Browsing by Author "Lin, Chih-Ta"

Now showing 1 - 9 of 9

Anchor-based classification and type-C inhibitors for tyrosine kinases
(2015-06-16)
Hsu, Kai-Cheng
;
Sung, Tzu-Ying
;
Lin, Chih-Ta
;
Chiu, Yi-Yuan
;
Hsu, John T. -A.
Tyrosine kinases regulate various biological processes and are drug targets for cancers. At present, the design of selective and anti-resistant inhibitors of kinases is an emergent task. Here, we inferred specific site-moiety maps containing two specific anchors to uncover a new binding pocket in the C-terminal hinge region by docking 4,680 kinase inhibitors into 51 protein kinases, and this finding provides an opportunity for the development of kinase inhibitors with high selectivity and anti-drug resistance. We present an anchor-based classification for tyrosine kinases and discover two type-C inhibitors, namely rosmarinic acid (RA) and EGCG, which occupy two and one specific anchors, respectively, by screening 118,759 natural compounds. Our profiling reveals that RA and EGCG selectively inhibit 3% (EGFR and SYK) and 14% of 64 kinases, respectively. According to the guide of our anchor model, we synthesized three RA derivatives with better potency. These type-C inhibitors are able to maintain activities for drug-resistant EGFR and decrease the invasion ability of breast cancer cells. Our results show that the type-C inhibitors occupying a new pocket are promising for cancer treatments due to their kinase selectivity and anti-drug resistance.
Dead Via Minimization by Simultaneous Routing and Redundant Via Insertion
(2010)
Lin, Chih-Ta
;
Lin, Yen-Hung
;
Su, Guan-Chan
;
Li, Yih-Lang
;
資訊工程學系
While via failure significantly contributes to yield loss during manufacturing, post-routing redundant via insertion method is the conventional means of reducing the via failure rate, but only alive vias can be protected. As existing dead vias still lower manufacturing yield, identifying a routing result with fewer dead vias can increase the redundant via insertion rate, subsequently enhancing the yield of chips. This work presents, for the first time, a redundant-via-aware routing system to retain redundant via resources in track assignment, in which redundant vias are inserted in detailed routing. The proposed via prediction scheme performs trial route using L-shaped patterns to estimate via positions. Meanwhile, the proposed redundant-via-aware detailed router gradually relaxes the limitation on the number of generated dead vias during path searching to minimize the number of dead vias. Experimental results indicate that the proposed redundant-via-aware routing system is, to our knowledge, the first routing system that can achieve 100% redundant via insertion rate with all MCNC benchmark circuits.
Homopharma: A new concept for exploring the molecular binding mechanisms and drug repurposing
(2014-12-08)
Chiu, Yi-Yuan
;
Tseng, Jen-Hu
;
Liu, Kuan-Hsiu
;
Lin, Chih-Ta
;
Hsu, Kai-Cheng
Background: Drugs that simultaneously target multiple proteins often improve efficacy, particularly in the treatment of complex diseases such as cancers and central nervous system disorders. Many approaches have been proposed to identify the potential targets of a drug. Recently, we have introduced Space-Related Pharmamotif (SRPmotif) method to recognize the proteins that share similar binding environments. In addition, compounds with similar topology may bind to similar proteins and have similar protein-compound interactions. However, few studies have focused on exploring the relationships between binding environments and protein-compound interactions, which is important for understanding molecular binding mechanisms and helpful to be used in discovering drug repurposing. Results: In this study, we propose a new concept of "Homopharma", combining similar binding environments and protein-compound interaction profiles, to explore the molecular binding mechanisms and drug repurposing. A Homopharma consists of a set of proteins which have the conserved binding environment and a set of compounds that share similar structures and functional groups. These proteins and compounds present conserved interactions and similar physicochemical properties. Therefore, these compounds are often able to inhibit the proteins in a Homopharma. Our experimental results show that the proteins and compounds in a Homopharma often have similar protein-compound interactions, comprising conserved specific residues and functional sites. Based on the Homopharma concept, we selected four flavonoid derivatives and 32 human protein kinases for enzymatic profiling. Among these 128 bioassays, the IC50 of 56 and 25 flavonoid-kinase inhibitions are less than 10 mu M and 1 mu M, respectively. Furthermore, these experimental results suggest that these flavonoids can be used as anticancer compounds, such as oral and colorectal cancer drugs. Conclusions: The experimental results show that the Homopharma is useful for identifying key binding environments of proteins and compounds and discovering new inhibitory effects. We believe that the Homopharma concept can have the potential for understanding molecular binding mechanisms and providing new clues for drug development.
Induction of HSPA4 and HSPA14 by NBS1 overexpression contributes to NBS1-induced in vitro metastatic and transformation activity
(2010-01-06)
Wu, Chung-Yin
;
Lin, Chih-Ta
;
Wu, Min-Zu
;
Wu, Kou-Juey
;
生物資訊及系統生物研究所
Background: Nijmegen breakage syndrome (NBS) is a chromosomal-instability syndrome associated with cancer predisposition, radiosensitivity, microcephaly, and growth retardation. The NBS gene product, NBS1 (p95) or nibrin, is a part of the MRN complex, a central player associated with double-strand break (DSB) repair. We previously demonstrated that NBS1 overexpression contributes to transformation through the activation of PI 3-kinase/Akt. NBS1 overexpression also induces epithelial-mesenchymal transition through the Snail/MMP2 pathway. Methods: RT-PCR, Western blot analysis, in vitro migration/invasion, soft agar colony formation, and gelatin zymography assays were performed. Results: Here we show that heat shock protein family members, A4 and A14, were induced by NBS1 overexpression. siRNA mediated knockdown of HSPA4 or HSPA14 decreased the in vitro migration, invasion, and transformation activity in H1299 cells overexpressing NBS1. However, HSPA4 or HSPA14 induced activity was not mediated through MMP2. NBS1 overexpression induced the expression of heat shock transcription factor 4b (HSF4b), which correlated with the expression of HSPA4 and HSPA14. Conclusion: These results identify a novel pathway (NBS1-HSF4b-HSPA4/HSPA14 axis) to induce migration, invasion, and transformation, suggesting the activation of multiple signaling events induced by NBS1 overexpression.
KIDFamMap: a database of kinase-inhibitor-disease family maps for kinase inhibitor selectivity and binding mechanisms
(2013-01-01)
Chiu, Yi-Yuan
;
Lin, Chih-Ta
;
Huang, Jhang-Wei
;
Hsu, Kai-Cheng
;
Tseng, Jen-Hu
Kinases play central roles in signaling pathways and are promising therapeutic targets for many diseases. Designing selective kinase inhibitors is an emergent and challenging task, because kinases share an evolutionary conserved ATP-binding site. KIDFamMap (http://gemdock.life.nctu.edu.tw/KIDFamMap/) is the first database to explore kinase-inhibitor families (KIFs) and kinase-inhibitor-disease (KID) relationships for kinase inhibitor selectivity and mechanisms. This database includes 1208 KIFs, 962 KIDs, 55 603 kinase-inhibitor interactions (KIIs), 35 788 kinase inhibitors, 399 human protein kinases, 339 diseases and 638 disease allelic variants. Here, a KIF can be defined as follows: (i) the kinases in the KIF with significant sequence similarity, (ii) the inhibitors in the KIF with significant topology similarity and (iii) the KIIs in the KIF with significant interaction similarity. The KIIs within a KIF are often conserved on some consensus KIDFamMap anchors, which represent conserved interactions between the kinase subsites and consensus moieties of their inhibitors. Our experimental results reveal that the members of a KIF often possess similar inhibition profiles. The KIDFamMap anchors can reflect kinase conformations types, kinase functions and kinase inhibitor selectivity. We believe that KIDFamMap provides biological insights into kinase inhibitor selectivity and binding mechanisms.
Module organization and variance in protein-protein interaction networks
(2015-03-23)
Lin, Chun-Yu
;
Lee, Tsai-Ling
;
Chiu, Yi-Yuan
;
Lin, Yi-Wei
;
Lo, Yu-Shu
A module is a group of closely related proteins that act in concert to perform specific biological functions through protein-protein interactions (PPIs) that occur in time and space. However, the underlying module organization and variance remain unclear. In this study, we collected module templates to infer respective module families, including 58,041 homologous modules in 1,678 species, and PPI families using searches of complete genomic database. We then derived PPI evolution scores and interface evolution scores to describe the module elements, including core and ring components. Functions of core components were highly correlated with those of essential genes. In comparison with ring components, core proteins/PPIs were conserved across multiple species. Subsequently, protein/module variance of PPI networks confirmed that core components form dynamic network hubs and play key roles in various biological functions. Based on the analyses of gene essentiality, module variance, and gene co-expression, we summarize the observations of module organization and variance as follows: 1) a module consists of core and ring components; 2) core components perform major biological functions and collaborate with ring components to execute certain functions in some cases; 3) core components are more conserved and essential during organizational changes in different biological states or conditions.
NEMO: A new implicit-connection-graph-based gridless router with multilayer planes and pseudo tile propagation
(2007-04-01)
Li, Yih-Lang
;
Chen, Hsin-Yu
;
Lin, Chih-Ta
;
交大名義發表
;
National Chiao Tung University
The implicit-connection-graph-based router is superior to the tile-based router in terms of routing graph construction and point querying. However, the implicit connection graph has a higher degree of routing graph complexity. In this paper, a new multilayer implicit-connection-graph-based gridless router called NEMO is developed. Unlike the first implicit-connectiongraph-based router that embeds all routing layers onto a routing plane, NEMO constructs a routing plane for each routing layer. Additionally, each routing plane comprises tiles, not an array of grid points with their connecting edges, and consequently, the complexity of the routing problem decreases. Each grid point then represents exactly one tile or its left-bottom corner such that a tile query is equivalent to any point query inside the queried tile, and a grid maze becomes tile propagation. Furthermore, to accelerate path search, continuous space tiles are combined as a pseudo maximum horizontally or vertically stripped tile. Experimental results reveal that NEMO conducts a point-to-point path search around ten times faster than the implicit-connection-graph-based router. General-purpose routing by NEMO also improves routing performance by approximately 1.69x-55.82x, as compared to previously published works based on a set of commonly used MCNC benchmark circuits.
Space-related pharma-motifs for fast search of protein binding motifs and polypharmacological targets
(2012-12-13)
Chiu, Yi-Yuan
;
Lin, Chun-Yu
;
Lin, Chih-Ta
;
Hsu, Kai-Cheng
;
Chang, Li-Zen
Background: To discover a compound inhibiting multiple proteins (i.e. polypharmacological targets) is a new paradigm for the complex diseases (e.g. cancers and diabetes). In general, the polypharmacological proteins often share similar local binding environments and motifs. As the exponential growth of the number of protein structures, to find the similar structural binding motifs (pharma-motifs) is an emergency task for drug discovery (e. g. side effects and new uses for old drugs) and protein functions. Results: We have developed a Space-Related Pharmamotifs (called SRPmotif) method to recognize the binding motifs by searching against protein structure database. SRPmotif is able to recognize conserved binding environments containing spatially discontinuous pharma-motifs which are often short conserved peptides with specific physico-chemical properties for protein functions. Among 356 pharma-motifs, 56.5% interacting residues are highly conserved. Experimental results indicate that 81.1% and 92.7% polypharmacological targets of each protein-ligand complex are annotated with same biological process (BP) and molecular function (MF) terms, respectively, based on Gene Ontology (GO). Our experimental results show that the identified pharma-motifs often consist of key residues in functional (active) sites and play the key roles for protein functions. The SRPmotif is available at http://gemdock.life.nctu.edu.tw/SRP/. Conclusions: SRPmotif is able to identify similar pharma-interfaces and pharma-motifs sharing similar binding environments for polypharmacological targets by rapidly searching against the protein structure database. Pharmamotifs describe the conservations of binding environments for drug discovery and protein functions. Additionally, these pharma-motifs provide the clues for discovering new sequence-based motifs to predict protein functions from protein sequence databases. We believe that SRPmotif is useful for elucidating protein functions and drug discovery.
Total Synthetic Protoapigenone WYC02 Inhibits Cervical Cancer Cell Proliferation and Tumour Growth through PIK3 Signalling Pathway
(2013-07-01)
Chen, Yun-Ju
;
Kay, Nari
;
Yang, Jinn-Moon
;
Lin, Chih-Ta
;
Chang, Hsueh-Ling
Flavonoids have been intensively explored for their anticancer activity. In this study, a total synthetic flavonoid protoapigenone, known as WYC02, was analysed for its potential anticancer activity on human cervical cancer cells as well as the underlying mechanisms for these effects. The site-moiety maps are used to explore the binding site similarity, pharmacophore and docking pose similarity. The effect of WYC02 on cell viability, migration, invasion and apoptosis as well as the underlying mechanisms was analysed in vitro using human cervical cancer cells. The effect of WYC02 on in vivo tumour growth was assessed in a tumour xenograft study. WYC02 inhibited cell proliferation, MMPs activity, migration and invasion in cervical cancer cells. We speculated that WYC02 might inhibit the activities of PIK3 family proteins, including PIK3CA, PIK3CB, PIK3CD and PIK3CG. Indeed, WYC02 decreased the expression of PIK3 family proteins, especially PIK3CG, through ubiquitination and inhibited the activities of PIK3CG and PIK3 downstream molecules AKT1 and MTOR in cervical cancer cells. Furthermore, PIK3 signalling pathway was involved in the inhibitory effect of WYC02 on cervical cancer cell proliferation and tumour growth in vitro and in vivo. WYC02 inhibits cervical cancer cell proliferation and tumourigenesis via PIK3 signalling pathway and has the potential to be developed as a chemotherapeutic agent in cervical cancer.