Expanding the Paradigm of Structure-Based Drug Design: Molecular Dynamics Simulations Support the Development of New Pyridine-Based Protein Kinase C‑Targeted Agonists

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.