GLIDA: GPCR—ligand database for chemical genomics drug discovery—database and tools update

Yasushi Okuno 1 Akiko Tamon 0 Hiroaki Yabuuchi 1 Satoshi Niijima 1 Yohsuke Minowa 1 Koichiro Tonomura 1 Ryo Kunimoto 1 Chunlai Feng 1 0 Bio Science Group , IT Solution Div.1, Industry Solution Business Unit , Mitsui Knowledge Industry, Osaka city, Japan 1 Department of PharmacoInformatics, Center for Integrative Education of Pharmacy Frontier, Graduate School of Pharmaceutical Sciences, Kyoto University G-protein coupled receptors (GPCRs) represent one of the most important families of drug targets in pharmaceutical development. GLIDA is a public GPCR-related Chemical Genomics database that is primarily focused on the integration of information between GPCRs and their ligands. It provides interaction data between GPCRs and their ligands, along with chemical information on the ligands, as well as biological information regarding GPCRs. These data are connected with each other in a relational database, allowing users in the field of Chemical Genomics research to easily retrieve such information from either biological or chemical starting points. GLIDA includes a variety of similarity search functions for the GPCRs and for their ligands. Thus, GLIDA can provide correlation maps linking the searched homologous GPCRs (or ligands) with their ligands (or GPCRs). By analyzing the correlation patterns between GPCRs and ligands, we can gain more detailed knowledge about their conserved molecular recognition patterns and improve drug design efforts by focusing on inferred candidates for GPCR-specific drugs. This article provides a summary of the GLIDA database and user facilities, and describes recent improvements to database design, data contents, ligand classification programs, similarity search options and graphical interfaces. GLIDA is publicly available at http://pharminfo.pharm.kyoto-u.ac.jp/ services/glida/. We hope that it will prove very useful for Chemical Genomics research and GPCRrelated drug discovery. - The family of G-protein coupled receptors (GPCRs) represents one of the most important classes of pharmaceutical targets (1). Among the more than 1000 GPCRs encoded in the human genome, more than 400 are of potential therapeutic interest (2). Currently the drugs available on the market address only 30 GPCRs, which represent a small fraction of the GPCR target family. A large majority of human-derived GPCRs still remain promising drug targets, and thus a key goal of GPCR research related to drug design is to identify new ligands for such target GPCRs. With the unprecedented accumulation of genomic information, databases and bioinformatics have become essential tools to guide GPCR research (3). The GPCRDB (2) and IUPHAR receptor database (IUPHAR-RD) (4) are representatives of widely used public databases covering GPCRs. These databases, which provide substantial data on the GPCR proteins and pharmacological information on receptor proteins containing GPCRs, are mainly focused on biological aspects of the GPCR gene products or proteins. In spite of the significance of ligand compounds as drug leads, the relationships between GPCRs and their ligands and/or chemical information on the ligands themselves are not yet fully covered. On the other hand, there is increasing interest in publicly collecting and applying chemical as well as biological information in the post-genome era (58). This new trend is called Chemical Genomics, and it aims to identify all possible chemical ligands and drugs for all targets families (9,10). There is a vast amount of information on the interactions between small molecules and proteins/genes. However, compoundprotein interactions have not yet been analyzed on a large scale, and there are no effective methods to extract meaningful information from the data in a comprehensive manner. Therefore, we need to integrate chemoinformatics and bioinformatics into a common computational platform for mining of Chemical Genomics data (11). GLIDA (GPCR-Ligand DAtabase) is a public GPCRrelated Chemical Genomics database designed to simultaneously mine biological information on GPCRs and chemical information on their ligands. It provides various analytical data regarding GPCRligand correlations by incorporating bioinformatics and chemoinformatics techniques, and thus it should prove very useful for GPCRrelated drug discovery from the viewpoint of Chemical Genomics research. There have been several major improvements to GLIDA since it was last described in Ref. (12): (i) there are more increments in the entries of the ligands and the corresponding ligandGPCR pairs; (ii) the ligands are originally classified using a new strategy; (iii) additional options are available within the similarity search program for the GPCRs and ligands and (iv) the graphical interface to display the correlation maps between GPCRs and ligands has been enhanced. GLIDA contains three types of primary data: biological information on GPCRs, chemical information on their ligands and information on binding of the GPCRligand pairs. The GPCR entries were acquired from human, mouse and rat entries deposited in the GPCRDB because these three species include sufficient information regarding ligands, and rats and mice are representative model animals used in drug discovery research. The ligandbinding information was manually collected and curated using various public web sites and commercial databases such as the IUPHAR-RD, PubMed (5), PubChem (5), DrugBank (13), Ki Database (14) and MDL ISIS/Base 2.5. Table 1 indicates the size and scope of the GLIDA database. In particular, we have dramatically expanded the entry number of ligands and the corresponding ligandGPCR pairs. The latest GLIDA version includes 24 077 ligand entries and 39 140 GPCRligand pair entries, representing nearly 35-fold and 20-fold increases, respectively, since the last publication of GLIDA in 2006. The total number of GPCR entries remains unchanged, but entries with associated ligand information have increased slightly, suggesting that it is difficult to de-orphan the GPCRs whose ligands have not yet been identified (15). GPCR and ligand data The database lists general information on GPCR and ligand data, respectively. The general information table listing GPCRs contains gene names, family names, protein sequences (in fasta format) and links to other biological databases, such as GPCRDB, UniProt (16), IUPHARRD, Entrez Gene (17) and KEGG (18). The ligand result page provides a general information table containing names, molecular structures, CAS registry numbers, formulas, molecular weights, structure files and links to aMolecular structures consist of MDL MOL files and original files converted into KEGG atom types. The numbers of MDL MOL files and KEGG-type files are 23 216 and 23 214, respectively. PCA calculation was performed for 23 214 KEGG-type files. bThis cluster number (300) is different from the number of the selected principal components (314). No compounds were assigned to 14 principal components. Pub (...truncated)