Autor: |
Lautala S; Drug Research Program, Division of Pharmaceutical Biosciences, University of Helsinki, P.O. Box 56, Viikinkaari 5 E, FI-00014 Helsinki, Finland., Provenzani R; Drug Research Program, Division of Pharmaceutical Chemistry and Technology, University of Helsinki, P.O. Box 56, Viikinkaari 5 E, FI-00014 Helsinki, Finland., Koivuniemi A; Drug Research Program, Division of Pharmaceutical Biosciences, University of Helsinki, P.O. Box 56, Viikinkaari 5 E, FI-00014 Helsinki, Finland., Kulig W; Department of Physics, University of Helsinki, P.O. Box 64, Gustaf Hällströmin katu 2, FI-00014 Helsinki, Finland., Talman V; Drug Research Program, Division of Pharmacology and Pharmacotherapy, University of Helsinki, P.O. Box 56, Viikinkaari 5 E, FI-00014 Helsinki, Finland.; National Heart and Lung Institute, Imperial College London, Hammersmith Campus, London W12 0NN, United Kingdom., Róg T; Department of Physics, University of Helsinki, P.O. Box 64, Gustaf Hällströmin katu 2, FI-00014 Helsinki, Finland., Tuominen RK; Drug Research Program, Division of Pharmacology and Pharmacotherapy, University of Helsinki, P.O. Box 56, Viikinkaari 5 E, FI-00014 Helsinki, Finland., Yli-Kauhaluoma J; Drug Research Program, Division of Pharmaceutical Chemistry and Technology, University of Helsinki, P.O. Box 56, Viikinkaari 5 E, FI-00014 Helsinki, Finland., Bunker A; Drug Research Program, Division of Pharmaceutical Biosciences, University of Helsinki, P.O. Box 56, Viikinkaari 5 E, FI-00014 Helsinki, Finland. |
Abstrakt: |
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 (clog P = 6.46) DAG mimetic. Although a less lipophilic pyrimidine analog, PYR-1gP (clog P = 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. |