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Current Computer-Aided Drug Design

Author(s): Jing Huang, Ye Yuan, Xiaoxiao Zhu, Guodong Li, Ya Xu, Wenlin Chen and Ying Zhu*

DOI: 10.2174/1573409918666220427120524

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Identification of Pim-1 Kinase Inhibitors by Pharmacophore Model, Molecular Docking-based Virtual Screening, and Biological Evaluation

Page: [240 - 246] Pages: 7

  • * (Excluding Mailing and Handling)

Abstract

Aim: This study aimed at screening and development of Pim-1 inhibitors as anticancer agent.

Background: Pim-1, a member of the Ser/Thr kinase family, plays a crucial role in cell proliferation and is being regarded as a promising target for cancer therapeutics.

Objective: The present work focused on screening more potent Pim-1 inhibitors by in-silico method and biological evaluation.

Materials and Methods: To identify more potent Pim-1 inhibitors, a GALAHAD pharmacophore model was constructed based on nine known Pim-1 inhibitors and followed by in silico screening including pharmacophore and molecular docking-based virtual screening. The hit compounds were further assessed the Pim-1, 2, and 3 kinase activities and the anticancer inhibition property against human myeloma RPMI-8226 and U266 cells using cytotoxicity studies.

Results: Based on Qfit value (from pharmacophore), docking score and clustering analysis, six compounds including C445_0268, C470_0769, 4456_0744, 0806_0325, G395_1510 and V023_3227 were hit. Binding mode analysis showed that hydrogen bond, hydrophobic and π-π stacking interactions dominated the bindings of these compounds to Pim-1. The further biological evaluation indicated that compounds C445_0268 and C470_0769 possessed excellent pan-Pim kinase activities and inhibited the growths of RPMI-8226 and U266 cell lines with IC50 values lower than 3.75 μM.

Conclusion: We reported a series of Pim-1 small molecule inhibitors that could serve as the lead compounds to develop new targeted anticancer therapeutics.

Keywords: Pim-1, pharmacophore, virtual screening, inhibitor, GALAHAD, molecular docking.

Graphical Abstract

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