Rigorous Computational Study Reveals What Docking Overlooks: Double Trouble from Membrane Association in Protein Kinase C Modulators

Increasing protein
kinase C (PKC) activity is of potential therapeutic
value. Its activation involves an interaction between the C1 domain
and diacylglycerol (DAG) at intracellular membrane surfaces; DAG mimetics
hold promise as new drugs. We previously developed the isophthalate
derivative HMI-1a3, an effective but highly lipophilic (clogP = 6.46) DAG mimetic. Although a less lipophilic pyrimidine
analog, PYR-1gP (clogP = 3.30), gave positive results
in computational docking, it unexpectedly presented greatly diminished
binding to PKC in vitro. Through more rigorous computational
molecular modeling, we reveal that, unlike HMI-1a3, PYR-1gP forms
an intramolecular hydrogen bond, which both obstructs binding and
reorients PYR-1gP in the membrane in a fashion that prevents it from
correctly accessing the PKC C1 domain. Our results highlight the great
value of molecular dynamics simulations as a key component for the
drug design process of ligands targeting weakly membrane-associated
proteins, where simulation in the relevant membrane environment is
crucial for obtaining biologically applicable results.