Tracing Potential Covalent Inhibitors of an E3 Ubiquitin Ligase through Target-Focused Modelling.
Identifieur interne : 000227 ( PubMed/Corpus ); précédent : 000226; suivant : 000228Tracing Potential Covalent Inhibitors of an E3 Ubiquitin Ligase through Target-Focused Modelling.
Auteurs : Imane Bjij ; Pritika Ramharack ; Shama Khan ; Driss Cherqaoui ; Mahmoud E S. SolimanSource :
- Molecules (Basel, Switzerland) [ 1420-3049 ] ; 2019.
English descriptors
- KwdEn :
- Binding Sites (MeSH), Computer Simulation (MeSH), Cysteine (metabolism), Drug Discovery (MeSH), Enzyme Inhibitors (chemistry), Enzyme Inhibitors (pharmacology), Humans (MeSH), Hydrogen Bonding (MeSH), Models, Molecular (MeSH), Molecular Docking Simulation (MeSH), Molecular Dynamics Simulation (MeSH), Molecular Structure (MeSH), Structure-Activity Relationship (MeSH), Ubiquitin-Protein Ligases (antagonists & inhibitors), Ubiquitin-Protein Ligases (chemistry).
- MESH :
- chemical , antagonists & inhibitors : Ubiquitin-Protein Ligases.
- chemical , chemistry : Enzyme Inhibitors, Ubiquitin-Protein Ligases.
- chemical , metabolism : Cysteine.
- chemical , pharmacology : Enzyme Inhibitors.
- Binding Sites, Computer Simulation, Drug Discovery, Humans, Hydrogen Bonding, Models, Molecular, Molecular Docking Simulation, Molecular Dynamics Simulation, Molecular Structure, Structure-Activity Relationship.
Abstract
The Nedd4-1 E3 Ubiquitin ligase has been implicated in multiple disease conditions due its overexpression. Although the enzyme may be targeted both covalently and non-covalently, minimal studies provide effective inhibitors against it. Recently, research has focused on covalent inhibitors based on their characteristic, highly-selective warheads and ability to prevent drug resistance. This prompted us to screen for new covalent inhibitors of Nedd4-1 using a combination of computational approaches. However, this task proved challenging due to the limited number of electrophilic moieties available in virtual libraries. Therefore, we opted to divide an existing covalent Nedd4-1 inhibitor into two parts: a non-covalent binding group and a pre-selected α, β-unsaturated ester that forms the covalent linkage with the protein. A non-covalent pharmacophore model was built based on molecular interactions at the binding site. The pharmacophore was then subjected to virtual screening to identify structurally similar hit compounds. Multiple filtrations were implemented prior to selecting four hits, which were validated with a covalent conjugation and later assessed by molecular dynamic simulations. The results showed that, of the four hit molecules, Zinc00937975 exhibited advantageous molecular groups, allowing for favourable interactions with one of the characteristic cysteine residues. Predictive pharmacokinetic analysis further justified the compound as a potential lead molecule, prompting its recommendation for confirmatory biological evaluation. Our inhouse, refined, pharmacophore model approach serves as a robust method that will encourage screening for novel covalent inhibitors in drug discovery.
DOI: 10.3390/molecules24173125
PubMed: 31466292
PubMed Central: PMC6749425
Links to Exploration step
pubmed:31466292Le document en format XML
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My Abdellah, BP2390 Marrakech, Morocco.</nlm:affiliation></affiliation></author><author><name sortKey="Soliman, Mahmoud E S" sort="Soliman, Mahmoud E S" uniqKey="Soliman M" first="Mahmoud E S" last="Soliman">Mahmoud E S. Soliman</name><affiliation><nlm:affiliation>Molecular Bio-Computation & Drug Design Lab, School of Health Sciences, University of KwaZulu-Natal, Westville, Durban 4000, South Africa. soliman@ukzn.ac.za.</nlm:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2019">2019</date><idno type="RBID">pubmed:31466292</idno><idno type="pmid">31466292</idno><idno type="doi">10.3390/molecules24173125</idno><idno type="pmc">PMC6749425</idno><idno type="wicri:Area/PubMed/Corpus">000227</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000227</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Tracing Potential Covalent Inhibitors of an E3 Ubiquitin Ligase through Target-Focused Modelling.</title><author><name sortKey="Bjij, Imane" sort="Bjij, Imane" uniqKey="Bjij I" first="Imane" last="Bjij">Imane Bjij</name><affiliation><nlm:affiliation>Molecular Bio-Computation & Drug Design Lab, School of Health Sciences, University of KwaZulu-Natal, Westville, Durban 4000, South Africa.</nlm:affiliation></affiliation><affiliation><nlm:affiliation>Département de Chimie, Faculté des Sciences Semlalia, Université Cadi Ayyad, Av. My Abdellah, BP2390 Marrakech, Morocco.</nlm:affiliation></affiliation></author><author><name sortKey="Ramharack, Pritika" sort="Ramharack, Pritika" uniqKey="Ramharack P" first="Pritika" last="Ramharack">Pritika Ramharack</name><affiliation><nlm:affiliation>Molecular Bio-Computation & Drug Design Lab, School of Health Sciences, University of KwaZulu-Natal, Westville, Durban 4000, South Africa.</nlm:affiliation></affiliation></author><author><name sortKey="Khan, Shama" sort="Khan, Shama" uniqKey="Khan S" first="Shama" last="Khan">Shama Khan</name><affiliation><nlm:affiliation>Department of Clinical Microbiology and Infectious Diseases, School of Pathology, University of the Witwatersrand, Johannesburg 2193, South Africa.</nlm:affiliation></affiliation></author><author><name sortKey="Cherqaoui, Driss" sort="Cherqaoui, Driss" uniqKey="Cherqaoui D" first="Driss" last="Cherqaoui">Driss Cherqaoui</name><affiliation><nlm:affiliation>Département de Chimie, Faculté des Sciences Semlalia, Université Cadi Ayyad, Av. My Abdellah, BP2390 Marrakech, Morocco.</nlm:affiliation></affiliation></author><author><name sortKey="Soliman, Mahmoud E S" sort="Soliman, Mahmoud E S" uniqKey="Soliman M" first="Mahmoud E S" last="Soliman">Mahmoud E S. Soliman</name><affiliation><nlm:affiliation>Molecular Bio-Computation & Drug Design Lab, School of Health Sciences, University of KwaZulu-Natal, Westville, Durban 4000, South Africa. soliman@ukzn.ac.za.</nlm:affiliation></affiliation></author></analytic><series><title level="j">Molecules (Basel, Switzerland)</title><idno type="eISSN">1420-3049</idno><imprint><date when="2019" type="published">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Binding Sites (MeSH)</term><term>Computer Simulation (MeSH)</term><term>Cysteine (metabolism)</term><term>Drug Discovery (MeSH)</term><term>Enzyme Inhibitors (chemistry)</term><term>Enzyme Inhibitors (pharmacology)</term><term>Humans (MeSH)</term><term>Hydrogen Bonding (MeSH)</term><term>Models, Molecular (MeSH)</term><term>Molecular Docking Simulation (MeSH)</term><term>Molecular Dynamics Simulation (MeSH)</term><term>Molecular Structure (MeSH)</term><term>Structure-Activity Relationship (MeSH)</term><term>Ubiquitin-Protein Ligases (antagonists & inhibitors)</term><term>Ubiquitin-Protein Ligases (chemistry)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Ubiquitin-Protein Ligases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Enzyme Inhibitors</term><term>Ubiquitin-Protein Ligases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Cysteine</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Enzyme Inhibitors</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Binding Sites</term><term>Computer Simulation</term><term>Drug Discovery</term><term>Humans</term><term>Hydrogen Bonding</term><term>Models, Molecular</term><term>Molecular Docking Simulation</term><term>Molecular Dynamics Simulation</term><term>Molecular Structure</term><term>Structure-Activity Relationship</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The Nedd4-1 E3 Ubiquitin ligase has been implicated in multiple disease conditions due its overexpression. Although the enzyme may be targeted both covalently and non-covalently, minimal studies provide effective inhibitors against it. Recently, research has focused on covalent inhibitors based on their characteristic, highly-selective warheads and ability to prevent drug resistance. This prompted us to screen for new covalent inhibitors of Nedd4-1 using a combination of computational approaches. However, this task proved challenging due to the limited number of electrophilic moieties available in virtual libraries. Therefore, we opted to divide an existing covalent Nedd4-1 inhibitor into two parts: a non-covalent binding group and a pre-selected α, β-unsaturated ester that forms the covalent linkage with the protein. A non-covalent pharmacophore model was built based on molecular interactions at the binding site. The pharmacophore was then subjected to virtual screening to identify structurally similar hit compounds. Multiple filtrations were implemented prior to selecting four hits, which were validated with a covalent conjugation and later assessed by molecular dynamic simulations. The results showed that, of the four hit molecules, Zinc00937975 exhibited advantageous molecular groups, allowing for favourable interactions with one of the characteristic cysteine residues. Predictive pharmacokinetic analysis further justified the compound as a potential lead molecule, prompting its recommendation for confirmatory biological evaluation. Our inhouse, refined, pharmacophore model approach serves as a robust method that will encourage screening for novel covalent inhibitors in drug discovery.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">31466292</PMID><DateCompleted><Year>2020</Year><Month>01</Month><Day>21</Day></DateCompleted><DateRevised><Year>2020</Year><Month>02</Month><Day>25</Day></DateRevised><Article PubModel="Electronic"><Journal><ISSN IssnType="Electronic">1420-3049</ISSN><JournalIssue CitedMedium="Internet"><Volume>24</Volume><Issue>17</Issue><PubDate><Year>2019</Year><Month>Aug</Month><Day>28</Day></PubDate></JournalIssue><Title>Molecules (Basel, Switzerland)</Title><ISOAbbreviation>Molecules</ISOAbbreviation></Journal><ArticleTitle>Tracing Potential Covalent Inhibitors of an E3 Ubiquitin Ligase through Target-Focused Modelling.</ArticleTitle><ELocationID EIdType="pii" ValidYN="Y">E3125</ELocationID><ELocationID EIdType="doi" ValidYN="Y">10.3390/molecules24173125</ELocationID><Abstract><AbstractText>The Nedd4-1 E3 Ubiquitin ligase has been implicated in multiple disease conditions due its overexpression. Although the enzyme may be targeted both covalently and non-covalently, minimal studies provide effective inhibitors against it. Recently, research has focused on covalent inhibitors based on their characteristic, highly-selective warheads and ability to prevent drug resistance. This prompted us to screen for new covalent inhibitors of Nedd4-1 using a combination of computational approaches. However, this task proved challenging due to the limited number of electrophilic moieties available in virtual libraries. Therefore, we opted to divide an existing covalent Nedd4-1 inhibitor into two parts: a non-covalent binding group and a pre-selected α, β-unsaturated ester that forms the covalent linkage with the protein. A non-covalent pharmacophore model was built based on molecular interactions at the binding site. The pharmacophore was then subjected to virtual screening to identify structurally similar hit compounds. Multiple filtrations were implemented prior to selecting four hits, which were validated with a covalent conjugation and later assessed by molecular dynamic simulations. The results showed that, of the four hit molecules, Zinc00937975 exhibited advantageous molecular groups, allowing for favourable interactions with one of the characteristic cysteine residues. Predictive pharmacokinetic analysis further justified the compound as a potential lead molecule, prompting its recommendation for confirmatory biological evaluation. Our inhouse, refined, pharmacophore model approach serves as a robust method that will encourage screening for novel covalent inhibitors in drug discovery.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Bjij</LastName><ForeName>Imane</ForeName><Initials>I</Initials><AffiliationInfo><Affiliation>Molecular Bio-Computation & Drug Design Lab, School of Health Sciences, University of KwaZulu-Natal, Westville, Durban 4000, South Africa.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Département de Chimie, Faculté des Sciences Semlalia, Université Cadi Ayyad, Av. My Abdellah, BP2390 Marrakech, Morocco.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ramharack</LastName><ForeName>Pritika</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Molecular Bio-Computation & Drug Design Lab, School of Health Sciences, University of KwaZulu-Natal, Westville, Durban 4000, South Africa.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Khan</LastName><ForeName>Shama</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Department of Clinical Microbiology and Infectious Diseases, School of Pathology, University of the Witwatersrand, Johannesburg 2193, South Africa.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Cherqaoui</LastName><ForeName>Driss</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Département de Chimie, Faculté des Sciences Semlalia, Université Cadi Ayyad, Av. My Abdellah, BP2390 Marrakech, Morocco.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Soliman</LastName><ForeName>Mahmoud E S</ForeName><Initials>MES</Initials><AffiliationInfo><Affiliation>Molecular Bio-Computation & Drug Design Lab, School of Health Sciences, University of KwaZulu-Natal, Westville, Durban 4000, South Africa. soliman@ukzn.ac.za.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>N/A</GrantID><Agency>College of Health Sciences, University of KwaZulu-Natal</Agency><Country></Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2019</Year><Month>08</Month><Day>28</Day></ArticleDate></Article><MedlineJournalInfo><Country>Switzerland</Country><MedlineTA>Molecules</MedlineTA><NlmUniqueID>100964009</NlmUniqueID><ISSNLinking>1420-3049</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D004791">Enzyme Inhibitors</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.3.2.27</RegistryNumber><NameOfSubstance UI="D044767">Ubiquitin-Protein Ligases</NameOfSubstance></Chemical><Chemical><RegistryNumber>K848JZ4886</RegistryNumber><NameOfSubstance UI="D003545">Cysteine</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D001665" MajorTopicYN="N">Binding Sites</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D003198" MajorTopicYN="N">Computer Simulation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D003545" 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