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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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| Published in: | ChemistrySelect (Weinheim) 2022-05, Vol.7 (18), p.n/a |
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| creator | Zaib, Sumera Akram, Fatima Liaqat, Syed Talha Zaib, Zainab Mustafa, Faisal Khan, Imtiaz |
| description | 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. |
| doi_str_mv | 10.1002/slct.202200379 |
| format | article |
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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.</description><identifier>ISSN: 2365-6549</identifier><identifier>EISSN: 2365-6549</identifier><identifier>DOI: 10.1002/slct.202200379</identifier><language>eng</language><subject>Bioinformatics ; Cortical lamina ; Molecular Dynamics ; PatchDock ; Peptide design</subject><ispartof>ChemistrySelect (Weinheim), 2022-05, Vol.7 (18), p.n/a</ispartof><rights>2022 Wiley‐VCH GmbH</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c1599-6a503a02f35925c8bcd106079f9aa092d511e212fd690e13024ae63a364bcd333</cites><orcidid>0000-0001-5331-110X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fslct.202200379$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fslct.202200379$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>315,786,790,27957,27958,50923,51032</link.rule.ids></links><search><creatorcontrib>Zaib, Sumera</creatorcontrib><creatorcontrib>Akram, Fatima</creatorcontrib><creatorcontrib>Liaqat, Syed Talha</creatorcontrib><creatorcontrib>Zaib, Zainab</creatorcontrib><creatorcontrib>Mustafa, Faisal</creatorcontrib><creatorcontrib>Khan, Imtiaz</creatorcontrib><title>Rational Design of Anti‐Epileptic Peptides to Inhibit MAPK/MKP‐2 Interactions for Epilepsy Therapeutics</title><title>ChemistrySelect (Weinheim)</title><description>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.</description><subject>Bioinformatics</subject><subject>Cortical lamina</subject><subject>Molecular Dynamics</subject><subject>PatchDock</subject><subject>Peptide design</subject><issn>2365-6549</issn><issn>2365-6549</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><recordid>eNqFkEFOwzAQRS0EElXplrUvkHZs1069jEqBqq2ooKwj17GpISRRbIS66xE4IyfBURGwY_VHM_99jT5ClwSGBICOfKnDkAKlACyVJ6hHmeCJ4GN5-mc-RwPvnwGAiImgPO2hl3sVXF2pEl8Z754qXFucVcF9Hj5mjStNE5zG604K43Go8bzaua0LeJWtF6PVYh2NNC6DaZXukjy2dYuPrN_jzS4eGvMWY_wFOrOq9GbwrX30eD3bTG-T5d3NfJotE024lIlQHJgCahmXlOvJVhcEBKTSSqVA0oITYiihthASDGFAx8oIppgYRytjrI-Gx1zd1t63xuZN615Vu88J5F1beddW_tNWBOQReI9f7_9x5w_L6eaX_QIs_HBS</recordid><startdate>20220513</startdate><enddate>20220513</enddate><creator>Zaib, Sumera</creator><creator>Akram, Fatima</creator><creator>Liaqat, Syed Talha</creator><creator>Zaib, Zainab</creator><creator>Mustafa, Faisal</creator><creator>Khan, Imtiaz</creator><scope>AAYXX</scope><scope>CITATION</scope><orcidid>https://orcid.org/0000-0001-5331-110X</orcidid></search><sort><creationdate>20220513</creationdate><title>Rational Design of Anti‐Epileptic Peptides to Inhibit MAPK/MKP‐2 Interactions for Epilepsy Therapeutics</title><author>Zaib, Sumera ; Akram, Fatima ; Liaqat, Syed Talha ; Zaib, Zainab ; Mustafa, Faisal ; Khan, Imtiaz</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c1599-6a503a02f35925c8bcd106079f9aa092d511e212fd690e13024ae63a364bcd333</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Bioinformatics</topic><topic>Cortical lamina</topic><topic>Molecular Dynamics</topic><topic>PatchDock</topic><topic>Peptide design</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zaib, Sumera</creatorcontrib><creatorcontrib>Akram, Fatima</creatorcontrib><creatorcontrib>Liaqat, Syed Talha</creatorcontrib><creatorcontrib>Zaib, Zainab</creatorcontrib><creatorcontrib>Mustafa, Faisal</creatorcontrib><creatorcontrib>Khan, Imtiaz</creatorcontrib><collection>CrossRef</collection><jtitle>ChemistrySelect (Weinheim)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zaib, Sumera</au><au>Akram, Fatima</au><au>Liaqat, Syed Talha</au><au>Zaib, Zainab</au><au>Mustafa, Faisal</au><au>Khan, Imtiaz</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Rational Design of Anti‐Epileptic Peptides to Inhibit MAPK/MKP‐2 Interactions for Epilepsy Therapeutics</atitle><jtitle>ChemistrySelect (Weinheim)</jtitle><date>2022-05-13</date><risdate>2022</risdate><volume>7</volume><issue>18</issue><epage>n/a</epage><issn>2365-6549</issn><eissn>2365-6549</eissn><notes>Mitogen‐activated protein kinase</notes><abstract>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.</abstract><doi>10.1002/slct.202200379</doi><tpages>7</tpages><orcidid>https://orcid.org/0000-0001-5331-110X</orcidid></addata></record> |
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| subjects | Bioinformatics Cortical lamina Molecular Dynamics PatchDock Peptide design |
| title | Rational Design of Anti‐Epileptic Peptides to Inhibit MAPK/MKP‐2 Interactions for Epilepsy Therapeutics |
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