Volume 6 Supplement 1

9th German Conference on Chemoinformatics

Open Access

Using structure- and Ligand-based pharmacophores as filters to discriminate Human Aryl Sulfotransferase 1A1 (SUL1A1) binders into substrates and inhibitors

Journal of Cheminformatics20146(Suppl 1):P32

https://doi.org/10.1186/1758-2946-6-S1-P32

Published: 11 March 2014

Predicting metabolictransformation is one of major challenges in drug discovery [1]. Sulfotransferase 1A1 (SULT1A1), one of phase II metabolismenzymes, is the major SULT in adult liver catalysis [2]. It metabolizes many endogenous compounds and is relevant in carcinogenesis due to its ability to modify diverse promutagen and procarcinogen xenobiotics [3].

In order to make a discriminative model that classifies group of SULT1A1 binders into substrates and inhibitors, a combination of structure, ligand-based, and docking based pharmacophores have been generated and validated by Ligandscout [4].

On one hand, structure-based pharmacophores have been derived from PDB files of good binders (substrates and inhibitors). On the other hand, ligand-based interaction maps have been conducted from some drug classes that show different substrate/inhibitor activity towards SULT1A1.Finally, highly active substrates and inhibitors have been docked into the enzyme using GOLD [5], and subsequently molecular interaction fields have been developed for the most plausible poses.

As a retrospective validation, all pharmacophores simultaneously have been used to screen more than 100 SULT1A1 binders covering several activity classes and different chemical scaffolds. The model showed good discriminative power to differentiate between inhibitors, substrates and mixed substrates/inhibitors.

Authors’ Affiliations

(1)
Freie Universitaet Berlin, Institute of Pharmacy, Department pharmaceutical, chemistry

References

  1. Moroy G, Martiny VY, Vayer P, Villoutreix BO, Miteva MA: Toward in silico structure-based ADMET prediction in drug discovery. Drug Discov Today. 2012, 17: 44-55. 10.1016/j.drudis.2011.10.023.View ArticleGoogle Scholar
  2. Jancova P, Anzenbacher P, Anzenbacherova E: Phase II drug metabolizing enzymes. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2010, 154: 103-116. 10.5507/bp.2010.017.View ArticleGoogle Scholar
  3. Glatt H, Pauly K, Piee-Staffa A, Seidel A, Hornhardt S, Czich A: Activation of promutagens by endogenous and heterologous sulfotransferases expressed in continuous cell cultures. Toxicol Lett. 1994, 72: 13-21. 10.1016/0378-4274(94)90005-1.View ArticleGoogle Scholar
  4. Wolber G, Langer T: LigandScout: 3-D pharmacophores derived from protein-bound ligands and their use as virtual screening filters. J Chem Inf Model. 2005, 45: 160-169. 10.1021/ci049885e.View ArticleGoogle Scholar
  5. Verdonk ML, Cole JC, Hartshorn MJ, Murray CW, Taylor RD: Improved protein-ligand docking using GOLD. Proteins. 2003, 52: 609-623. 10.1002/prot.10465.View ArticleGoogle Scholar

Copyright

© Soliman and Wolber; licensee Chemistry Central Ltd. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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