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AI-Assisted chemical probe discovery for the understudied Calcium-Calmodulin Dependent Kinase, PNCK.

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Τίτλος: AI-Assisted chemical probe discovery for the understudied Calcium-Calmodulin Dependent Kinase, PNCK.
Συγγραφείς: Essegian DJ; Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, Florida, United States of America., Chavez V; Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, United States of America., Khurshid R; Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, Florida, United States of America., Merchan JR; Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, United States of America., Schürer SC; Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, Florida, United States of America.; Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
Πηγή: PLoS computational biology [PLoS Comput Biol] 2023 May 26; Vol. 19 (5), pp. e1010263. Date of Electronic Publication: 2023 May 26 (Print Publication: 2023).
Τύπος έκδοσης: Journal Article; Research Support, N.I.H., Extramural
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Public Library of Science Country of Publication: United States NLM ID: 101238922 Publication Model: eCollection Cited Medium: Internet ISSN: 1553-7358 (Electronic) Linking ISSN: 1553734X NLM ISO Abbreviation: PLoS Comput Biol Subsets: MEDLINE
Imprint Name(s): Original Publication: San Francisco, CA : Public Library of Science, [2005]-
Ιατρικοί όροι (MeSH): Calcium* , Calmodulin*, Artificial Intelligence
Περίληψη: PNCK, or CAMK1b, is an understudied kinase of the calcium-calmodulin dependent kinase family which recently has been identified as a marker of cancer progression and survival in several large-scale multi-omics studies. The biology of PNCK and its relation to oncogenesis has also begun to be elucidated, with data suggesting various roles in DNA damage response, cell cycle control, apoptosis and HIF-1-alpha related pathways. To further explore PNCK as a clinical target, potent small-molecule molecular probes must be developed. Currently, there are no targeted small molecule inhibitors in pre-clinical or clinical studies for the CAMK family. Additionally, there exists no experimentally derived crystal structure for PNCK. We herein report a three-pronged chemical probe discovery campaign which utilized homology modeling, machine learning, virtual screening and molecular dynamics to identify small molecules with low-micromolar potency against PNCK activity from commercially available compound libraries. We report the discovery of a hit-series for the first targeted effort towards discovering PNCK inhibitors that will serve as the starting point for future medicinal chemistry efforts for hit-to-lead optimization of potent chemical probes.
(Copyright: © 2023 Essegian et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Competing Interests: The authors have declared that no competing interests exist.
Σχόλια: Erratum in: PLoS Comput Biol. 2023 Nov 22;19(11):e1011672. doi: 10.1371/journal.pcbi.1011672.. (PMID: 37992014)
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Grant Information: P30 CA240139 United States CA NCI NIH HHS; U01 LM012630 United States LM NLM NIH HHS; U24 TR002278 United States TR NCATS NIH HHS; U54 HL127624 United States HL NHLBI NIH HHS
Substance Nomenclature: SY7Q814VUP (Calcium)
0 (Calmodulin)
Entry Date(s): Date Created: 20230526 Date Completed: 20230612 Latest Revision: 20250423
Update Code: 20260130
PubMed Central ID: PMC10249896
DOI: 10.1371/journal.pcbi.1010263
PMID: 37235579
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:1553-7358
DOI:10.1371/journal.pcbi.1010263