Design and synthesis of pyridopyrimidines targeting NEK6 kinase
We designed a series of pyrido[2,3-d]pyrimidine derivatives based on the structure of the NEK6 kinase inhibitor, compound 21 (2-amino-5-phenyl-5,11-dihydro-3H-indeno[2',1':5,6]pyrido[2,3-d]pyrimidine-4,6-dione), which share the same heterocyclic core. Chemical modifications, aimed at altering the molecular planarity of 21 to enhance water solubility, were guided by receptor-based ligand design and further supported by molecular docking, molecular dynamics simulations, and free energy perturbation calculations. Our results indicate that disrupting the planarity of 21 increases aqueous solubility - nearly doubling it in two cases- while reducing lipophilicity. Among the compounds tested, three showed both improved solubility and NEK6 inhibitory activity exceeding 50 % in single-dose assay.
Authors
- Alessandro Semeraro (ORCID: https://orcid.org/0000-0002-9946-6331)
- Luka Đorđević∞ (ORCID: https://orcid.org/0000-0002-8346-7110)
- Daniela Gallo (ORCID: https://orcid.org/0000-0002-1918-1054)
- Paolo Zardi (ORCID: https://orcid.org/0000-0001-5716-5672)
- Giovanni Scambia (ORCID: https://orcid.org/0000-0002-9503-9041)
- Natalia Cappoli (ORCID: https://orcid.org/0000-0002-4705-3340)
- Marta De Donato
- Michele Maggini (ORCID: https://orcid.org/0000-0001-8149-5903)
- Benedetta Righino (ORCID: https://orcid.org/0000-0002-1042-3731)
- Davide Pirolli (ORCID: https://orcid.org/0000-0003-2303-2577)
- Maria Cristina De Rosa (ORCID: https://orcid.org/0000-0002-9611-2490)
- Marianna Buttarelli (ORCID: https://orcid.org/0000-0002-9062-8605)
- VC Romano
- Juan José Galano-Frutos
- Matteo Gramanzini
- Anna Königs
Institutions
- Università Cattolica del Sacro Cuore (IT)
- University of Padua (IT)
- Agostino Gemelli University Polyclinic (IT)
- Institute of Condensed Matter Chemistry and Technologies for Energy (IT)
- Istituto di Metodologie Chimiche (IT)
- Tecnologie Avanzate (Italy) (IT)
- Sapienza University of Rome (IT)
Publication Details
- Journal
- Archives of Biochemistry and Biophysics
- Published
- 2025-03-14
- DOI
- https://doi.org/10.1016/j.abb.2025.110391
- Citations
- 1
- Primary Topic
- Synthesis and biological activity
- Type
- article
- Field-Weighted Citation Impact
- 0.94