Rigorous computational study reveals what docking overlooks : Double trouble from membrane association in protein kinase C modulators

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Lautala , S , Provenzani , R , Koivuniemi , A , Kulig , W , Talman , V , Rog , T , Tuominen , R K , Yli-Kauhaluoma , J & Bunker , A E 2020 , ' Rigorous computational study reveals what docking overlooks : Double trouble from membrane association in protein kinase C modulators ' , Journal of Chemical Information and Modeling , vol. 60 , no. 11 , pp. 5624-5633 . https://doi.org/10.1021/acs.jcim.0c00624

Title: Rigorous computational study reveals what docking overlooks : Double trouble from membrane association in protein kinase C modulators
Author: Lautala, Saara; Provenzani, Riccardo; Koivuniemi, Artturi; Kulig, Waldemar; Talman, Virpi; Rog, Tomasz; Tuominen, Raimo K.; Yli-Kauhaluoma, Jari; Bunker, Alex Edwin
Contributor organization: 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
Date: 2020-11-23
Language: eng
Number of pages: 10
Belongs to series: Journal of Chemical Information and Modeling
ISSN: 1549-9596
DOI: https://doi.org/10.1021/acs.jcim.0c00624
URI: http://hdl.handle.net/10138/334259
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.
Subject: 116 Chemical sciences
317 Pharmacy
Peer reviewed: Yes
Rights: unspecified
Usage restriction: openAccess
Self-archived version: acceptedVersion


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