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Furanone derivatives as new inhibitors of CDC7 kinase: development of structure activity relationship model using 3D QSAR, molecular docking, and in silico ADMET

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Abstract

Cell division cycle 7 (CDC7) is a serine/threonine kinase, which plays a vital role in the replication initiation of DNA synthesis. Overexpression of the CDC7 in various tumor growths and in cell proliferation makes it a promising target for treatment of cancers. To investigate the binding between the CDC7 and furanone inhibitors, and in order to design highly potent inhibitors, a three-dimensional quantitative structure activity relationship (3D-QSAR) with molecular docking was performed. The optimum CoMSIA model showed significant statistical quality on all validation methods with a determination coefficient (R2 = 0.945), bootstrapping R2 mean (BS-R2 = 0.960), and leave-one-out cross-validation (Q2) coefficient of 0.545. The predictability of this model was evaluated by external validation using a test set of nine compounds with a predicted determination coefficient R2test of 0.96, besides the mean absolute error (MAE) of the test set was 0.258 log units. The extracted contour maps were used to identify the important regions, where the modification was necessary to design a new molecule with improved activity. Furthermore, a good consistency between the molecular docking and contour maps strongly demonstrates that the molecular modeling is reliable. Based on those obtained results, we designed several new potent CDC7 inhibitors, and their inhibitory activities were validated by the molecular models. Additionally, those newly designed inhibitors showed promising results in the preliminary in silico ADMET evaluations.

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Acknowledgments

We are grateful to the “Association Marocaine des Chimistes Théoriciens” (AMCT) and “Moroccan Centre of Scientific and Technique research” (CNRST) for their pertinent help concerning the programs.

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Authors and Affiliations

  1. School of Sciences, Moulay Ismail University, Meknes, Morocco

    Adnane Aouidate, Adib Ghaleb, Mounir Ghamali, Samir Chtita, Abdellah Ousaa, M’barek Choukrad, Abdelouahid Sbai & Tahar Lakhlifi

  2. High School of Technology, Moulay Ismail University, Meknes, Morocco

    Mohammed Bouachrine

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  1. Adnane Aouidate
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Correspondence to Adnane Aouidate.

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This chapter does not contain any studies with human participants or animals performed by any of the authors.”

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Aouidate, A., Ghaleb, A., Ghamali, M. et al. Furanone derivatives as new inhibitors of CDC7 kinase: development of structure activity relationship model using 3D QSAR, molecular docking, and in silico ADMET. Struct Chem 29, 1031–1043 (2018). https://doi.org/10.1007/s11224-018-1086-4

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