Dissertation/ Thesis
Rational design and preliminary validation of novel glutaminase C modulators
| Τίτλος: | Rational design and preliminary validation of novel glutaminase C modulators |
|---|---|
| Συγγραφείς: | Zammit, Lara (2021) |
| Στοιχεία εκδότη: | University of Malta Faculty of Medicine and Surgery. Department of Pharmacy |
| Έτος έκδοσης: | 2021 |
| Συλλογή: | University of Malta: OAR@UM / L-Università ta' Malta |
| Θεματικοί όροι: | Cancer -- Treatment, Cancer cells -- Growth -- Regulation, Enzyme inhibitors, Drug development -- Computer simulation, Ligand binding (Biochemistry) -- Computer simulation, Pharmaceutical chemistry -- Computer simulation |
| Περιγραφή: | M.Pharm.(Melit.) ; Glutaminolysis is a process which drives cell proliferation in tumours. This process is driven by Glutaminase C (Gc). Literature indicates that Gc is over-expressed in solid tumours mainly those of the lung and that its antagonism could inhibit tumour growth. The objective in this study is to design & identify novel Gc modulators through Virtual Screening (VS) & de novo design. The design of this project uses high affinity Gc inhibitor experimental molecule CB-839, used as a lead for the identification of optimised analogues using VS. A consensus pharmacophore was generated by superimposing pharmacophores of inhibitor molecules obtained from PDB crystallographic depositions 5HL1 & 5WJ6 using Ligand Scout®. Sybyl-X® was used to model a protomol; followed by docking of hits obtained through VS. The ligand binding affinities of the 2 hit molecular structures were calculated in Sybyl-X®. The de novo approach was used to design novel modulators, where seed structures derived from CB-839 were modelled and allowed growth within the CB-839 ligand binding pocket (LBP). The main outcome of this project is to obtain two molecular cohorts of high affinity lead-like Gc modulators. Through virtual screening, 2 high affinity lead-like molecules were yielded; which are structurally diverse from the lead. CB-839 derived seeds were modelled and will be docked into the Gc LBP in de novo phase. This study was valuable in modelling a unique pharmacophore that explored maximal pharmacophoric space using VS. The de novo design was used as a complementary approach. The optimal structures will be optimised further. ; N/A |
| Τύπος εγγράφου: | master thesis |
| Γλώσσα: | English |
| Relation: | Zammit, L. (2021). Rational design and preliminary validation of novel glutaminase C modulators (Master's dissertation).; https://www.um.edu.mt/library/oar/handle/123456789/88564 |
| Διαθεσιμότητα: | https://www.um.edu.mt/library/oar/handle/123456789/88564 |
| Rights: | info:eu-repo/semantics/openAccess ; The copyright of this work belongs to the author(s)/publisher. The rights of this work are as defined by the appropriate Copyright Legislation or as modified by any successive legislation. Users may access this work and can make use of the information contained in accordance with the Copyright Legislation provided that the author must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the prior permission of the copyright holder. |
| Αριθμός Καταχώρησης: | edsbas.30CB091F |
| Βάση Δεδομένων: | BASE |
| FullText | Text: Availability: 0 CustomLinks: – Url: https://www.um.edu.mt/library/oar/handle/123456789/88564# Name: EDS - BASE (ns324271) Category: fullText Text: View record from BASE |
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| Header | DbId: edsbas DbLabel: BASE An: edsbas.30CB091F RelevancyScore: 828 AccessLevel: 3 PubType: Dissertation/ Thesis PubTypeId: dissertation PreciseRelevancyScore: 828.347900390625 |
| IllustrationInfo | |
| Items | – Name: Title Label: Title Group: Ti Data: Rational design and preliminary validation of novel glutaminase C modulators – Name: Author Label: Authors Group: Au Data: <searchLink fieldCode="AR" term="%22Zammit%2C+Lara+%282021%29%22">Zammit, Lara (2021)</searchLink> – Name: Publisher Label: Publisher Information Group: PubInfo Data: University of Malta<br />Faculty of Medicine and Surgery. Department of Pharmacy – Name: DatePubCY Label: Publication Year Group: Date Data: 2021 – Name: Subset Label: Collection Group: HoldingsInfo Data: University of Malta: OAR@UM / L-Università ta' Malta – Name: Subject Label: Subject Terms Group: Su Data: <searchLink fieldCode="DE" term="%22Cancer+--+Treatment%22">Cancer -- Treatment</searchLink><br /><searchLink fieldCode="DE" term="%22Cancer+cells+--+Growth+--+Regulation%22">Cancer cells -- Growth -- Regulation</searchLink><br /><searchLink fieldCode="DE" term="%22Enzyme+inhibitors%22">Enzyme inhibitors</searchLink><br /><searchLink fieldCode="DE" term="%22Drug+development+--+Computer+simulation%22">Drug development -- Computer simulation</searchLink><br /><searchLink fieldCode="DE" term="%22Ligand+binding+%28Biochemistry%29+--+Computer+simulation%22">Ligand binding (Biochemistry) -- Computer simulation</searchLink><br /><searchLink fieldCode="DE" term="%22Pharmaceutical+chemistry+--+Computer+simulation%22">Pharmaceutical chemistry -- Computer simulation</searchLink> – Name: Abstract Label: Description Group: Ab Data: M.Pharm.(Melit.) ; Glutaminolysis is a process which drives cell proliferation in tumours. This process is driven by Glutaminase C (Gc). Literature indicates that Gc is over-expressed in solid tumours mainly those of the lung and that its antagonism could inhibit tumour growth. The objective in this study is to design & identify novel Gc modulators through Virtual Screening (VS) & de novo design. The design of this project uses high affinity Gc inhibitor experimental molecule CB-839, used as a lead for the identification of optimised analogues using VS. A consensus pharmacophore was generated by superimposing pharmacophores of inhibitor molecules obtained from PDB crystallographic depositions 5HL1 & 5WJ6 using Ligand Scout®. Sybyl-X® was used to model a protomol; followed by docking of hits obtained through VS. The ligand binding affinities of the 2 hit molecular structures were calculated in Sybyl-X®. The de novo approach was used to design novel modulators, where seed structures derived from CB-839 were modelled and allowed growth within the CB-839 ligand binding pocket (LBP). The main outcome of this project is to obtain two molecular cohorts of high affinity lead-like Gc modulators. Through virtual screening, 2 high affinity lead-like molecules were yielded; which are structurally diverse from the lead. CB-839 derived seeds were modelled and will be docked into the Gc LBP in de novo phase. This study was valuable in modelling a unique pharmacophore that explored maximal pharmacophoric space using VS. The de novo design was used as a complementary approach. The optimal structures will be optimised further. ; N/A – Name: TypeDocument Label: Document Type Group: TypDoc Data: master thesis – Name: Language Label: Language Group: Lang Data: English – Name: NoteTitleSource Label: Relation Group: SrcInfo Data: Zammit, L. (2021). Rational design and preliminary validation of novel glutaminase C modulators (Master's dissertation).; https://www.um.edu.mt/library/oar/handle/123456789/88564 – Name: URL Label: Availability Group: URL Data: https://www.um.edu.mt/library/oar/handle/123456789/88564 – Name: Copyright Label: Rights Group: Cpyrght Data: info:eu-repo/semantics/openAccess ; The copyright of this work belongs to the author(s)/publisher. The rights of this work are as defined by the appropriate Copyright Legislation or as modified by any successive legislation. Users may access this work and can make use of the information contained in accordance with the Copyright Legislation provided that the author must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the prior permission of the copyright holder. – Name: AN Label: Accession Number Group: ID Data: edsbas.30CB091F |
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| RecordInfo | BibRecord: BibEntity: Languages: – Text: English Subjects: – SubjectFull: Cancer -- Treatment Type: general – SubjectFull: Cancer cells -- Growth -- Regulation Type: general – SubjectFull: Enzyme inhibitors Type: general – SubjectFull: Drug development -- Computer simulation Type: general – SubjectFull: Ligand binding (Biochemistry) -- Computer simulation Type: general – SubjectFull: Pharmaceutical chemistry -- Computer simulation Type: general Titles: – TitleFull: Rational design and preliminary validation of novel glutaminase C modulators Type: main BibRelationships: HasContributorRelationships: – PersonEntity: Name: NameFull: Zammit, Lara (2021) IsPartOfRelationships: – BibEntity: Dates: – D: 01 M: 01 Type: published Y: 2021 Identifiers: – Type: issn-locals Value: edsbas – Type: issn-locals Value: edsbas.oa |
| ResultId | 1 |