibitors of SIRT6, it is essential to reveal details of the interaction mechanisms between inhibitors and SIRT6 at the atomic level. The nature of small molecules from herbs have many advantages as inhibitors. Based on the conformational characteristics of the inhibitor Compound 9 (Asinex ID: BAS13555470), we explored the natural molecule Scutellarin, one compound of Huang Qin, which is an effective herb for curing cancer that has been described in the Traditional Chinese Medicine (TCMS) library. We investigated the interactions between SIRT6 and the inhibitors using molecular dynamics (MD) simulations. We illustrated that the structurally similar inhibitors have a similar binding mode to SIRT6 with residues-Leu9, Phe64, Val115, His133 and Trp188. Hydrophobic and π-stacking interactions play important roles in the interactions between SIRT6 and inhibitors. In summary, our results reveal the interactive mechanism of SIRT6 and the inhibitors and we also provide Scutellarin as a new potential inhibitor of SIRT6.Our study provides a new potential way to explore potential inhibitors from TCMS.Int. J. Mol. Sci. 2020, 21, 2601 2 of 15 cancers and rectal adenocarcinoma, according to the Cancer Genome Atlas database [17]. Crystal structure of SIRT6 (PDB code 3K35) [23,24] includes the hydrophobic channel, the Rossman fold and the small domain shown in Figure S1A [25]. The Rossman fold is one of the most common and widely distributed super-secondary structures. The dinucleotide such as FAD, NAD and NADP can bind in the domain [26]. There is a long hydrophobic-channel pocket that binds the small molecules [27].Probing potential inhibitors has become essential for the development of cancer drug design [4,28,29]. Several potential inhibitors of SIRT6 have been reported, such as Compound 9 [3,30], trichostatin A [23] and inhibitors with a salicylate-linked structure [31]. Parenti et al. synthesized three (SYN17739303, BAS13555470 or Compound 9 and BAS00417531) potential inhibitors for SIRT6 [30]. Interestingly we found that the three inhibitors have similar chemical structure. The structures of these inhibitors can give insight into the direction of the design of improved inhibitors. However, the mechanism of interactions between the inhibitors and SIRT6 is still elusive. The relationship between the interactions and the bioactivity of SIRT6 is also not clear.Small molecules from herbs have many advantages as inhibitors. For example, herbal medicine has low toxicity and can be easily absorbed and easily expelled from the body. In this investigation, we therefore sought to probe structure-based inhibitors similar to Compound 9 [30] from Traditional Chinese Medicines (TCMS). Scutellarin is one compound of Scutellaria baicalensis Georgi, named Huang Qin in TCMS. It has been reported that ...

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“…Gold complexes may inhibit the aggregation of amyloid peptides mainly by metal coordination [ 95 , 130 ]. Some Au complexes showed good inhibitory effects on amyloid peptides, such as PrP106–126, hIAPP, and Aβ protein [ 94 , 131 , 132 , 133 ].…”

Section: Metal Binding Sites In Amyloid Oligomers and Their Polymementioning

confidence: 99%

“What Doesn’t Kill You Makes You Stronger”: Future Applications of Amyloid Aggregates in Biomedicine

et al. 2020

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Amyloid proteins are linked to the pathogenesis of several diseases including Alzheimer’s disease, but at the same time a range of functional amyloids are physiologically important in humans. Although the disease pathogenies have been associated with protein aggregation, the mechanisms and factors that lead to protein aggregation are not completely understood. Paradoxically, unique characteristics of amyloids provide new opportunities for engineering innovative materials with biomedical applications. In this review, we discuss not only outstanding advances in biomedical applications of amyloid peptides, but also the mechanism of amyloid aggregation, factors affecting the process, and core sequences driving the aggregation. We aim with this review to provide a useful manual for those who engineer amyloids for innovative medicine solutions.

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Exploring the Mechanism of Inhibition of Au Nanoparticles on the Aggregation of Amyloid-β(16-22) Peptides at the Atom Level by All-Atom Molecular Dynamics

Cited by 43 publications

References 49 publications

Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development

Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development

Structural Insight into the Interactions between Structurally Similar Inhibitors and SIRT6

“What Doesn’t Kill You Makes You Stronger”: Future Applications of Amyloid Aggregates in Biomedicine

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