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Mixed 2D–3D-LQTA-QSAR study of a series of Plasmodium falciparum dUTPase inhibitors

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Abstract

The spread of antimalarial drug resistance and lack of effective vaccines into consideration drive significant role to develop novel antimalarial agents for the treatment of malaria. The Plasmodium falciparum deoxyuridine 5′-triphosphate nucleotidohydrolase (dUTPase) has been identified as a promising target for new drug development. In this study, we report a receptor-dependent mixed 2D- and 3D-QSAR model using the LQTA-QSAR methodology on a series of dUTPase inhibitors. QSAR models were constructed by a training set of 55 compounds with specific stereochemistry and an external set of 18. The model satisfied a set of rigorous validation criteria and performed well in the prediction of an external test set. The proposed model also checked for free from chance correlation, reliability, and robustness by y-randomization and leave-N-out tests. Final model provided the following statistics (R 2 = 0.85, Q 2LOO  = 0.78 and Q 2ext  = 0.76) with only 12 descriptors and 3 latent variables. We showed that a combination of 2D classic and 3D molecular field descriptors could lead to relevant QSAR models, that in comparison with model solely generated by 3D descriptors has improved and illustrated more robustness and prediction ability. Visualization of the descriptors of the best model helps us to interpret the model from the chemical point of view, supporting the applicability of this new approach in rational drug design.

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Acknowledgments

The authors wish to thank the department of pharmacy of the Federal University of Rio Grande do Norte, in the name of Prof. Nilsen Carvalho Fernandes de Oliveira Filho, for providing the required resources so that this work could be developed. I also wish to thank PPgCF/UFRN for the English revision.

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Authors and Affiliations

  1. Pharmacy Department, Federal University of Rio Grande do Norte, General Gustavo Cordeiro de Farias Street, Petrópolis, Natal, RN, CEP 59012-570, Brazil

    Rodolfo André de Araújo Santos, Carolina Arruda Braz & Euzébio Guimarães Barbosa

  2. Department of Chemistry, Faculty of Sciences, K. N. Toosi University of Technology, Tehran, Iran

    Jahan B. Ghasemi & Reihaneh Safavi-Sohi

Authors
  1. Rodolfo André de Araújo Santos
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  2. Carolina Arruda Braz
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  3. Jahan B. Ghasemi
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  4. Reihaneh Safavi-Sohi
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  5. Euzébio Guimarães Barbosa
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Correspondence to Euzébio Guimarães Barbosa.

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de Araújo Santos, R.A., Braz, C.A., Ghasemi, J.B. et al. Mixed 2D–3D-LQTA-QSAR study of a series of Plasmodium falciparum dUTPase inhibitors. Med Chem Res 24, 1098–1111 (2015). https://doi.org/10.1007/s00044-014-1189-4

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  • DOI: https://doi.org/10.1007/s00044-014-1189-4

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