Abstract
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-IgP (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.
Original language | English |
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Journal | Journal of Chemical Information and Modeling |
Volume | 60 |
Issue number | 11 |
Pages (from-to) | 5624-5633 |
Number of pages | 10 |
ISSN | 1549-9596 |
DOIs | |
Publication status | Published - 23 Nov 2020 |
MoE publication type | A1 Journal article-refereed |
Fields of Science
- 116 Chemical sciences
- 317 Pharmacy