Interrogating the druggable genome with structural informatics.
Structural genomics projects are producing protein structure data at an unprecedented rate. In this paper, we present the Target Informatics Platform (TIP), a novel structural informatics approach for amplifying the rapidly expanding body of experimental protein structure information to enhance the discovery and optimization of small molecule protein modulators on a genomic scale. In TIP, existing experimental structure information is augmented using a homology modeling approach, and binding sites across multiple target families are compared using a clique detection algorithm. We report here a detailed analysis of the structural coverage for the set of druggable human targets, highlighting drug target families where the level of structural knowledge is currently quite high, as well as those areas where structural knowledge is sparse. Furthermore, we demonstrate the utility of TIP's intra- and inter-family binding site similarity analysis using a series of retrospective case studies. Our analysis underscores the utility of a structural informatics infrastructure for extracting drug discovery-relevant information from structural data, aiding researchers in the identification of lead discovery and optimization opportunities as well as potential "off-target" liabilities.
Hambly
Kevin
K
Eidogen-Sertanty, Inc., 9381 Judicial Dr.,Suite 200, San Diego, CA 92121, USA. khambly@eidogen-sertanty.com
Danzer
Joseph
J
Muskal
Steven
S
Debe
Derek A
DA
D016208:Databases, Factual; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015894:Genome, Human; D023281:Genomics / Q000379:methods; D006801:Humans; D048088:Informatics; D008958:Models, Molecular; D015394:Molecular Structure; D011506:Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D011506:Proteins