| Title: | Enabling the hypothesis-driven prioritization of ligand candidates in big databases: Screenlamp and its application to GPCR inhibitor discovery for invasive species control |
| Author(s): | Raschka S; Scott AM; Liu N; Gunturu S; Huertas M; Li W; Kuhn LA; |
| Address: | "Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, 48824, USA. Department of Fisheries and Wildlife, Michigan State University, East Lansing, MI, 48824, USA. Department of Chemistry, Michigan State University, East Lansing, MI, 48824, USA. Department of Computer Science and Engineering, Michigan State University, East Lansing, MI, 48824, USA. Department of Biology, Texas State University, San Marcos, TX, 78666, USA. Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, 48824, USA. KuhnL@msu.edu. Department of Fisheries and Wildlife, Michigan State University, East Lansing, MI, 48824, USA. KuhnL@msu.edu. Department of Computer Science and Engineering, Michigan State University, East Lansing, MI, 48824, USA. KuhnL@msu.edu. Protein Structural Analysis and Design Lab, Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, 48824-1319, USA. KuhnL@msu.edu" |
| DOI: | 10.1007/s10822-018-0100-7 |
| ISSN/ISBN: | 1573-4951 (Electronic) 0920-654X (Linking) |
| 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" |
| Keywords: | "Animals Bile Acids and Salts/chemistry *Databases, Chemical *Drug Discovery Drug Evaluation, Preclinical/methods Introduced Species Ligands Petromyzon Protein Binding Receptors, G-Protein-Coupled/*antagonists & inhibitors Small Molecule Libraries/chemistr;" |
| Notes: | "MedlineRaschka, Sebastian Scott, Anne M Liu, Nan Gunturu, Santosh Huertas, Mar Li, Weiming Kuhn, Leslie A eng Research Support, Non-U.S. Gov't Netherlands 2018/02/01 J Comput Aided Mol Des. 2018 Mar; 32(3):415-433. doi: 10.1007/s10822-018-0100-7. Epub 2018 Jan 30" |
