Dissertation/ Thesis
Rational design and preliminary validation of novel BU10119 analogs for the management of SSRI refractory depression
| Title: | Rational design and preliminary validation of novel BU10119 analogs for the management of SSRI refractory depression |
|---|---|
| Authors: | Grech, Matthew (2021) |
| Publisher Information: | University of Malta Faculty of Medicine and Surgery. Department of Pharmacy |
| Publication Year: | 2021 |
| Collection: | University of Malta: OAR@UM / L-Università ta' Malta |
| Subject Terms: | Depression, Mental -- Treatment, Serotonin uptake inhibitors, Drug development -- Computer simulation, Ligand binding (Biochemistry) -- Computer simulation |
| Description: | M.Pharm.(Melit.) ; Kappa Opioid Receptor and Mu Opioid Receptor Antagonism has been shown to be useful in the treatment of SSRI Refractory Depression. BU10119 is a dual Kappa Opioid Receptor and Mu Opioid Receptor antagonist that is used in this study as a lead. The crystallographic structures of both the opioid receptors were obtained from Protein Data Banks 4DJH and 4DKL. The Virtual Screening Approach and the de novo Design Approach are performed in this study. Virtual Screening Approach involves a Ligand Based Drug Design, while the de novo Design Approach involves a Structure Based Drug Design. During the Virtual Screening Approach, BU10119 was superimposed onto antagonists for both receptors to identify the optimal conformers. Consensus Pharmacophores were created for each antagonist using LigandScout®. During the de novo Approach, different seed structures were created derived from the optimal BU10119 spatial arrangement and allowed to grow within the ligand binding pocket of the respective receptor. This approach resulted in a total of six molecular seed structures of high affinity to the Kappa Opioid Receptor, and limited activity to the Mu Opioid Receptor. These six molecular seed structures had diverse structures from the novel BU10119 molecule. This study proved valuable in exploring the maximum ligand binding pocket area through the creation of a pharmacophore during the Virtual Screening Approach. The de novo Approach was used as further validation to this study in as a more innovative approach. ; N/A |
| Document Type: | master thesis |
| Language: | English |
| Relation: | Grech, M. (2021). Rational design and preliminary validation of novel BU10119 analogs for the management of SSRI refractory depression (Master's dissertation).; https://www.um.edu.mt/library/oar/handle/123456789/88520 |
| Availability: | https://www.um.edu.mt/library/oar/handle/123456789/88520 |
| 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. |
| Accession Number: | edsbas.53CA0802 |
| Database: | BASE |
| FullText | Text: Availability: 0 CustomLinks: – Url: https://www.um.edu.mt/library/oar/handle/123456789/88520# Name: EDS - BASE (ns324271) Category: fullText Text: View record from BASE |
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| Header | DbId: edsbas DbLabel: BASE An: edsbas.53CA0802 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 BU10119 analogs for the management of SSRI refractory depression – Name: Author Label: Authors Group: Au Data: <searchLink fieldCode="AR" term="%22Grech%2C+Matthew+%282021%29%22">Grech, Matthew (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="%22Depression%22">Depression</searchLink><br /><searchLink fieldCode="DE" term="%22Mental+--+Treatment%22">Mental -- Treatment</searchLink><br /><searchLink fieldCode="DE" term="%22Serotonin+uptake+inhibitors%22">Serotonin uptake 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> – Name: Abstract Label: Description Group: Ab Data: M.Pharm.(Melit.) ; Kappa Opioid Receptor and Mu Opioid Receptor Antagonism has been shown to be useful in the treatment of SSRI Refractory Depression. BU10119 is a dual Kappa Opioid Receptor and Mu Opioid Receptor antagonist that is used in this study as a lead. The crystallographic structures of both the opioid receptors were obtained from Protein Data Banks 4DJH and 4DKL. The Virtual Screening Approach and the de novo Design Approach are performed in this study. Virtual Screening Approach involves a Ligand Based Drug Design, while the de novo Design Approach involves a Structure Based Drug Design. During the Virtual Screening Approach, BU10119 was superimposed onto antagonists for both receptors to identify the optimal conformers. Consensus Pharmacophores were created for each antagonist using LigandScout®. During the de novo Approach, different seed structures were created derived from the optimal BU10119 spatial arrangement and allowed to grow within the ligand binding pocket of the respective receptor. This approach resulted in a total of six molecular seed structures of high affinity to the Kappa Opioid Receptor, and limited activity to the Mu Opioid Receptor. These six molecular seed structures had diverse structures from the novel BU10119 molecule. This study proved valuable in exploring the maximum ligand binding pocket area through the creation of a pharmacophore during the Virtual Screening Approach. The de novo Approach was used as further validation to this study in as a more innovative approach. ; 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: Grech, M. (2021). Rational design and preliminary validation of novel BU10119 analogs for the management of SSRI refractory depression (Master's dissertation).; https://www.um.edu.mt/library/oar/handle/123456789/88520 – Name: URL Label: Availability Group: URL Data: https://www.um.edu.mt/library/oar/handle/123456789/88520 – 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.53CA0802 |
| PLink | https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=edsbas&AN=edsbas.53CA0802 |
| RecordInfo | BibRecord: BibEntity: Languages: – Text: English Subjects: – SubjectFull: Depression Type: general – SubjectFull: Mental -- Treatment Type: general – SubjectFull: Serotonin uptake inhibitors Type: general – SubjectFull: Drug development -- Computer simulation Type: general – SubjectFull: Ligand binding (Biochemistry) -- Computer simulation Type: general Titles: – TitleFull: Rational design and preliminary validation of novel BU10119 analogs for the management of SSRI refractory depression Type: main BibRelationships: HasContributorRelationships: – PersonEntity: Name: NameFull: Grech, Matthew (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 |