Rational Design of Anti‐Epileptic Peptides to Inhibit MAPK/MKP‐2 Interactions for Epilepsy Therapeutics

Mitogen Activated Protein Kinase (MAPK) inhibitory protein is a potent endogenous inhibitor in the neo‐cortex of human for epileptic signaling, also known as DUSP4 (dual specificity phosphate 4). In human epileptic brain the MAPK pathway is activated, importantly in its cortical lamina. MAPK execute...

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Bibliographic Details
Published in:ChemistrySelect (Weinheim) 2022-05, Vol.7 (18), p.n/a
Main Authors: Zaib, Sumera, Akram, Fatima, Liaqat, Syed Talha, Zaib, Zainab, Mustafa, Faisal, Khan, Imtiaz
Format: Article
Language:English
Subjects:
Bioinformatics
Cortical lamina
Molecular Dynamics
PatchDock
Peptide design
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Summary:Mitogen Activated Protein Kinase (MAPK) inhibitory protein is a potent endogenous inhibitor in the neo‐cortex of human for epileptic signaling, also known as DUSP4 (dual specificity phosphate 4). In human epileptic brain the MAPK pathway is activated, importantly in its cortical lamina. MAPK executes its special effects by binding to crystal structure of human MKP‐2. The inhibition of MAPK/MKP‐2 interaction is known as an effective epileptic therapeutic strategy. The present study targeted the construction of an MKP‐2 peptides based on MAPK binding regions. Peptide ranker serves were used to generate the possible peptide library with the prediction of peptides bioactivity. The interaction of MKP‐2 and all library peptides were analyzed using Hex 8.0.0, ClusPro tools and PatchDock. A number of six peptides with favorable docking scores were achieved. The best docking scores of peptides complexed with MKP‐2 were evaluated for their stability using molecular dynamics simulation (MD) with the help of the iMODS. As a result, two peptides with 16 residues of PepA (TICLAYLMMKKRVRL) and PepB (DNHKADISSWFMEAI) were achieved and introduced to inhibit MAPK/MKP‐2 interactions. In summary, PepA and PepB are recommended as a promising antiepileptic agents and suitable candidates for experimental evaluations. Additionally, this study provides new insights into the peptide engineering and development of therapeutics for epilepsy. The Figure depicts the Pep B/MKP‐2 complex with its binding interactions visualized by PyMOL, showing strong and unique bond length and binding interactions between peptide and target at 2.3, 2.1 and 1.8 Å.
ISSN:2365-6549
2365-6549
DOI:10.1002/slct.202200379