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AI-Assisted Chemical Probe Discovery for the Understudied Calcium-Calmodulin Dependent Kinase, PNCK
Open accessPreprint — published as 10.1371/journal.pcbi.1010263 · Paper page
Abstract
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 first described inhibitor hit series for PNCK that will serve as the starting point for future medicinal chemistry efforts for hit-to-lead optimization of potent chemical probes.
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Metadata
- Authors
- Essegian, D. J., Chavez, V., Khurshid, R., Merchan, J. R., & Schürer, S. C.
- Affiliations
- University of Miami (US)
- Corresponding author
- Schürer, Stephan C.
- Venue
- PLoS Computational Biology
- Publisher
- openRxiv
- Published
- 2022-06-01
- Volume
- 19
- Issue
- 5
- Pages
- e1010263-e1010263
- ISSN
- 1553-734X (ISSN-L)
- PMC
- PMC10249896
- OpenAlex
- W4378373554
- Cited by
- 4
- References
- 1
- Citations by year
- 2025: 2 · 2023: 1 · 2022: 1
- FWCI
- 0.43
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- PLoS Computational Biology (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (U24TR002278)
- National Heart, Lung, and Blood Institute (U54HL127624)
- National Cancer Institute (P30CA240139)
- U.S. National Library of Medicine (U01LM012630)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and Characterization of Heterocyclic Compounds
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- calcium/calmodulin-dependent protein kinase, kinase inhibitors, small molecule inhibitors, homology modeling, virtual screening, molecular dynamics, tumor progression markers, carcinogenesis
- MeSH terms
- Artificial Intelligence, Calcium, Calmodulin
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