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Enabling the hypothesis-driven prioritization of ligand candidates in big databases: Screenlamp and its application to GPCR inhibitor discovery for invasive species control

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Abstract

While the advantage of screening vast databases of molecules to cover greater molecular diversity is often mentioned, in reality, only a few studies have been published demonstrating inhibitor discovery by screening more than a million compounds for features that mimic a known three-dimensional (3D) ligand. Two factors contribute: the general difficulty of discovering potent inhibitors, and the lack of free, user-friendly software to incorporate project-specific knowledge and user hypotheses into 3D ligand-based screening. The Screenlamp modular toolkit presented here was developed with these needs in mind. We show Screenlamp’s ability to screen more than 12 million commercially available molecules and identify potent in vivo inhibitors of a G protein-coupled bile acid receptor within the first year of a discovery project. This pheromone receptor governs sea lamprey reproductive behavior, and to our knowledge, this project is the first to establish the efficacy of computational screening in discovering lead compounds for aquatic invasive species control. Significant enhancement in activity came from selecting compounds based on one of the hypotheses: that matching two distal oxygen groups in the 3D structure of the pheromone is crucial for activity. Six of the 15 most active compounds met these criteria. A second hypothesis—that presence of an alkyl sulfate side chain results in high activity—identified another 6 compounds in the top 10, demonstrating the significant benefits of hypothesis-driven screening.

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Abbreviations

2D:

Two-dimensional

3D:

Three-dimensional

3kPZS:

3-keto petromyzonol sulfate

3sPZS:

Trisulfated petromyzonol sulfate

GLL:

GPCR Ligand Library

GPCR:

G protein-coupled receptor

Mgβ1AR:

β1-Adrenergic receptor from Meleagris gallopavo

PAIN:

Pan-assay interference compound

PZS:

Petromyzonol sulfate

SQL:

Structured Query Language

SLOR1:

Sea lamprey olfactory receptor 1

TFM:

Trifluoromethyl nitrophenol

EOG:

Electro-olfactogram

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Acknowledgements

We thank Qinghua Yuan for her contributions to the homology modeling of SLOR1 and Stacey Kneeshaw for evaluating protein–ligand energy minimization protocols for SLOR1-3kPZS docking and analyzing charge distributions for matching functional groups. This research was supported by funding from the Great Lakes Fishery Commission from 2012-present (Project ID: 2015_KUH_54031). We gratefully acknowledge OpenEye Scientific Software (Santa Fe, NM) for providing academic licenses for the use of their ROCS, OMEGA, QUACPAC (molcharge), and OEChem toolkit software.

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Author notes

  1. Mar Huertas

    Present address: Department of Biology, Texas State University, San Marcos, TX, 78666, USA

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, 48824, USA

    Sebastian Raschka, Nan Liu, Santosh Gunturu & Leslie A. Kuhn

  2. Department of Fisheries and Wildlife, Michigan State University, East Lansing, MI, 48824, USA

    Anne M. Scott, Mar Huertas, Weiming Li & Leslie A. Kuhn

  3. Department of Chemistry, Michigan State University, East Lansing, MI, 48824, USA

    Nan Liu

  4. Department of Computer Science and Engineering, Michigan State University, East Lansing, MI, 48824, USA

    Nan Liu & Leslie A. Kuhn

  5. Protein Structural Analysis and Design Lab, Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, 48824-1319, USA

    Leslie A. Kuhn

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  1. Sebastian Raschka
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Correspondence to Leslie A. Kuhn.

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Sebastian Raschka and Anne M. Scott contributed equally to this work.

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Raschka, S., Scott, A.M., Liu, N. et al. Enabling the hypothesis-driven prioritization of ligand candidates in big databases: Screenlamp and its application to GPCR inhibitor discovery for invasive species control. J Comput Aided Mol Des 32, 415–433 (2018). https://doi.org/10.1007/s10822-018-0100-7

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