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3D QSAR pharmacophore model based on diverse IKKβ inhibitors

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Abstract

The inhibitor kappaB kinase β (IKKβ) is a serine-threonine protein kinase that is critically involved in the activation of the transcription factor nuclear factor kappa B (NF-κB) in response to various inflammatory stimuli. IKKβ-selective inhibitors could prove useful for the treatment of inflammatory diseases. In the absence of structural information, a ligand-based approach can serve as an alternative to the virtual screening of large databases. We have developed a 3D QSAR pharmacophore model based on 23 IKKβ inhibitors with 3 nM ≤ IC50 ≤ 50000 nM. A four-feature pharmacophore containing a hydrophobic (Hy) feature, two ring aromatic (RA) features, and a hydrogen bond donor (D) feature was constructed. It yielded a correlation coefficient of 0.93 with experimentally determined activity data, and a correlation coefficient of 0.77 with training set activity data. The best hypothesis, Hypo 1, was validated by estimating the activities of 136 compounds in a test set. As well as the correlation analysis and test set activity estimation, a Fisher’s validation test was conducted at the 95% confidence level. The pharmacophore model’s specificity and selectivity were determined in an exhaustive enrichment study.

A 3D-QSAR pharmacophore model based on the IKKβ inhibitors

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Acknowledgments

This work was supported by the Korea Institute of Science and Technology (KIST).

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Authors and Affiliations

  1. Center for Chemoinformatics Research, Life Sciences Division, Korea Institute of Science and Technology, P.O. Box 131, Cheongryang, Seoul, 130-650, Republic of Korea

    Shanthi Nagarajan, Asif Ahmed, Hyunah Choo, Yong Seo Cho, Kye Jung Shin & Ae Nim Pae

  2. School of Science, Korea University of Science and Technology, 52 Eoeun dong, Yuseong-gu, Daejeon, 305-333, Republic of Korea

    Shanthi Nagarajan & Asif Ahmed

  3. Biotechnology and Genetic Engineering Discipline, Khulna University, Khulna, 9208, Bangladesh

    Asif Ahmed

  4. Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea

    Kwang-Seok Oh & Byung Ho Lee

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  1. Shanthi Nagarajan
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  2. Asif Ahmed
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  3. Hyunah Choo
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  4. Yong Seo Cho
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  5. Kwang-Seok Oh
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  6. Byung Ho Lee
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  7. Kye Jung Shin
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  8. Ae Nim Pae
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Correspondence to Ae Nim Pae.

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Nagarajan, S., Ahmed, A., Choo, H. et al. 3D QSAR pharmacophore model based on diverse IKKβ inhibitors. J Mol Model 17, 209–218 (2011). https://doi.org/10.1007/s00894-010-0714-8

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  • DOI: https://doi.org/10.1007/s00894-010-0714-8

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