In silico Approaches for the Design and Optimization of Interfering Peptides Against Protein–Protein Interactions

Hashemi, Zahra Sadat; Zarei, Mahboubeh; Fath, Mohsen Karami; Ganji, Mahmoud; Farahani, Mahboube Shahrabi; Afsharnouri, Fatemeh; Pourzardosht, Navid; Khalesi, Bahman; Jahangiri, Abolfazl; Rahbar, Mahtab; Khalili, Saeed

doi:10.3389/fmolb.2021.669431

Cited by 51 publications

(45 citation statements)

References 249 publications

(272 reference statements)

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“…Protein/peptide docking remains a challenging task due to the high flexibility of peptides, which undermines the prediction of accurate bound conformations (Rentzsch and Renard, 2015;Ciemny et al, 2018;Hashemi et al, 2021). To address this issue, existing protein/peptide docking methodologies have relied on different strategies.…”

Section: Discussionmentioning

confidence: 99%

“…2001; Staneva and Wallin, 2009;Hashemi et al, 2021). However, this approach, coined as de novo docking, is not suitable for larger peptides, as exhaustive conformational sampling becomes prohibitive due to the presence of many freely-rotatable covalent bonds (Yan et al, 2017;Ansar and Vetrivel, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…This step completed the preparation of the peptide library containing 9,261 D-tripeptides and 194,481 D-tetrapeptides. Libraries of larger peptides were not prepared, as docking algorithms tend to produce less accurate results for molecules bearing many freely-rotatable bonds (Rentzsch and Renard, 2015;Ciemny et al, 2018;Hashemi et al, 2021).…”

Section: Preparation Of the Protein Structure For Virtual Screening A...mentioning

confidence: 99%

“…In several cases, this approach has led to the successful identification of compounds displaying in vitro inhibitory activity against 3CL pro (Ghahremanpour et al, 2020;Gupta et al, 2020;Jin et al, 2020;Li et al, 2020;Alves et al, 2021;Banerjee et al, 2021;Gunther et al, 2021;Guo et al, 2021;Gupta et al, 2021;Hamdy et al, 2021;Pathak et al, 2021;Yang et al, 2021). On the other hand, protein-peptide docking remains far more challenging compared to other small molecules due to the higher flexibility of peptides (Rentzsch and Renard, 2015;Ciemny et al, 2018;Hashemi et al, 2021). Nonetheless, at least one work has reported two L-pentapeptides as potential 3CL pro inhibitors by screening a 70,000-peptide library (Porto, 2021), using AutoDock Vina for the docking simulations (Trott and Olson, 2010).…”

Section: Introductionmentioning

confidence: 99%

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A Computer-Aided Approach for the Discovery of D-Peptides as Inhibitors of SARS-CoV-2 Main Protease

González

Eberle

Willbold

et al. 2022

Front. Mol. Biosci.

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The SARS-CoV-2 main protease, also known as 3-chymotrypsin-like protease (3CLpro), is a cysteine protease responsible for the cleavage of viral polyproteins pp1a and pp1ab, at least, at eleven conserved sites, which leads to the formation of mature nonstructural proteins essential for the replication of the virus. Due to its essential role, numerous studies have been conducted so far, which have confirmed 3CLpro as an attractive drug target to combat Covid-19 and have reported a vast number of inhibitors and their co-crystal structures. Despite all the ongoing efforts, D-peptides, which possess key advantages over L-peptides as therapeutic agents, have not been explored as potential drug candidates against 3CLpro. The current work fills this gap by reporting an in silico approach for the discovery of D-peptides capable of inhibiting 3CLpro that involves structure-based virtual screening (SBVS) of an in-house library of D-tripeptides and D-tetrapeptides into the protease active site and subsequent rescoring steps, including Molecular Mechanics Generalized-Born Surface Area (MM-GBSA) free energy calculations and molecular dynamics (MD) simulations. In vitro enzymatic assays conducted for the four top-scoring D-tetrapeptides at 20 μM showed that all of them caused 55–85% inhibition of 3CLpro activity, thus highlighting the suitability of the devised approach. Overall, our results present a promising computational strategy to identify D-peptides capable of inhibiting 3CLpro, with broader application in problems involving protein inhibition.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Preparation Of the Protein Structure For Virtual Screening A...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A Computer-Aided Approach for the Discovery of D-Peptides as Inhibitors of SARS-CoV-2 Main Protease

González

Eberle

Willbold

et al. 2022

Front. Mol. Biosci.

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“…These amino acids could be determined in vitro or silico (using bioinformatics tools). Bioinformatics is an expanding field applied in rapid and accurate diagnosis of diseases using protein biomarkers (Hashemi et al 2019 ; Jamadi et al 2020 ; Khalili et al 2017 ; Khodashenas et al 2019 ; Mard-Soltani et al 2018 ; Rahbar et al 2019 ; Ramezani et al 2019 ), cost-effective production of vaccines (Asadi-Ghalehni et al 2018 ; Asadi-Ghalehni et al 2017 ), design of newer and more effective drugs (Hashemi et al 2021 ; Pourzardosht et al 2020 ), improving the quality and quantity of agricultural products, and a better understanding of the biological mechanisms (Noori et al 2020 ). Recently, an engineered ACE2 was designed and evaluated as a novel therapeutics against COVID-19 (Payandeh et al 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Pierce into Structural Changes of Interactions Between Mutated Spike Glycoproteins and ACE2 to Evaluate Its Potential Biological and Therapeutic Consequences

Hashemi

Zarei

Mubarak

et al. 2021

Int J Pept Res Ther

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The structural consequences of ongoing mutations on the SARS-CoV-2 spike-protein remains to be fully elucidated. These mutations could change the binding affinity between the virus and its target cell. Moreover, obtaining new mutations would also change the therapeutic efficacy of the designed drug candidates. To evaluate these consequences, 3D structure of a mutant spike protein was predicted and checked for stability, cavity sites, and residue depth. The docking analyses were performed between the 3D model of the mutated spike protein and the ACE2 protein and an engineered therapeutic ACE2 against COVID-19. The obtained results revealed that the N501Y substitution has altered the interaction orientation, augmented the number of interface bonds, and increased the affinity against the ACE2. On the other hand, the P681H mutation contributed to the increased cavity size and relatively higher residue depth. The binding affinity between the engineered therapeutic ACE2 and the mutant spike was significantly higher with a distinguished binding orientation. It could be concluded that the mutant spike protein increased the affinity, preserved the location, changed the orientation, and altered the interface amino acids of its interaction with both the ACE2 and its therapeutic engineered version. The obtained results corroborate the more aggressive nature of mutated SARS-CoV-2 due to their higher binding affinity. Moreover, designed ACe2-baased therapeutics would be still highly effective against covid-19, which could be the result of conserved nature of cellular ACE2. Supplementary Information The online version contains supplementary material available at 10.1007/s10989-021-10346-1.

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De Novo Rational Design of Peptide‐Based Protein–Protein Inhibitors (Pep‐PPIs) Approach by Mapping the Interaction Motifs of the PP Interface and Physicochemical Filtration: A Case on p25‐Cdk5‐Mediated Neurodegenerative Diseases

Oduro‐Kwateng,

Ali,

Kehinde

et al. 2024

J of Cellular Biochemistry

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Protein–protein interactions, or PPIs, are a part of every biological activity and have been linked to a number of diseases, including cancer, infectious diseases, and neurological disorders. As such, targeting PPIs is considered a strategic and vital approach in the development of new medications. Nonetheless, the wide and flat contact interface makes it difficult to find small‐molecule PP inhibitors. An alternative strategy would be to use the PPI interaction motifs as building blocks for the design of peptide‐based inhibitors. Herein, we designed 12‐mer peptide inhibitors to target p25‐inducing‐cyclin‐dependent kinase (Cdk5) hyperregulation, a PPI that has been shown to perpetuate neuroinflammation, which is one of the major causal implications of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and frontotemporal dementia. We generated a library of 5 062 500 peptide combination sequences (PCS) derived from the interaction motif of Cdk5/p25 PP interface. The 20 amino acids were differentiated into six groups, namely, hydrophobic (aliphatic), aromatic, basic, acidic, unique, and polar uncharged, on the basis of their physiochemical properties. To preserve the interaction motif necessary for ideal binding, de novo modeling of all possible peptide sequence substitutions was considered. A set of filters, backed by the Support Vector Machine (SVM) algorithm, was then used to create a shortlisted custom peptide library that met specific bioavailability, toxicity, and therapeutic relevance, leading to a refined library of 15 PCS. A greedy algorithm and coarse‐grained force field were used to predict peptide structure and folding before subsequent modeling studies. Molecular docking was performed to estimate the relative binding affinities, and out of the top hits, Pep15 was subjected to molecular dynamics simulations and binding free‐energy calculations in comparison to a known peptide inhibitor with experimental data (template peptide). Interestingly, the identified peptide through our protocol, Pep15, was found to show a significantly higher binding affinity than the reference template peptide (−48.10 ± 0.23 kcal/mol and −17.53 ± 0.27 kcal/mol, respectively). In comparison to the template peptide, Pep15 was found to possess a more compact and buried surface area, tighter binding landscape, and reduced conformational variability, leading to enhanced structural and kinetic stability of the Cdk5/p25 complex. Notably, both peptide inhibitors were found to have a minimal impact on the architectural integrity of the Cdk5/p25 secondary structure.Herein, we propose Pep15 as a novel and potentially disruptive peptide drug for Cdk5/p25‐mediated neurodegenerative phenotypes that require further clinical investigation. The systematic protocol and findings of this report would serve as a valuable tool in the identification of critical PPI interface reactive residues, designing of analogs, and identification of more potent peptide‐based PPI inhibitors.

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In silico Approaches for the Design and Optimization of Interfering Peptides Against Protein–Protein Interactions

Cited by 51 publications

References 249 publications

A Computer-Aided Approach for the Discovery of D-Peptides as Inhibitors of SARS-CoV-2 Main Protease

A Computer-Aided Approach for the Discovery of D-Peptides as Inhibitors of SARS-CoV-2 Main Protease

Pierce into Structural Changes of Interactions Between Mutated Spike Glycoproteins and ACE2 to Evaluate Its Potential Biological and Therapeutic Consequences

De Novo Rational Design of Peptide‐Based Protein–Protein Inhibitors (Pep‐PPIs) Approach by Mapping the Interaction Motifs of the PP Interface and Physicochemical Filtration: A Case on p25‐Cdk5‐Mediated Neurodegenerative Diseases

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