Molecular and Cellular Pharmacology, Vol 5, No 2 (2013)

Identification of Novel c-Jun-N-Terminal Kinase-1 Inhibitors: Application of Ligand and Structure Based Virtual Screening

Abstract

In quest of novel selective JNK-1 inhibitors targeted towards type II diabetes, ligand and structure based pharmacophore generation approach were employed. In ligand based approach, a dataset of 40 inhibitors was selected as training set. The best hypothesis with one H-bond acceptor, two H-bond donor and one hydrophobic feature was selected on the basis of correlation coefficient, RMSD and cost difference of 0.89, 0.89 and 49.73, respectively. The reliability of Hypo 1 was established using three different methods, namely, cost analysis, test set prediction and cat scramble. All three methods confirmed the predictive power and robustness of the developed hypothesis. In addition to ligand based, a structure-based pharmacophore generation approach was also employed to discover novel structural characteristics for JNK-1 inhibitors. Like ligand-based approach, the structure-based hypothesis suggests the significance of hydrogen bond donors, hydrogen bond acceptors and hydrophobic groups involved in the inhibitor-JNK-1 receptor interaction. The validated pharmacophore model was then used for searching new lead compounds from NCI database. Three compounds (NSC687937, NSC210378 and NSC120934) were retrieved as structurally diverse druggable novel leads.

Keywords: JNK-1; Pharmacophore modeling; Virtual screening; Ligand-based approach; Structure-based approach; Type II diabetes; NCI database.

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