Structure activity relationships of quinoxalin-2-one derivatives as platelet-derived growth factor-beta receptor (PDGFbeta R) inhibitors, derived from molecular modeling.
We previously reported a quinoxalin-2-one compound (Compound 1) that had inhibitory activity equivalent to existing platelet-derived growth factor-beta receptor (PDGFbeta R) inhibitors. Lead optimization of Compound 1 to increase its activity and selectivity, using structural information regarding PDGFbeta R-ligand interactions, is urgently needed. Here we present models of the PDGFbeta R kinase domain complexed with quinoxalin-2-one derivatives. The models were constructed using comparative modeling, molecular dynamics (MD) and ligand docking. In particular, conformations derived from MD, and ligand binding site information presented by alpha-spheres in the pre-docking processing, allowed us to identify optimal protein structures for docking of target ligands. By carrying out molecular modeling and MD of PDGFbeta R in its inactive state, we obtained two structural models having good Compound 1 binding potentials. In order to distinguish the optimal candidate, we evaluated the structural activity relationships (SAR) between the ligand-binding free energies and inhibitory activity values (IC50 values) for available quinoxalin-2-one derivatives. Consequently, a final model with a high SAR was identified. This model included a molecular interaction between the hydrophobic pocket behind the ATP binding site and the substitution region of the quinoxalin-2-one derivatives. These findings should prove useful in lead optimization of quinoxalin-2-one derivatives as PDGFb R inhibitors.
Mori
Yoshikazu
Y
R & D Division, Tsumura & Co, Japan.
Hirokawa
Takatsugu
T
Aoki
Katsuyuki
K
Satomi
Hisanori
H
Takeda
Shuichi
S
Aburada
Masaki
M
Miyamoto
Ken-ichi
K
D000595:Amino Acid Sequence; D003198:Computer Simulation; D015195:Drug Design; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D010766:Phosphorylation; D011485:Protein Binding; D011810:Quinoxalines / Q000737:chemistry* / Q000494:pharmacology*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D011810:Quinoxalines; D020797:Receptor, Platelet-Derived Growth Factor beta