Structure-Based Target-Specific Screening Leads to Small-Molecule CaMKII Inhibitors

David Xu, Liwei Li, Donghui Zhou, Degang Liu, Andy Hudmon, Samy Meroueh

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Target-specific scoring methods are more commonly used to identify small-molecule inhibitors among compounds docked to a target of interest. Top candidates that emerge from these methods have rarely been tested for activity and specificity across a family of proteins. In this study we docked a chemical library into CaMKIIδ, a member of the Ca2+/calmodulin (CaM)-dependent protein kinase (CaMK) family, and re-scored the resulting protein–compound structures using Support Vector Machine SPecific (SVMSP), a target-specific method that we developed previously. Among the 35 selected candidates, three hits were identified, such as quinazoline compound 1 (KIN-1; N4-[7-chloro-2-[(E)-styryl]quinazolin-4-yl]-N1,N1-diethylpentane-1,4-diamine), which was found to inhibit CaMKIIδ kinase activity at single-digit micromolar IC50. Activity across the kinome was assessed by profiling analogues of 1, namely 6 (KIN-236; N4-[7-chloro-2-[(E)-2-(2-chloro-4,5-dimethoxyphenyl)vinyl]quinazolin-4-yl]-N1,N1-diethylpentane-1,4-diamine), and an analogue of hit compound 2 (KIN-15; 2-[4-[(E)-[(5-bromobenzofuran-2-carbonyl)hydrazono]methyl]-2-chloro-6-methoxyphenoxy]acetic acid), namely 14 (KIN-332; N-[(E)-[4-(2-anilino-2-oxoethoxy)-3-chlorophenyl]methyleneamino]benzofuran-2-carboxamide), against 337 kinases. Interestingly, for compound 6, CaMKIIδ and homologue CaMKIIγ were among the top ten targets. Among the top 25 targets of 6, IC50 values ranged from 5 to 22 μm. Compound 14 was found to be not specific toward CaMKII kinases, but it does inhibit two kinases with sub-micromolar IC50 values among the top 25. Derivatives of 1 were tested against several kinases including several members of the CaMK family. These data afforded a limited structure–activity relationship study. Molecular dynamics simulations with explicit solvent followed by end-point MM-GBSA free-energy calculations revealed strong engagement of specific residues within the ATP binding pocket, and also changes in the dynamics as a result of binding. This work suggests that target-specific scoring approaches such as SVMSP may hold promise for the identification of small-molecule kinase inhibitors that exhibit some level of specificity toward the target of interest across a large number of proteins.

Original languageEnglish (US)
Pages (from-to)660-677
Number of pages18
JournalChemMedChem
Volume12
Issue number9
DOIs
StatePublished - May 9 2017

Fingerprint

Calcium-Calmodulin-Dependent Protein Kinase Type 2
Screening
Phosphotransferases
Molecules
Inhibitory Concentration 50
Diamines
Support vector machines
Quinazolines
Small Molecule Libraries
Calcium-Calmodulin-Dependent Protein Kinases
Molecular Dynamics Simulation
Acetic Acid
Protein Kinases
Free energy
Molecular dynamics
Proteins
Research Design
Adenosine Triphosphate
Derivatives
Computer simulation

Keywords

  • Docking
  • Kinases
  • Molecular dynamics
  • Support vector machines
  • Target specificity

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

Cite this

Structure-Based Target-Specific Screening Leads to Small-Molecule CaMKII Inhibitors. / Xu, David; Li, Liwei; Zhou, Donghui; Liu, Degang; Hudmon, Andy; Meroueh, Samy.

In: ChemMedChem, Vol. 12, No. 9, 09.05.2017, p. 660-677.

Research output: Contribution to journalArticle

Xu, David ; Li, Liwei ; Zhou, Donghui ; Liu, Degang ; Hudmon, Andy ; Meroueh, Samy. / Structure-Based Target-Specific Screening Leads to Small-Molecule CaMKII Inhibitors. In: ChemMedChem. 2017 ; Vol. 12, No. 9. pp. 660-677.
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