Structure-based approach to the design of BakBH3 mimetic peptides with increased helical propensity

Delgado-Soler, Laura; Orzáez, Mar; Rubio-Martínez, Jaime

doi:10.1007/s00894-013-1944-3

Cited by 4 publications

(7 citation statements)

References 42 publications

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“…Experimental studies as well as computational studies reveal that BH3 peptides do not exhibit a helical structure in solution ( Petros et al, 2000 ; Perez et al, 2016 ). In order to avoid negative configurational entropy effects, the affinity of the analogs can be increased by designing analogs that enhance the bioactive conformation population in solution by embedding helix enhancer residues in the sequence ( Delgado-Soler et al, 2013 ). An alternative approach focused on constraining the helical structure of the analogs in solution.…”

Section: The Bh3-bcl-2 Interactionmentioning

confidence: 99%

Computational Modeling as a Tool to Investigate PPI: From Drug Design to Tissue Engineering

Pérez

2021

Front. Mol. Biosci.

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Protein-protein interactions (PPIs) mediate a large number of important regulatory pathways. Their modulation represents an important strategy for discovering novel therapeutic agents. However, the features of PPI binding surfaces make the use of structure-based drug discovery methods very challenging. Among the diverse approaches used in the literature to tackle the problem, linear peptides have demonstrated to be a suitable methodology to discover PPI disruptors. Unfortunately, the poor pharmacokinetic properties of linear peptides prevent their direct use as drugs. However, they can be used as models to design enzyme resistant analogs including, cyclic peptides, peptide surrogates or peptidomimetics. Small molecules have a narrower set of targets they can bind to, but the screening technology based on virtual docking is robust and well tested, adding to the computational tools used to disrupt PPI. We review computational approaches used to understand and modulate PPI and highlight applications in a few case studies involved in physiological processes such as cell growth, apoptosis and intercellular communication.

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Section: The Bh3-bcl-2 Interactionmentioning

confidence: 99%

Computational Modeling as a Tool to Investigate PPI: From Drug Design to Tissue Engineering

Pérez

2021

Front. Mol. Biosci.

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“…They act through modifying mitochondrial membrane integrity and function, and also affect apoptotic signaling. The Bcl-2 family consists of three subgroups, pro-survival proteins (BCL2, BCLxl [BCL2L1], BCLw [BCL2L2], MCL-1, and A1), multi-domain pro-apoptotic proteins (BAX and BAK), and BH3 domain-only pro-apoptotic proteins (BIM, PUMA [BBC3], BID, BAD, BIK, BMF, HRK, and NOXA [PMAIP1]) ( 17 – 19 ). As an important anti-apoptotic protein in the Bcl-2 family, inhibition of MCL-1 promotes cell death through the mitochondrial pathway and there is some data suggesting it is also involved in the apoptosis that occurs during cerebral ischemic reperfusion ( 20 ).…”

Section: Discussionmentioning

confidence: 99%

miR‑29b affects neurocyte apoptosis by targeting MCL‑1 during cerebral ischemia/reperfusion injury

Huang

Lu²,

Jiang

et al. 2018

Exp Ther Med

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The present study aimed to determine whether an miRNA (miR)-29b inhibitor protected against cerebral ischemia/reperfusion (I/R) injury in vitro and to investigate the underlying mechanisms. As a model for induced cerebral IR injury, N2a cells were exposed to an oxygen-glucose deprivation/reoxygenation (OGD/R) environment. Using this model, it was demonstrated that miR-29b was significantly upregulated compared with cells in a normal environment. The interactions between miR-29b and myeloid cell leukemia sequence (MCL)-1 were then investigated using dual-luciferase assays, revealing a strong regulation of MCL-1 through the 3′untranslated region. Using the OGD/R model, the present study additionally examined the effects of miR-29b and miR-29b inhibitor on cell viability and apoptosis using Cell Counting kit 8 and flow cytometry assays, respectively. miR-29b transfection led to increased N2a cell apoptosis and reduced cell viability under an OGD/R environment. However, this effect was reversed by the miR-29b inhibitor. Finally, the effects of miR-29b on the expression of several Wnt-associating proteins were examined. It was observed that B cell lymphoma-2 was inhibited by miR-29b, as was MCL-1, whereas caspase-3 expression was promoted. The miR-29b inhibitor demonstrated the opposite effect. Overall, miR-29b promoted neurocyte apoptosis by targeting MCL-1 during cerebral I/R injury. The results of the present study suggest a potential novel therapeutic target for the treatment of ischemic stroke.

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“…31,32 The Bak/BidAib 2 complex has two special residues, the α-aminoisobutyric acid residues (Aib), which are used because of their strong helicogenic tendency, as they can promote helical folding in synthetic and natural sequences. 33,34 This complex was used to determine whether the use of BH3 mimetic peptides with an increased helical content can improve the binding affinity. Moreover, it is important to analyze if these residues have any implication on the molecular determinants of the Bak/BH3 interaction.…”

Section: ■ Methodsmentioning

confidence: 99%

“…Parameters for the h3Pc nonnatural residue were obtained using the distance, angles, and dihedrals from glutamate, whereas the missing parameters were obtained using the general amber force field . Charges were generated with the restrained electrostatic potential at the HF/6-31G* level, which is the default charge approach applied in Amber protein force fields. , The Bak/BidAib 2 complex has two special residues, the α-aminoisobutyric acid residues (Aib), which are used because of their strong helicogenic tendency, as they can promote helical folding in synthetic and natural sequences. , This complex was used to determine whether the use of BH3 mimetic peptides with an increased helical content can improve the binding affinity. Moreover, it is important to analyze if these residues have any implication on the molecular determinants of the Bak/BH3 interaction.…”

Section: Methodsmentioning

confidence: 99%

Molecular Determinants for the Activation/Inhibition of Bak Protein by BH3 Peptides

Vila-Julià

Granadino‐Roldán

Pérez

et al. 2020

J. Chem. Inf. Model.

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Apoptosis is a key cell death pathway in mammalian cells. Understanding this process and its regulation has been a subject of study in the last three decades. Members of the Bcl-2 family of proteins are involved in the regulation of apoptosis through mitochondrial poration with the subsequent initiation of apoptosis. Deregulation of proapoptotic proteins contributes to the progression of many tumor processes. Understanding how these pore-forming Bcl-2 proteins Bak and Bax are activated is key to find new anticancer treatments. As no drug capable of activating Bak has been disclosed yet, the study of the structural features of BH3 peptides−known as Bak activators−relevant for binding along with its binding energy decomposition analysis, becomes essential for designing novel small-molecule mimics of BH3. Interestingly, a BH3 Bim analogue-inactivating Bak has recently been discovered, opening a question on the molecular features that determine the functions of BH3 peptides. Therefore, the present work is aimed at understanding the way BH3 peptides activate or inactivate Bak in order to identify differential structural features that can be used in drug design. For this purpose, complexes of Bak with an activator and an inhibitor have been subjected to a molecular dynamics study. Structural differences were assessed by means of the fluctuations of the corresponding principal components. Moreover, the MMPB/GBSA approach was used to compute the binding free energy of the diverse complexes to identify those residues of the BH3 peptide that exhibit the larger contributions to complex formation. The results obtained in this work show differences between activators and inhibitors, both in structural and energetic terms, which can be used in the design of new molecules that can activate or inactivate proapoptotic Bak.

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Structure-based approach to the design of BakBH3 mimetic peptides with increased helical propensity

Cited by 4 publications

References 42 publications

Computational Modeling as a Tool to Investigate PPI: From Drug Design to Tissue Engineering

Computational Modeling as a Tool to Investigate PPI: From Drug Design to Tissue Engineering

miR‑29b affects neurocyte apoptosis by targeting MCL‑1 during cerebral ischemia/reperfusion injury

Molecular Determinants for the Activation/Inhibition of Bak Protein by BH3 Peptides

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