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

• Published in: Journal of chemical information and modeling 2020-11, Vol.60 (11), p.5624-5633
• Main Authors: Lautala, Saara, Provenzani, Riccardo, Koivuniemi, Artturi, Kulig, Waldemar, Talman, Virpi, Róg, Tomasz, Tuominen, Raimo K, Yli-Kauhaluoma, Jari, Bunker, Alex
• Format: Article
• Language: English
• Subjects: Binding; Biological effects; Domains; Hydrogen bonds; Kinases; Lipophilicity; Membranes; Modulators; Molecular dynamics; Pharmaceutical Modeling; Proteins
• ISSN: 1549-9596; 1549-960X
• DOI: 10.1021/acs.jcim.0c00624

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.