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Selenoglycosides in silico: ab initio-derived reparameterization of MM4, conformational analysis using histo-blood group ABH antigens and lectin docking as indication for potential of bioactivity

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Abstract

The identification of glycan epitopes such as the histo-blood group ABH determinants as docking sites for bacterial/viral infections and signals in growth regulation fuels the interest to develop non-hydrolysable mimetics for therapeutic applications. Inevitably, the required substitution of the linkage oxygen atom will alter the derivative’s topology. Our study addresses the question of the impact of substitution of oxygen by selenium. In order to characterize spatial parameters and flexibility of selenoglycosides, we first performed ab initio calculations on model compounds to refine the MM4 force field. The following application of the resulting MM4R version appears to reduce the difference to ab initio data when compared to using the MM4 estimator. Systematic conformational searches on the derivatives of histo-blood group ABH antigens revealed increased flexibility with acquisition of additional low-energy conformer(s), akin to the behavior of S-glycosides. Docking analysis using the Glide program for eight test cases indicated potential for bioactivity, giving further experimental investigation a clear direction to testing Se-glycosides as lectin ligands.

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Acknowledgments

Financial support from the Swedish Medical Research Council (K2000-03x-00006-36A), the research initiative LMUexcellent, an EC Marie Curie Research Training Network grant (MRTN-CT-2005-019561) and Biognos AB (Göteborg) is gratefully acknowledged. Also, access to the Linux cluster at the Institute of Biomedicine, Gothenburg University, Sweden is gratefully acknowledged. We are also grateful to the reviewers of the manuscript for their expert input.

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Authors and Affiliations

  1. Institute of Biomedicine/Section of Medical Biochemistry, University of Gothenburg, Medicinaregatan 9, 40530, Gothenburg, Sweden

    Francesco Strino & Per-Georg Nyholm

  2. Biognos AB, Generatorsgatan 1, 40274, Gothenburg, Sweden

    Francesco Strino, Chaitanya A. K. Koppisetty & Per-Georg Nyholm

  3. Department of Chemistry, National Changhua University of Education, Changhua, 50058, Taiwan

    Jenn-Huei Lii

  4. Department of Computer Science and Engineering, Chalmers University of Technology, 41296, Gothenburg, Sweden

    Chaitanya A. K. Koppisetty

  5. Institut für Physiologische Chemie, Tierärztliche Fakultät, Ludwig-Maximilians-Universität München, Veterinärstr. 13, 80539, München, Germany

    Hans-Joachim Gabius

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  1. Francesco Strino
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  2. Jenn-Huei Lii
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Correspondence to Per-Georg Nyholm.

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Strino, F., Lii, JH., Koppisetty, C.A.K. et al. Selenoglycosides in silico: ab initio-derived reparameterization of MM4, conformational analysis using histo-blood group ABH antigens and lectin docking as indication for potential of bioactivity. J Comput Aided Mol Des 24, 1009–1021 (2010). https://doi.org/10.1007/s10822-010-9392-y

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  • DOI: https://doi.org/10.1007/s10822-010-9392-y

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