Rigorous Computational Study Reveals What Docking Overlooks: Double Trouble from Membrane Association in Protein Kinase C Modulators
| Autor: | Riccardo Provenzani, Alex Bunker, Raimo K. Tuominen, Virpi Talman, Jari Yli-Kauhaluoma, Saara Lautala, Waldemar Kulig, Artturi Koivuniemi, Tomasz Róg |
|---|---|
| Přispěvatelé: | Division of Pharmaceutical Biosciences, Division of Pharmaceutical Chemistry and Technology, Pharmaceutical biophysics group, Department of Physics, Drug Research Program, Division of Pharmacology and Pharmacotherapy, Regenerative cardiac pharmacology, Regenerative pharmacology group, Pharmaceutical Design and Discovery group |
| Rok vydání: | 2020 |
| Předmět: |
General Chemical Engineering
116 Chemical sciences Molecular Dynamics Simulation Library and Information Sciences Ligands 01 natural sciences Intracellular membrane 0103 physical sciences Phosphorylation Protein Kinase C Protein kinase C C1 domain Diacylglycerol kinase 010304 chemical physics urogenital system Kinase Chemistry General Chemistry 0104 chemical sciences Computer Science Applications 010404 medicinal & biomolecular chemistry Membrane 317 Pharmacy Docking (molecular) Drug Design Biophysics lipids (amino acids peptides and proteins) |
| Zdroj: | Journal of Chemical Information and Modeling. 60:5624-5633 |
| ISSN: | 1549-960X 1549-9596 |
| DOI: | 10.1021/acs.jcim.0c00624 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|