Computational Tools and Strategies to Develop Peptide-Based Inhibitors of Protein-Protein Interactions

Delaunay, Maxence; Ha-Duong, Tâp

doi:10.1007/978-1-0716-1855-4_11

Cited by 11 publications

(5 citation statements)

References 193 publications

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“…These interactions were previously observed in simulations [18] and mutagenesis experiments [8]. Our binding pose appears to be qualitatively consistent with a proposed docking model of the inhibitor aprotinin [19] and offers a starting point for further computational studies concerning protein-protein interface design [22].…”

Section: Discussionsupporting

confidence: 87%

Molecular Insights into Substrate Binding of the Outer Membrane Enzyme OmpT

Zhang

Baaden

2023

Catalysts

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The enzyme OmpT of the outer membrane of Escherichia coli shows proteolytic activity and cleaves peptides and proteins. Using molecular dynamics simulations in a fully hydrated lipid bilayer on a time scale of hundreds of nanoseconds, we draw a detailed atomic picture of substrate recognition in the OmpT-holo enzyme complex. Hydrogen bonds and salt bridges are essential for maintaining the integrity of the active site and play a central role for OmpT in recognizing its substrate. Electrostatic interactions are critical at all stages from approaching the substrate to docking at the active site. Computational alanine scanning based on the Molecular Mechanics Generalized Born Surface Area (MM-GBSA) approach confirms the importance of multiple residues in the active site that form salt bridges. The substrate fluctuates along the axis of the β-barrel, which is associated with oscillations of the binding cleft formed by the residue pairs D210-H212 and D83-D85. Principal component analysis suggests that substrate and protein movements are correlated. We observe the transient presence of putative catalytic water molecules near the active site, which may be involved in the nucleophilic attack on the cleavable peptide bond of the substrate.

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Section: Discussionsupporting

confidence: 87%

Molecular Insights into Substrate Binding of the Outer Membrane Enzyme OmpT

Zhang

Baaden

2023

Catalysts

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“…Proteins can bind to their receptors with high affinity when acting as ligands. However, the majority of protein inhibitors are focused on functional subunits rather than the entire protein, with only a few residues of the RBD sequence interacting with the receptor [37]. Hence, it would be feasible to use functional peptides as a mimic for protein ligands.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of ACE2–S Protein Interaction by a Short Functional Peptide with a Boomerang Structure

Wei,

Liu,

Zhang

et al. 2024

Molecules

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Considering the high evolutionary rate and great harmfulness of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it is imperative to develop new pharmacological antagonists. Human angiotensin-converting enzyme-2 (ACE2) functions as a primary receptor for the spike protein (S protein) of SARS-CoV-2. Thus, a novel functional peptide, KYPAY (K5), with a boomerang structure, was developed to inhibit the interaction between ACE2 and the S protein by attaching to the ACE2 ligand-binding domain (LBD). The inhibition property of K5 was evaluated via molecular simulations, cell experiments, and adsorption kinetics analysis. The molecular simulations showed that K5 had a high affinity for ACE2 but a low affinity for the cell membrane. The umbrella sampling (US) simulations revealed a significant enhancement in the binding potential of this functional peptide to ACE2. The fluorescence microscopy and cytotoxicity experiments showed that K5 effectively prevented the interaction between ACE2 and the S protein without causing any noticeable harm to cells. Further flow cytometry research indicated that K5 successfully hindered the interaction between ACE2 and the S protein, resulting in 78% inhibition at a concentration of 100 μM. This work offers an innovative perspective on the development of functional peptides for the prevention and therapy of SARS-CoV-2.

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“…These approaches can includes, search by homology modeling, molecular dynamics and protein docking. The advantages of computational in silico methods include their low cost, faster procedure speed, simple process ( Porto et al, 2018 ; Costa et al, 2020 ; Hashemi et al, 2021 ; Delaunay and Ha-Duong, 2022 ). These approaches can be employed i.e.…”

Section: A Tool To Achieve Food Security: the Potential Of Antimicrob...mentioning

confidence: 99%

Nanoparticles in association with antimicrobial peptides (NanoAMPs) as a promising combination for agriculture development

Maximiano

Rios

Campos³

et al. 2022

Front. Mol. Biosci.

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Antimicrobial peptides are small molecules, up to 10 kDa, present in all kingdoms of life, including in plants. Several studies report that these molecules have a broad spectrum of activity, including antibacterial, antifungal, antiviral, and insecticidal activity. Thus, they can be employed in agriculture as alternative tools for phytopathogen and pest control. However, the application of peptides in agriculture can present challenges, such as loss of activity due to degradation of these molecules, off-target effects, and others. In this context, nanotechnology can offer versatile structures, including metallic nanoparticles, liposomes, polymeric nanoparticles, nanofibers, and others, which might act both in protection and in release of AMPs. Several polymers and biomaterials can be employed for the development of nanostructures, such as inorganic metals, natural or synthetic lipids, synthetic and hybrid polymers, and others. This review addresses the versatility of NanoAMPs (Nanoparticles in association with antimicrobial peptides), and their potential applications in agribusiness, as an alternative for the control of phytopathogens in crops.

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Computational Tools and Strategies to Develop Peptide-Based Inhibitors of Protein-Protein Interactions

Cited by 11 publications

References 193 publications

Molecular Insights into Substrate Binding of the Outer Membrane Enzyme OmpT

Molecular Insights into Substrate Binding of the Outer Membrane Enzyme OmpT

Inhibition of ACE2–S Protein Interaction by a Short Functional Peptide with a Boomerang Structure

Nanoparticles in association with antimicrobial peptides (NanoAMPs) as a promising combination for agriculture development

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