Docking and 3D-QSAR studies of N-benzyl isatin oximes as JNK3 inhibitors

Abstract

Abstract:

The c-Jun N-terminal kinase (JNK) is involved in a variety of important cellular processes and aberrant JNK activity is associated with many human diseases.The ligand-based and receptor-based alignment rules were used to build 3D-QSAR modelsfor a series of N-benzyl isatin oximes JNK inhibitors. The best models were obtained for the receptor-based alignment with CoMSIA combining steric (S), electrostatic (E), and hydrogen bond donor (D) and hydrogen bond acceptor (A) fields (q² = 0.759, r² = 0.966, r²_pred= 0.703). Based on the contour maps of RB CoMSIA model, some key structural factors responsible for inhibitory activity were investigated. Large groups at N-substituent or R6 position are preferred to interact with hydrophobic residues Ile70, Asp150, Ala151, Asn152 and Ser193. Electron-donating or hydrogen bond donor groups on the isatin ring would form polar and hydrogen bond with the negative-charged residue Glu147. In addition, electron-withdrawing groups or hydrogen bond acceptor group near the N-substituent would enhance inhibitory activity. The results are in good accordance and complementary to each other. The developed models could provide guidance in the rational design of more potent and selective JNK inhibitors.

Key words: JNK3, N-benzyl isatin oximes, 3D-QSAR, Molecular docking

CLC Number:

R916

Supporting:

Yue Zhou, Na Zhang^*, Rugang Zhong. Docking and 3D-QSAR studies of N-benzyl isatin oximes as JNK3 inhibitors[J]. .

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