Evolution of In Silico Strategies for Protein-Protein Interaction Drug Discovery

Macalino, Stephani Joy Y.; Basith, Shaherin; Clavio, Nina Abigail B.; Chang, Hyerim; Kang, Soosung; Choi, Sun

doi:10.3390/molecules23081963

Cited by 92 publications

(79 citation statements)

References 366 publications

(261 reference statements)

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“…adenine [65]. Consistent with our observations in mammalian cells, the linear d PMI-δ peptide and the double stapled d PMI-δ (1)(2)(3)(4)(5)(9)(10)(11)(12) peptide had no effect on p53-Mdm2 interaction ( Figure 9A-B). In contrast, the d PMI-δ (1,5,12) peptide completely prevented the growth of yeast cells expressing p53/Mdm2 at 12.5 µM ( Figure 9C, left panel).…”

Section: )/Mdm2 Interaction Inhibits Growth Of Yeast Cells In a Nutsupporting

confidence: 91%

“…From the 6 stapled peptides designed we found that two, d PMI-δ(1-5) and d PMI-δ(5-12), both exhibited improved binding and cellular properties. We introduced an addition staple between positions 9 and 12 (i+3) in d PMI-δ (1)(2)(3)(4)(5) resulting in a d PMI-δ(1-5,9-12) double stapled peptide [ Figure 8]. Combining d PMI-δ(1-5) and d PMI-δ(5-12) resulted in a stitched peptide, d PMI-δ (1,5,12), with the common attachment point for the two staples localised at residue 5 [ Figure 8].…”

Section: Several Double-stapled Peptides Have Been Shown To Successfumentioning

confidence: 99%

“…We also tested the ability of d PMI-δ, d PMI-δ (1)(2)(3)(4)(5)(9)(10)(11)(12), d PMI-δ (1,5,12) and scrambled d PMIδ (1,5,12) peptides to inhibit the p53 (1-52)-Mdm2 interaction in a Yeast 2-hybrid (Y2H) assay optimized for detecting small-molecule inhibitors [65]. In this assay, inactivation of p53(1-…”

Section: Several Double-stapled Peptides Have Been Shown To Successfumentioning

confidence: 99%

“…We tried to obtain crystal structures of the stitched peptide d PMI-δ (1,5,12) in complex with Mdm2 (6-125) and of the double stapled peptide d PMI-δ (1)(2)(3)(4)(5)(9)(10)(11)(12) in complex with Mdm2 (6-125). We could only obtain crystals for the latter and were able to resolve its structure ( Figures 11 A, B).…”

Section: Crystal Structure Of Mdm2 -D Pmi-δ(1-5 9-12) Complexmentioning

confidence: 99%

“…Protein-protein interactions (PPIs) are central to most biological processes and are often dysregulated in disease [1,2] . Therefore, PPIs are attractive therapeutic targets for novel drug discovery.…”

Section: Introductionmentioning

confidence: 99%

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Macrocyclization of an all-D linear peptide improves target affinity and imparts cellular activity: A novel stapled α-helical peptide modality

Kannan¹,

Aronica²,

Ng³

et al. 2019

Preprint

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Peptide-based inhibitors hold great potential for targeted modulation of intracellular proteinprotein interactions (PPIs) by leveraging vast chemical space relative to primary structure via sequence diversity as well as conformationally through varying secondary and tertiary structures. However, the development of peptide therapeutics has been hindered because of their limited conformational stability, proteolytic sensitivity and cell permeability. Several contemporary peptide design strategies address these issues to varying degrees. Strategic macrocyclization through optimally placed chemical braces such as olefinic hydrocarbon crosslinks, commonly referred to as staples, may address these issues by i) restricting conformational freedom to improve target affinities, ii) improving proteolytic resistance, and iii) enhancing cell permeability. Conversely, molecules constructed entirely from D-amino acids are hyper-resistant to proteolytic cleavage, but generally lack conformational stability and membrane permeability. Since neither approach is a complete solution, we have combined these strategies to identify the first examples of all-D α-helical stapled and stitched peptides.As a template, we used a recently reported all D-linear peptide that is a potent inhibitor of the p53-Mdm2 interaction, but is devoid of cellular activity. To design both stapled and stitched all-D-peptide analogues, we used computational modelling to predict optimal staple placement.The resultant novel macrocyclic all D-peptide was determined to exhibit increased α-helicity, improved target binding, complete proteolytic stability and, most notably, cellular activity.

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Section: )/Mdm2 Interaction Inhibits Growth Of Yeast Cells In a Nutsupporting

confidence: 91%

Section: Several Double-stapled Peptides Have Been Shown To Successfumentioning

confidence: 99%

Section: Several Double-stapled Peptides Have Been Shown To Successfumentioning

confidence: 99%

Section: Crystal Structure Of Mdm2 -D Pmi-δ(1-5 9-12) Complexmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Macrocyclization of an all-D linear peptide improves target affinity and imparts cellular activity: A novel stapled α-helical peptide modality

Kannan¹,

Aronica²,

Ng³

et al. 2019

Preprint

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Peptidomimetics in Silico

Tomasella

Floris

Guccione

et al. 2020

Molecular Informatics

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Endogenous peptides as part of physiological processes are targets of interest when it comes to finding desirable therapeutics which are able to modulate molecular interactions. The major limits presented by peptides when they are used as drugs have motivated the research of the synthesis of peptidomimetics obtained through chemical modification and the use of in silico approaches. Here recent works on the discovery of peptidomimetics by computational methods are reported. Together with molecular dynamic simulations, the use of pharmacophore research simulations helps to gain insight into and understand the molecular determinants underlying the physiological processes.

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Using machine‐learning‐driven approaches to boost hot‐spot's knowledge

Rosário‐Ferreira

Bonvin

Moreira

2022

WIREs Comput Mol Sci

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Understanding protein-protein interactions (PPIs) is fundamental to describe and to characterize the formation of biomolecular assemblies, and to establish the energetic principles underlying biological networks. One key aspect of these interfaces is the existence and prevalence of hot-spots (HS) residues that, upon mutation to alanine, negatively impact the formation of such proteinprotein complexes. HS have been widely considered in research, both in case studies and in a few large-scale predictive approaches. This review aims to pre-

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Evolution of In Silico Strategies for Protein-Protein Interaction Drug Discovery

Cited by 92 publications

References 366 publications

Macrocyclization of an all-D linear peptide improves target affinity and imparts cellular activity: A novel stapled α-helical peptide modality

Macrocyclization of an all-D linear peptide improves target affinity and imparts cellular activity: A novel stapled α-helical peptide modality

Peptidomimetics in Silico

Using machine‐learning‐driven approaches to boost hot‐spot's knowledge

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