Tracing Potential Covalent Inhibitors of an E3 Ubiquitin Ligase through Target-Focused Modelling
Identifieur interne : 000593 ( Main/Exploration ); précédent : 000592; suivant : 000594Tracing Potential Covalent Inhibitors of an E3 Ubiquitin Ligase through Target-Focused Modelling
Auteurs : Imane Bjij [Afrique du Sud, Maroc] ; Pritika Ramharack [Afrique du Sud] ; Shama Khan [Afrique du Sud] ; Driss Cherqaoui [Maroc] ; Mahmoud E. S. Soliman [Afrique du Sud]Source :
- Molecules [ 1420-3049 ] ; 2019.
Descripteurs français
- KwdFr :
- Antienzymes (composition chimique), Antienzymes (pharmacologie), Cystéine (métabolisme), Découverte de médicament (MeSH), Humains (MeSH), Liaison hydrogène (MeSH), Modèles moléculaires (MeSH), Relation structure-activité (MeSH), Simulation de docking moléculaire (MeSH), Simulation de dynamique moléculaire (MeSH), Simulation numérique (MeSH), Sites de fixation (MeSH), Structure moléculaire (MeSH), Ubiquitin-protein ligases (antagonistes et inhibiteurs), Ubiquitin-protein ligases (composition chimique).
- MESH :
- antagonistes et inhibiteurs : Ubiquitin-protein ligases.
- composition chimique : Antienzymes, Ubiquitin-protein ligases.
- métabolisme : Cystéine.
- pharmacologie : Antienzymes.
- Découverte de médicament, Humains, Liaison hydrogène, Modèles moléculaires, Relation structure-activité, Simulation de docking moléculaire, Simulation de dynamique moléculaire, Simulation numérique, Sites de fixation, Structure moléculaire.
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.
Url:
DOI: 10.3390/molecules24173125
PubMed: 31466292
PubMed Central: 6749425
Affiliations:
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My Abdellah, BP2390 Marrakech, Morocco</nlm:aff><country xml:lang="fr">Maroc</country><wicri:regionArea>Département de Chimie, Faculté des Sciences Semlalia, Université Cadi Ayyad, Av. My Abdellah, BP2390 Marrakech</wicri:regionArea></affiliation></author><author><name sortKey="Ramharack, Pritika" sort="Ramharack, Pritika" uniqKey="Ramharack P" first="Pritika" last="Ramharack">Pritika Ramharack</name><affiliation wicri:level="1"><nlm:aff id="af1-molecules-24-03125">Molecular Bio-Computation & Drug Design Lab, School of Health Sciences, University of KwaZulu-Natal, Westville, Durban 4000, South Africa</nlm:aff><country xml:lang="fr">Afrique du Sud</country><wicri:regionArea>Molecular Bio-Computation & Drug Design Lab, School of Health Sciences, University of KwaZulu-Natal, Westville, Durban 4000</wicri:regionArea></affiliation></author><author><name sortKey="Khan, Shama" sort="Khan, Shama" uniqKey="Khan S" first="Shama" last="Khan">Shama Khan</name><affiliation wicri:level="1"><nlm:aff id="af3-molecules-24-03125">Department of Clinical Microbiology and Infectious Diseases, School of Pathology, University of the Witwatersrand, Johannesburg 2193, South Africa</nlm:aff><country xml:lang="fr">Afrique du Sud</country><wicri:regionArea>Department of Clinical Microbiology and Infectious Diseases, School of Pathology, University of the Witwatersrand, Johannesburg 2193</wicri:regionArea></affiliation></author><author><name sortKey="Cherqaoui, Driss" sort="Cherqaoui, Driss" uniqKey="Cherqaoui D" first="Driss" last="Cherqaoui">Driss Cherqaoui</name><affiliation wicri:level="1"><nlm:aff id="af2-molecules-24-03125">Département de Chimie, Faculté des Sciences Semlalia, Université Cadi Ayyad, Av. My Abdellah, BP2390 Marrakech, Morocco</nlm:aff><country xml:lang="fr">Maroc</country><wicri:regionArea>Département de Chimie, Faculté des Sciences Semlalia, Université Cadi Ayyad, Av. My Abdellah, BP2390 Marrakech</wicri:regionArea></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 wicri:level="1"><nlm:aff id="af1-molecules-24-03125">Molecular Bio-Computation & Drug Design Lab, School of Health Sciences, University of KwaZulu-Natal, Westville, Durban 4000, South Africa</nlm:aff><country xml:lang="fr">Afrique du Sud</country><wicri:regionArea>Molecular Bio-Computation & Drug Design Lab, School of Health Sciences, University of KwaZulu-Natal, Westville, Durban 4000</wicri:regionArea></affiliation></author></analytic><series><title level="j">Molecules</title><idno type="eISSN">1420-3049</idno><imprint><date when="2019">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="KwdFr" xml:lang="fr"><term>Antienzymes (composition chimique)</term><term>Antienzymes (pharmacologie)</term><term>Cystéine (métabolisme)</term><term>Découverte de médicament (MeSH)</term><term>Humains (MeSH)</term><term>Liaison hydrogène (MeSH)</term><term>Modèles moléculaires (MeSH)</term><term>Relation structure-activité (MeSH)</term><term>Simulation de docking moléculaire (MeSH)</term><term>Simulation de dynamique moléculaire (MeSH)</term><term>Simulation numérique (MeSH)</term><term>Sites de fixation (MeSH)</term><term>Structure moléculaire (MeSH)</term><term>Ubiquitin-protein ligases (antagonistes et inhibiteurs)</term><term>Ubiquitin-protein ligases (composition chimique)</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" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Ubiquitin-protein ligases</term></keywords><keywords scheme="MESH" qualifier="composition chimique" xml:lang="fr"><term>Antienzymes</term><term>Ubiquitin-protein ligases</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Cystéine</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antienzymes</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><keywords scheme="MESH" xml:lang="fr"><term>Découverte de médicament</term><term>Humains</term><term>Liaison hydrogène</term><term>Modèles moléculaires</term><term>Relation structure-activité</term><term>Simulation de docking moléculaire</term><term>Simulation de dynamique moléculaire</term><term>Simulation numérique</term><term>Sites de fixation</term><term>Structure moléculaire</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>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.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Rotin, D" uniqKey="Rotin D">D. Rotin</name></author><author><name sortKey="Kumar, S" uniqKey="Kumar S">S. 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Soliman</name></country><country name="Maroc"><noRegion><name sortKey="Bjij, Imane" sort="Bjij, Imane" uniqKey="Bjij I" first="Imane" last="Bjij">Imane Bjij</name></noRegion><name sortKey="Cherqaoui, Driss" sort="Cherqaoui, Driss" uniqKey="Cherqaoui D" first="Driss" last="Cherqaoui">Driss Cherqaoui</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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