View in EDS

Comparison of irreversible inhibition targeting HSP72 protein: the resurgence of covalent drug developments.

Saved in:
Bibliographic Details
Title: Comparison of irreversible inhibition targeting HSP72 protein: the resurgence of covalent drug developments.
Authors: Aljoundi, Aimen1 (AUTHOR), El Rashedy, Ahmed1 (AUTHOR), Soliman, Mahmoud E. S.1 (AUTHOR) soliman@ukzn.ac.za
Source: Molecular Simulation. Sep2021, Vol. 47 Issue 13, p1093-1103. 11p.
Subjects: Drug development, Principal components analysis, Cancer cells, Proteins, Binding sites
Abstract: The covalent inhibition mechanism of action, which overcomes competition with high-affinity, high-abundance substrates of challenging protein targets, can deliver effective chemical probes and drugs. Heat shock protein 72 (HSP72) expressed in cancer cells may be responsible for tumorigenesis and tumour progression by providing resistance to chemotherapy. In this study, we explore the most optimal binding mechanism in the inhibition of the HSP72 nucleotide-binding domain by two different covalent generation, TCI2 and TCI8. However, the structural basis and conformational changes associated with this preferential covalent inhibition to HSP72-TCI2 over HSP72-TCI8 remain unclear. Our results revealed that HSP72-TCI2 covalent complex was more able to stabilise and induce better interaction with high correlated dynamic motion of HSP72-NBD at ATP binding site throughout the simulation in comparison to the HSP72-TCI8 covalent complex. This is supported by the dynamic cross-correlation and principal component analysis that was more dominant in the HSP72-TCI2 inhibited complex. The insights demonstrating the above binding mechanism of HSP72 establish TCI2 covalent inhibition as the preferred method of inhibiting the HSP72 protein. This investigation aids in the understanding of the structural mechanism of HSP72 inhibition and would assist in the design of more potent covalent inhibitors of HSP72. [ABSTRACT FROM AUTHOR]
Copyright of Molecular Simulation is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Engineering Source
FullText Text:
  Availability: 0
Header DbId: egs
DbLabel: Engineering Source
An: 151912607
AccessLevel: 6
PubType: Academic Journal
PubTypeId: academicJournal
PreciseRelevancyScore: 0
IllustrationInfo
Items – Name: Title
  Label: Title
  Group: Ti
  Data: Comparison of irreversible inhibition targeting HSP72 protein: the resurgence of covalent drug developments.
– Name: Author
  Label: Authors
  Group: Au
  Data: <searchLink fieldCode="AR" term="%22Aljoundi%2C+Aimen%22">Aljoundi, Aimen</searchLink><relatesTo>1</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22El+Rashedy%2C+Ahmed%22">El Rashedy, Ahmed</searchLink><relatesTo>1</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Soliman%2C+Mahmoud+E%2E+S%2E%22">Soliman, Mahmoud E. S.</searchLink><relatesTo>1</relatesTo> (AUTHOR)<i> soliman@ukzn.ac.za</i>
– Name: TitleSource
  Label: Source
  Group: Src
  Data: <searchLink fieldCode="JN" term="%22Molecular+Simulation%22">Molecular Simulation</searchLink>. Sep2021, Vol. 47 Issue 13, p1093-1103. 11p.
– Name: Subject
  Label: Subjects
  Group: Su
  Data: <searchLink fieldCode="DE" term="%22Drug+development%22">Drug development</searchLink><br /><searchLink fieldCode="DE" term="%22Principal+components+analysis%22">Principal components analysis</searchLink><br /><searchLink fieldCode="DE" term="%22Cancer+cells%22">Cancer cells</searchLink><br /><searchLink fieldCode="DE" term="%22Proteins%22">Proteins</searchLink><br /><searchLink fieldCode="DE" term="%22Binding+sites%22">Binding sites</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: The covalent inhibition mechanism of action, which overcomes competition with high-affinity, high-abundance substrates of challenging protein targets, can deliver effective chemical probes and drugs. Heat shock protein 72 (HSP72) expressed in cancer cells may be responsible for tumorigenesis and tumour progression by providing resistance to chemotherapy. In this study, we explore the most optimal binding mechanism in the inhibition of the HSP72 nucleotide-binding domain by two different covalent generation, TCI2 and TCI8. However, the structural basis and conformational changes associated with this preferential covalent inhibition to HSP72-TCI2 over HSP72-TCI8 remain unclear. Our results revealed that HSP72-TCI2 covalent complex was more able to stabilise and induce better interaction with high correlated dynamic motion of HSP72-NBD at ATP binding site throughout the simulation in comparison to the HSP72-TCI8 covalent complex. This is supported by the dynamic cross-correlation and principal component analysis that was more dominant in the HSP72-TCI2 inhibited complex. The insights demonstrating the above binding mechanism of HSP72 establish TCI2 covalent inhibition as the preferred method of inhibiting the HSP72 protein. This investigation aids in the understanding of the structural mechanism of HSP72 inhibition and would assist in the design of more potent covalent inhibitors of HSP72. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of Molecular Simulation is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
PLink https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=egs&AN=151912607
RecordInfo BibRecord:
  BibEntity:
    Identifiers:
      – Type: doi
        Value: 10.1080/08927022.2021.1949457
    Languages:
      – Code: eng
        Text: English
    PhysicalDescription:
      Pagination:
        PageCount: 11
        StartPage: 1093
    Subjects:
      – SubjectFull: Drug development
        Type: general
      – SubjectFull: Principal components analysis
        Type: general
      – SubjectFull: Cancer cells
        Type: general
      – SubjectFull: Proteins
        Type: general
      – SubjectFull: Binding sites
        Type: general
    Titles:
      – TitleFull: Comparison of irreversible inhibition targeting HSP72 protein: the resurgence of covalent drug developments.
        Type: main
  BibRelationships:
    HasContributorRelationships:
      – PersonEntity:
          Name:
            NameFull: Aljoundi, Aimen
      – PersonEntity:
          Name:
            NameFull: El Rashedy, Ahmed
      – PersonEntity:
          Name:
            NameFull: Soliman, Mahmoud E. S.
    IsPartOfRelationships:
      – BibEntity:
          Dates:
            – D: 01
              M: 09
              Text: Sep2021
              Type: published
              Y: 2021
          Identifiers:
            – Type: issn-print
              Value: 08927022
          Numbering:
            – Type: volume
              Value: 47
            – Type: issue
              Value: 13
          Titles:
            – TitleFull: Molecular Simulation
              Type: main
ResultId 1