Protein-ligand interaction prediction: an improved chemogenomics approach.
BACKGROUND
Predicting interactions between small molecules and proteins is a crucial step to decipher many biological processes, and plays a critical role in drug discovery. When no detailed 3D structure of the protein target is available, ligand-based virtual screening allows the construction of predictive models by learning to discriminate known ligands from non-ligands. However, the accuracy of ligand-based models quickly degrades when the number of known ligands decreases, and in particular the approach is not applicable for orphan receptors with no known ligand.


RESULTS
We propose a systematic method to predict ligand-protein interactions, even for targets with no known 3D structure and few or no known ligands. Following the recent chemogenomics trend, we adopt a cross-target view and attempt to screen the chemical space against whole families of proteins simultaneously. The lack of known ligand for a given target can then be compensated by the availability of known ligands for similar targets. We test this strategy on three important classes of drug targets, namely enzymes, G-protein-coupled receptors (GPCR) and ion channels, and report dramatic improvements in prediction accuracy over classical ligand-based virtual screening, in particular for targets with few or no known ligands.


BACKGROUND
All data and algorithms are available as Supplementary Material.
Jacob
Laurent
L
Mines ParisTech, Centre for Computational Biology, 35 rue Saint Honoré, F-77305 Fontainebleau, Institut Curie and INSERM, U900, F-75248, Paris, France. laurent.jacob@ensmp.fr
Vert
Jean-Philippe
JP
D000465:Algorithms; D001665:Binding Sites; D030562:Databases, Protein; D015195:Drug Design; D023281:Genomics; D007473:Ion Channels / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
D007473:Ion Channels; D008024:Ligands; D011506:Proteins; D043562:Receptors, G-Protein-Coupled