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Tytuł pozycji:

Phosphorylation-dependent activity-based conformational changes in P21-activated kinase family members and screening of novel ATP competitive inhibitors.

Tytuł:
Phosphorylation-dependent activity-based conformational changes in P21-activated kinase family members and screening of novel ATP competitive inhibitors.
Autorzy:
Gul M; National Center for Bioinformatics, Quaid-i-Azam University, Islamabad, Pakistan.
Fakhar M; National Center for Bioinformatics, Quaid-i-Azam University, Islamabad, Pakistan.
Najumuddin; National Center for Bioinformatics, Quaid-i-Azam University, Islamabad, Pakistan.
Rashid S; National Center for Bioinformatics, Quaid-i-Azam University, Islamabad, Pakistan.
Źródło:
PloS one [PLoS One] 2019 Nov 18; Vol. 14 (11), pp. e0225132. Date of Electronic Publication: 2019 Nov 18 (Print Publication: 2019).
Typ publikacji:
Journal Article
Język:
English
Imprint Name(s):
Original Publication: San Francisco, CA : Public Library of Science
MeSH Terms:
Drug Screening Assays, Antitumor*/methods
Quantitative Structure-Activity Relationship*
Adenosine Triphosphate/*chemistry
Protein Kinase Inhibitors/*chemistry
Protein Kinase Inhibitors/*pharmacology
p21-Activated Kinases/*antagonists & inhibitors
p21-Activated Kinases/*chemistry
Amino Acid Sequence ; Binding, Competitive ; Models, Biological ; Models, Molecular ; Molecular Conformation ; Phosphorylation ; Protein Binding ; Protein Isoforms ; p21-Activated Kinases/metabolism
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Substance Nomenclature:
0 (Protein Isoforms)
0 (Protein Kinase Inhibitors)
8L70Q75FXE (Adenosine Triphosphate)
EC 2.7.11.1 (p21-Activated Kinases)
Entry Date(s):
Date Created: 20191119 Date Completed: 20200323 Latest Revision: 20200323
Update Code:
20240104
PubMed Central ID:
PMC6860928
DOI:
10.1371/journal.pone.0225132
PMID:
31738805
Czasopismo naukowe
P21-activated kinases (PAKs) are serine/threonine protein kinases that are subdivided into two groups on the basis of their domain architecture: group-I (PAK1-3) and group-II (PAK4-6). PAKs are considered as attractive drug targets that play vital role in cell proliferation, survival, motility, angiogenesis and cytoskeletal dynamics. In current study, molecular dynamics simulation-based comparative residual contributions and differential transitions were monitored in both active and inactive states of human PAK homologs for therapeutic intervention. Due to their involvement in cancer, infectious diseases, and neurological disorders, it is inevitable to develop novel therapeutic strategies that specifically target PAKs on the basis of their activity pattern. In order to isolate novel inhibitors that are able to bind at the active sites of PAK1 and PAK4, high throughput structure-based virtual screening was performed. Multiple lead compounds were proposed on the basis of their binding potential and targeting region either phosphorylated (active) or unphosphorylated PAK isoform (inactive). Thus, ATP-competitive inhibitors may prove ideal therapeutic choice against PAK family members. The detailed conformational readjustements occurring in the PAKs upon phosphorylation-dephosphorylation events may serve as starting point for devising novel drug molecules that are able to target on activity basis. Overall, the observations of current study may add valuable contribution in the inventory of novel inhibitors that may serve as attractive lead compounds for targeting PAK family members on the basis of activity-based conformational changes.
Competing Interests: The authors have declared that no competing interests exist.
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