It is very difficult to identify a pocket by using this incomplete structure Open in a separate window Fig. the potential drugs can be further selected and optimized by analyzing the sequence conservation, critical interactions, and hydrophobicity of recognized drug pockets. HKPocket also provides online visualization and pse files of all recognized pouches. Conclusion The HKPocket database would be helpful for drug testing and optimization. Besides, drugs targeting the non-catalytic pouches would cause fewer side effects. HKPocket is usually available at http://zhaoserver.com.cn/HKPocket/HKPocket.html. strong class=”kwd-title” Keywords: Pocket database, Human kinase proteins, Drug discovery, Side effects Background Kinase proteins are considered as one of the most attractive drug targets for drug discovery targeting cancer, chronic neurodegenerative or other diseases [1C4]. Previous studies have highlighted two major strategies targeting kinases: ATP-binding inhibitors (type I and II) and non-ATP inhibitors (type III and IV) [3, 5]. Currently, most developed drugs are ATP-competitive inhibitors [6, 7]. Andrea et al. performed a systematic analysis of catalytic ATP-binding pouches. Their results showed that ATP-binding pouches are highly conserved [8]. Therefore, the ATP-competitive drugs may inhibit most of the kinase proteins and cause side effects, such as hypertension, hand-foot skin reaction and acute renal failure [9C11]. Type III and type IV inhibitors are usually very selective and have fewer side effects because their targeted binding sites are usually unique to a particular kinase [3, 5, 12]. Thus, there is an urgent need to develop new drugs targeting non-catalytic pockets to reduce side effects. Computer-aided drug design is usually widely used in drug development to shorten the time and reduce the cost of experiments [13C22]. There are several existing kinase databases with sequence, structure or drug information. For example, (1) kinase protein databases (the Kinase.com, the Protein Kinase Resource, the Target Informatics Platform and the KinG database) explore the genomics, development and function of protein kinases [23C26]; (2) experimental information databases (the Kinase Validation Set, the KINOMEscan data, the PhosphoBase, the KinMutBase, and the Kinase Pathway Database) contain compound bioactivity, phosphorylation and mutation experimental data [27C32]; (3) kinase catalytic pocket databases (the Kinase Knowledgebase and the Kinase-Ligand Conversation Fingerprints tBID and Structure database) analyzed the structural and sequence features of ATP-binding and closely nearby pouches [33C35]. However, most of the drugs in these databases are ATP-competitive leading to many side effects. In addition, the available kinase information cannot be tBID directly used in the kinase drug study. The well-analyzed kinase structures are still limited. Thus, a comprehensive and tBID updated human kinase pocket database is usually urgently needed especially for inhibitors targeting non-catalytic pouches with fewer side effects. Recently, the tBID kinase family is very well covered by tertiary structures, making it possible to perform a systematic analysis of potential selective binding pouches. Here, we performed a systematic analysis of binding pouches from 255 available human kinase structures to provide potential selective binding pouches and tBID developed HKPocket database with sequence, structure, hydrophilic-hydrophobic and druggability information for kinase drug design. Construction and content HKPocket database construction The whole human kinome contains a total of 518 kinases with 478 common kinases and 40 atypical kinases. The 478 common kinases were divided into nine groups (AGC: 63, CAMK: 74, CK1: 12, CMGC: 61, RGC: 5, STE: 47, TK: 90, TKL: 43, Other: 83) [36]. A workflow of building the HKPocket database is usually shown in Fig.?1. We extracted structures from your PDB (Protein Data Lender) database [37] based on the human kinase UniProt ID [38]. You will find 313 human kinase structures (AGC: 41, CAMK: 43, CK1: 10, CMGC: 37, RGC: Mouse monoclonal to CD64.CT101 reacts with high affinity receptor for IgG (FcyRI), a 75 kDa type 1 trasmembrane glycoprotein. CD64 is expressed on monocytes and macrophages but not on lymphocytes or resting granulocytes. CD64 play a role in phagocytosis, and dependent cellular cytotoxicity ( ADCC). It also participates in cytokine and superoxide release 0, STE: 31, TK: 73, TKL: 34, Other: 44). We obtained the kinase protein structures by keeping high-resolution structures (resolution ?4??) and removing the short proteins with the length fewer than 250 residues. We considered the length cut off based on the following considerations: (i) 90% of kinase proteins are larger than 250 residues [39, 40]. (ii) it is very.
