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Multivariate QSAR, similarity search and ADMET studies based in a set of methylamine derivatives described as dopamine transporter inhibitors

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Abstract

The dopamine transporter (DAT), responsible for the regulation of dopaminergic neurotransmission, is implicated in the etiology of several neuropsychiatric disorders which, in turn, have contributed to high rates of disability and numerous deaths in recent years, significantly impacting the global health system. Although the research for new drugs for the treatment of neuropsychiatric disorders has evolved in recent years, the availability of DAT-selective drugs that do not generate the same psychostimulant effects observed in drugs of abuse remains scarce. Therefore, we performed a QSAR study based on a dataset of 36 methylamine derivatives described as DAT inhibitors. The model was obtained based only in descriptors derived from 2D structures, and it was validated and generated satisfactory results considering the metrics used for internal and external validation. Subsequently, a virtual screening step also based on 2D similarity was performed, where it was possible to identify a total of 1157 compounds. After a series of reductions of the set using toxicity filters, applicability domain evaluation, and pharmacokinetic properties in silico assessment, seven hit compounds were selected as the most promising to be used, in future studies, as new scaffolds for the development of new DAT inhibitors.

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Acknowledgements

The authors would like to thank the Fundação Araucária (FAPPR) and PROAP/CAPES.

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Authors and Affiliations

  1. Theorical Medicinal and Environmental Chemistry Laboratory (LQMAT), Department of Pharmacy, Western Paraná State University (UNIOESTE), 2069 Universitária St., Cascavel, PR, 85819-110, Brazil

    Luiz Henrique Dias de Oliveira & Eduardo Borges de Melo

  2. Laboratory of Modeling and Computational Chemistry, Department of Biological and Health Sciences, Federal University of Amapá, Macapá, AP, 68902-280, Brazil

    Jorddy Neves Cruz & Cleydson Breno Rodrigues dos Santos

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  1. Luiz Henrique Dias de Oliveira
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All authors contributed equally to the study, through periodic meetings to discuss the study data.

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de Oliveira, L.H.D., Cruz, J.N., dos Santos, C.B.R. et al. Multivariate QSAR, similarity search and ADMET studies based in a set of methylamine derivatives described as dopamine transporter inhibitors. Mol Divers (2023). https://doi.org/10.1007/s11030-023-10724-5

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