Scaffold hopping from (5-hydroxymethyl) isophthalates to multisubstituted pyrimidines diminishes binding affinity to the C1 domain of protein kinase C

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Abstract

Protein kinase C (PKC) isoforms play a pivotal role in the regulation of numerous cellular functions, making them extensively studied and highly attractive drug targets. Utilizing the crystal structure of the PKC delta C1B domain, we have developed hydrophobic isophthalic acid derivatives that modify PKC functions by binding to the C1 domain of the enzyme. In the present study, we aimed to improve the drug-like properties of the isophthalic acid derivatives by increasing their solubility and enhancing the binding affinity. Here we describe the design and synthesis of a series of multisubstituted pyrimidines as analogs of C1 domain - targeted isophthalates and characterize their binding affinities to the PKC alpha isoform. In contrast to our computational predictions, the scaffold hopping from phenyl to pyrimidine core diminished the binding affinity. Although the novel pyrimidines did not establish improved binding affinity for PKC alpha compared to our previous isophthalic acid derivatives, the present results provide useful structure-activity relationship data for further development of ligands targeted to the C1 domain of PKC.
Original languageEnglish
Article number0195668
JournalPLoS One
Volume13
Issue number4
Number of pages27
ISSN1932-6203
DOIs
Publication statusPublished - 11 Apr 2018
MoE publication typeA1 Journal article-refereed

Fields of Science

  • 116 Chemical sciences
  • 317 Pharmacy
  • PHORBOL ESTER RECEPTO RS
  • BIOLOGICAL-ACTIVITY
  • DIACYLGLYCEROL DAG
  • CHEMICAL SPACE
  • PKC-ALPHA
  • DESIGN
  • SELECTIVITY
  • LIGAND
  • RASGRP
  • DERIVATIVES

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