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Dihydrofolate reductase inhibitors: a quantitative structure–activity relationship study using 2D-QSAR and 3D-QSAR methods

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Abstract

In this work, we study the structure–activity relationship of a series of Dihydrofolate reductase inhibitors by two-dimensional quantitative activity–structure relationship and three-dimensional quantitative activity–structure relationship techniques. The two-dimensional quantitative activity–structure relationship models were developed by using two different types of topological molecular descriptors, PaDEL and Dragon descriptors. The models showed an excellent predictive power, R 2 train = 0.916 and R 2 val = 0.806 for the PaDEL, and R 2 train = 0.952 and R 2 val = 0.963 for those obtained with Dragon descriptors. Simple molecular descriptors as maxHCsats, IC3, SPI, SIC2, and GATS5p were adequate to obtain predictive models. The three-dimensional quantitative activity–structure relationship was performed through three variable selected approaches, Partial Linear Square (PLS), Fractional Factorial Design (FFD) and Uninformative Variable Elimination-Partial Linear Square (UVE-PLS) using the Open3DQSAR software. All the 2D and 3D models were validated using two compounds (number 24 and 25), which were synthesized and presented here for the first time. Their biological activities were correctly predicted by all the quantitative activity–structure relationship models. Finally, we proposed three compounds (26, 27, and 28), which showed a high predicted Dihydrofolate reductase inhibitory activity. Molecular docking study suggested that compounds bind to receptor similarly to the most active inhibitors.

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Acknowledgments

This work was supported by Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional de San Luis (UNSL), Universidad de Jaén and the Consejería de Innovación, Ciencia y Empresa (Junta de Andalucía, Spain). We thank “Centro de Instrumentación Científico-Técnica” of Universidad de Jaén and the staff for the data collection.

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Authors and Affiliations

  1. Departamento de Química, Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, Chacabuco 915, San Luis, 5700, Argentina

    Juan C. Garro Martinez, Matias F. Andrada, Esteban G. Vega-Hissi, Francisco M. Garibotto, Ricardo D. Enriz & Mario R. Estrada

  2. IMIBIO-CONICET, UNSL, Chacabuco 915, San Luis, 5700, Argentina

    Juan C. Garro Martinez, Esteban G. Vega-Hissi, Francisco M. Garibotto & Ricardo D. Enriz

  3. Departamento de Química Inorgánica y Orgánica, Universidad de Jaén, 23071, Jaén, Spain

    Manuel Nogueras, Ricaurte Rodríguez & Justo Cobo

  4. Departamento de Química, Universidad Nacional de Colombia, Ciudad Universitaria, Carrera 30, No. 45-03, Bogotá, Colombia

    Ricaurte Rodríguez

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  1. Juan C. Garro Martinez
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  2. Matias F. Andrada
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Correspondence to Juan C. Garro Martinez.

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Garro Martinez, J.C., Andrada, M.F., Vega-Hissi, E.G. et al. Dihydrofolate reductase inhibitors: a quantitative structure–activity relationship study using 2D-QSAR and 3D-QSAR methods. Med Chem Res 26, 247–261 (2017). https://doi.org/10.1007/s00044-016-1742-4

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