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

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-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.

journal_name

J Chem Inf Model

journal_title

Journal of chemical information and modeling

authors

Lautala S,Provenzani R,Koivuniemi A,Kulig W,Talman V,Róg T,Tuominen RK,Yli-Kauhaluoma J,Bunker A

doi

10.1021/acs.jcim.0c00624

subject

Has Abstract

pub_date

2020-11-23 00:00:00

pages

5624-5633

issue

11

eissn

1549-9596

issn

1549-960X

journal_volume

60

pub_type

杂志文章

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