Protein kinase C (PKC) modulators hold therapeutic potential for various diseases, including cancer, heart failure, and Alzheimer's disease. Targeting the C1 domain of PKC represents a promising strategy; the available protein structures warrant the design of PKC-targeted ligands via a structure-based approach. However, the PKC C1 domain penetrates the lipid membrane during binding, complicating the design of drug candidates. The standard docking-scoring approach for PKC lacks information regarding the dynamics and the membrane environment. Molecular dynamics (MD) simulations with PKC, ligands, and membranes have been used to address these shortcomings. Previously, we observed that less computationally intensive simulations of just ligand-membrane interactions may help elucidate C1 domain-binding prospects. Here, we present the design, synthesis, and biological evaluation of new pyridine-based PKC agonists implementing an enhanced workflow with ligand-membrane MD simulations. This workflow holds promise to expand the approach in drug design for ligands targeted to weakly membrane-associated proteins.
Original languageEnglish
JournalJournal of Medicinal Chemistry
Issue number7
Pages (from-to)4588-4602
Number of pages15
Publication statusPublished - 13 Apr 2023
MoE publication typeA1 Journal article-refereed

Fields of Science

  • Activation
  • Acyl-chain
  • Amber
  • Derivatives
  • Domain
  • Gromacs
  • Ligand
  • Membranes
  • Orientation
  • Proliferation
  • 317 Pharmacy

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