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

  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 and Anne M. Scott and Nan Liu and Santosh Gunturu and Mar Huertas and Weiming Li and Leslie A. Kuhn},
  journal={Journal of Computer-Aided Molecular Design},
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… 
6 Citations
Automated discovery of GPCR bioactive ligands.
  • S. Raschka
  • Biology
    Current opinion in structural biology
  • 2019
Automated Inference of Chemical Discriminants of Biological Activity.
The quantitative structure-activity relationship machine learning protocols described here, using decision trees, random forests, and sequential feature selection, take as input the chemical structure of a single, known active small molecule for comparison with the structure of each tested molecule.
Behavioral Responses of Sea Lamprey to Varying Application Rates of a Synthesized Pheromone in Diverse Trapping Scenarios
This study highlights that a pheromone component in a stream environment does not ubiquitously increase trap catch in all contexts, but that where, how, and when the phersomone is applied has major impacts on whether it benefits or hinders trapping efforts.
A pheromone antagonist liberates female sea lamprey from a sensory trap to enable reliable communication
This study discovered a mechanism whereby a manipulative male signal guides reliable communication in sea lamprey (Petromyzon marinus), and elucidates how communication systems that arise via deception can facilitate reliable communication.


Enabling Large-Scale Design, Synthesis and Validation of Small Molecule Protein-Protein Antagonists
A novel pharmacophore-based interactive screening technology that builds on the role anchor residues, or deeply buried hot spots, have in PPIs, and redesigns these entry points with anchor-biased virtual multicomponent reactions, delivering tens of millions of readily synthesizable novel compounds.
Ultra-High-Throughput Structure-Based Virtual Screening for Small-Molecule Inhibitors of Protein-Protein Interactions
This approach exhibits comparable performance as traditional docking methods for identifying known inhibitors acting at protein interaction sites, but because this approach is predicated on ligand/exemplar overlays, and thus does not require explicit calculation of protein-ligand interactions, exemplar screening provides a tremendous speed advantage over docking.
Large-Scale Computational Screening Identifies First in Class Multitarget Inhibitor of EGFR Kinase and BRD4
A general computational screening approach to identify novel dual kinase/bromodomain inhibitors from millions of commercially available small molecules and identified several novel BRD4 inhibitors, among them a first in class dual EGFR-BRD4 inhibitor.
Prospective Virtual Screening in a Sparse Data Scenario: Design of Small‐Molecule TLR2 Antagonists
A combined structure‐ and ligand‐based virtual screening approach to discover small‐molecule antagonists of TLR2 by computer‐aided drug design, leading to the identification of several compounds with antagonistic activity in the low‐micromolar range.
ZINC - A Free Database of Commercially Available Compounds for Virtual Screening
This paper has prepared a library of 727,842 molecules, each with 3D structure, using catalogs of compounds from vendors, and hopes that this database will bring virtual screening libraries to a wide community of structural biologists and medicinal chemists.
Scoring ligand similarity in structure‐based virtual screening
The hypothesis is that a hybrid approach, using ligand‐based scoring to rank dockings selected by protein–ligand scoring, can ensure that high‐ranking molecules mimic the shape and chemistry of a known ligand while also complementing the binding site.
Multiple protein structures and multiple ligands: effects on the apparent goodness of virtual screening results
It is seen that the relative effectiveness of virtual screening methods, as measured by the enrichment factor, is highly dependent on the particular crystal structure or ligand, and on the database being searched.
Virtual screening of chemical libraries
Interest in virtual screening is re-ignited, which is now widely used in drug discovery, albeit on a more limited scale than empirical screening.
SwissSimilarity: A Web Tool for Low to Ultra High Throughput Ligand-Based Virtual Screening
Users can be carried out on-the-fly using six different screening approaches, including 2D molecular fingerprints as well as superpositional and fast nonsuperpositional 3D similarity methodologies to provide proficient virtual screening capabilities to specialists and nonexperts in the field.