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Structure‐Based Target‐Specific Screening Leads to Small‐Molecule CaMKII Inhibitors
Author(s) -
Xu David,
Li Liwei,
Zhou Donghui,
Liu Degang,
Hudmon Andy,
Meroueh Samy O.
Publication year - 2017
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201600636
Subject(s) - kinase , kinome , chemistry , docking (animal) , lead compound , small molecule , quinazoline , lipinski's rule of five , benzofuran , ic50 , biochemistry , stereochemistry , in vitro , in silico , medicine , gene , nursing
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 Ca 2+ /calmodulin (CaM)‐dependent protein kinase (CaMK) family, and re‐scored the resulting protein–compound structures using S upport V ector M achine SP ecific (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; N 4‐[7‐chloro‐2‐[( E )‐styryl]quinazolin‐4‐yl]‐ N 1, N 1‐diethylpentane‐1,4‐diamine), which was found to inhibit CaMKIIδ kinase activity at single‐digit micromolar IC 50 . Activity across the kinome was assessed by profiling analogues of 1 , namely 6 (KIN‐236; N 4‐[7‐chloro‐2‐[( E )‐2‐(2‐chloro‐4,5‐dimethoxyphenyl)vinyl]quinazolin‐4‐yl]‐ N 1, N 1‐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 , IC 50 values ranged from 5 to 22 μ m . Compound 14 was found to be not specific toward CaMKII kinases, but it does inhibit two kinases with sub‐micromolar IC 50 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.