Design and development of high affinity dual anticancer peptide-inhibitors against p53-MDM2/X interaction

Rasafar, Nasim; Barzegar, Abolfazl; Aghdam, Elnaz Mehdizadeh

doi:10.1016/j.lfs.2020.117358

Cited by 17 publications

(12 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3 and Fig. S3 by DSSP method 29 , β-sheets were completely disappeared by changing to coil structure in Flvs-treated monomeric Aβ systems (see also Table 2). It should be mentioned that transformation of the harmful secondary structure content into coil or α-helical features is an essential early step in preventing the amyloid fibrillation process through inhibiting primary nucleation.…”

Section: Secondary and 3d Structural Changes Of Flvs-aβ Peptide Complmentioning

confidence: 82%

“…In order to calculate the interaction between A and B chains within U-shaped oligomeric peptides at fibril-like pentameric manner in the absence and presence of Flv compounds, we performed umbrella sampling simulations. Umbrella sampling is a robust method to obtain the ΔG binding of a particular event along a reaction coordinate 29 , 30 . It can be seen in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…

Figure 6 Average inter-chain backbone hydrogen bonds of pentameric protofibril with neighbor chains in the absence and presence of Flvs. The distance of 0.35 nm was assigned between H-bond donor and acceptor atoms to determine H-bond formation possibility 29 . All systems, including Flv-free Aβ, Aβ in complex with myricetin (Aβ-Myc) and morin (Aβ-Mor) Flvs are shown.…”

Section: Resultsmentioning

confidence: 99%

“…For further equilibration, each window was equilibrated for 100 ps and then 5 ns was performed for umbrella sampling simulations. Results obtained from the US simulations were analyzed by the weighted histogram analysis method (WHAM) 29 in order to extract the potential mean force (PMF).…”

Section: Methodsmentioning

confidence: 99%

“…The umbrella sampling simulation is a very useful approach to extract the potential of mean force (PMF) and to achieve the ΔG for the binding condition, especially for the protein–protein or peptide-peptide interactions (PPI) 29 , 30 . For this aim, the previously simulated structures were used as starting configurations for pulling additional simulations.…”

Section: Methodsmentioning

confidence: 99%

See 4 more Smart Citations

Simulations on the dual effects of flavonoids as suppressors of Aβ42 fibrillogenesis and destabilizers of mature fibrils

Gargari

Barzegar

2020

Sci Rep

Self Cite

View full text Add to dashboard Cite

Structural studies of the aggregation inhibition of the amyloid-β peptide (Aβ) by different natural compounds are of the utmost importance due to their great potential as neuroprotective and therapeutic agents for Alzheimer’s disease. We provided the simulation of molecular dynamics for two different states of Aβ42, including “monomeric aggregation-prone state (APS)” and “U-shaped pentamers of amyloidogenic protofilament intermediates” in the absence and presence of polyphenolic flavonoids (Flvs, myricetin and morin) in order to verify the possible mechanism of Flvs fibrillogenesis suppression. Data showed that Flvs directly bind into Aβ42 species in both states of “monomeric APS β-sheets” and “pentameric amyloidogenic intermediates”. Binding of Flvs with amyloidogenic protofilament intermediates caused the attenuation of some inter-chains H-bonds, salt bridges, van der Waals and interpeptide interaction energies without interfering with their secondary β-sheets. Therefore, Flvs redirect oligomeric amyloidogenic intermediates into unstructured aggregates by significant disruption of the "steric zipper" motif of fibrils—pairs of self-complementary β-sheets—without changing the amount of β-sheets. It is while Flvs completely destruct the disadvantageous secondary β-sheets of monomeric APS conformers by converting them into coil/helix structures. It means that Flvs suppress the fibrillogenesis process of the monomeric APS structures by converting their β-sheets into proper soluble coil/helices structures. The different actions of Flvs in contact with two different states of Aβ conformers are related to high interaction tendency of Flvs with additional H-bonds for monomeric APS β-sheet, rather than oligomeric protofilaments. Linear interaction energy (LIE) analysis confirmed the strong binding of monomeric Aβ-Flvs with more negative ∆Gbinding, rather than oligomeric Aβ-Flvs system. Therefore, atomic scale computational evaluation of Flvs actions demonstrated different dual functions of Flvs, concluded from the application of two different monomeric and pentameric Aβ42 systems. The distinct dual functions of Flvs are proposed as suppressing the aggregation by converting β-sheets of monomeric APS to proper soluble structures and disrupting the "steric zipper" fibril motifs of oligomeric intermediate by converting on-pathway into off-pathway. Taken together, our data propose that Flvs exert dual and more effective functions against monomeric APS (fibrillogenesis suppression) and remodel the Aβ aggregation pathway (fibril destabilization).

show abstract

Section: Secondary and 3d Structural Changes Of Flvs-aβ Peptide Complmentioning

confidence: 82%

Section: Resultsmentioning

confidence: 99%

“…

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

Simulations on the dual effects of flavonoids as suppressors of Aβ42 fibrillogenesis and destabilizers of mature fibrils

Gargari

Barzegar

2020

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

Plausible blockers of Spike RBD in SARS-CoV2—molecular design and underlying interaction dynamics from high-level structural descriptors

et al. 2021

View full text Add to dashboard Cite

COVID-19 is characterized by an unprecedented abrupt increase in the viral transmission rate (SARS-CoV-2) relative to its pandemic evolutionary ancestor, SARS-CoV (2003). The complex molecular cascade of events related to the viral pathogenicity is triggered by the Spike protein upon interacting with the ACE2 receptor on human lung cells through its receptor binding domain (RBD Spike ). One potential therapeutic strategy to combat COVID-19 could thus be limiting the infection by blocking this key interaction. In this current study, we adopt a protein design approach to predict and propose non-virulent structural mimics of the RBD Spike which can potentially serve as its competitive inhibitors in binding to ACE2. The RBD Spike is an independently foldable protein domain, resilient to conformational changes upon mutations and therefore an attractive target for strategic re-design. Interestingly, in spite of displaying an optimal shape fit between their interacting surfaces (attributed to a consequently high mutual affinity), the RBD Spike –ACE2 interaction appears to have a quasi-stable character due to a poor electrostatic match at their interface. Structural analyses of homologous protein complexes reveal that the ACE2 binding site of RBD Spike has an unusually high degree of solvent-exposed hydrophobic residues, attributed to key evolutionary changes, making it inherently “reaction-prone.” The designed mimics aimed to block the viral entry by occupying the available binding sites on ACE2, are tested to have signatures of stable high-affinity binding with ACE2 (cross-validated by appropriate free energy estimates), overriding the native quasi-stable feature. The results show the apt of directly adapting natural examples in rational protein design, wherein, homology-based threading coupled with strategic “hydrophobic ↔ polar” mutations serve as a potential breakthrough. Graphical Abstract Supplementary Information The online version contains supplementary material available at 10.1007/s00894-021-04779-0.

show abstract

Design of a hybrid peptide derived from Melittin and CXCL14 –C17: A molecular dynamics simulation study

et al. 2022

View full text Add to dashboard Cite

Design and development of high affinity dual anticancer peptide-inhibitors against p53-MDM2/X interaction

Cited by 17 publications

References 58 publications

Simulations on the dual effects of flavonoids as suppressors of Aβ42 fibrillogenesis and destabilizers of mature fibrils

Simulations on the dual effects of flavonoids as suppressors of Aβ42 fibrillogenesis and destabilizers of mature fibrils

Plausible blockers of Spike RBD in SARS-CoV2—molecular design and underlying interaction dynamics from high-level structural descriptors

Design of a hybrid peptide derived from Melittin and CXCL14 –C17: A molecular dynamics simulation study

Contact Info

Product

Resources

About