Browsing by Author "Hsu, Kai-Cheng"

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5-Demethyltangeretin is more potent than tangeretin in inhibiting dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin tumorigenesis
(2014-11-01)
Ma, Nianhan
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Lai, Ching-Shu
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Chung, Chih-Han
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Yang, Jinn-Moon
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Hsu, Kai-Cheng
5-Demethyltangeretin (5-DTAN), an autohydrolysis product of tangeretin (TAN) found in citrus peel, exhibited more potent anti-proliferative activity in human cancer cells than TAN itself. In this study, we investigated the anti-tumor promoting effect and underlying molecular mechanism of 5-DTAN on 7,12-dimethyl-benz(a)anthracene (DMBA)-induced and 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted skin carcinogenesis. Application of 5-DTAN prior to each TPA-treatment was more effective than that of TAN on reducing the number, incidence and size of papillomas in DMBA-initiated mouse skin. Moreover, 5-DTAN suppressed cyclooxygenase-2 (COX-2) protein expression more strongly than TAN through interfering with phosphatidylinositiol 3-kinase (PI3K)/Akt signaling and further activation of transcription factor NF-kappa B. Taken together, these results revealed for the first time the in vivo chemopreventive efficacy of 5-DTAN on inhibition of skin carcinogenesis through promoting apoptosis and molecular interactions with residues of PI3K, COX-2, and AKT that may potentially serve as a novel functional agent capable of preventing inflammation-associated tumorigenesis. (C) 2014 Elsevier Ltd. All rights reserved.
7-Chloro-6-piperidin-1-yl-quinoline-5,8-dione (PT-262), a novel ROCK inhibitor blocks cytoskeleton function and cell migration
(2011-04-01)
Tsai, Chih-Chien
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Liu, Huei-Fang
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Hsu, Kai-Cheng
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Yang, Jinn-Moon
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Chen, Chinpiao
The 5,8-quinolinediones are precursors for producing multiple types of bioactive products. In this study, we investigated a new compound derived from 5,8-quinolinediones, 7-chloro-6-piperidin-1-yl-quinoline-5,8-dione (designated as PT-262), which markedly induced cytoskeleton remodeling and migration inhibition in lung carcinoma cells. Comparison with various cytoskeleton inhibitors, including paclitaxel, colchicine and phallacidin, the cell morphology following treatment with PT-262 was similar to phallacidin on the cell elongation and abnormal actin polymerization. However, PT-262 did not directly bind to actin filaments. ROCK (Rho-associated coiled-coil forming protein kinase) is a downstream effector of RhoA to mediate the phosphorylation of myosin light chain (MLC) and cytoskeleton reorganization. The RhoA-ROCK-MLC pathway has been shown to promote cancer cell migration and metastasis. Interestingly. PT-262 was more effective on inhibiting ROCK kinase activities than specific ROCK inhibitors Y-27632 and H-1152. PT-262 induced cytoskeleton remodeling and migration inhibition in A549 lung carcinoma cells. The total MLC and phosphorylated MLC proteins and stress fibers were blocked after treatment with PT-262. Nonetheless, the RhoA protein and GTPase activity were not altered by PT-262. A computational model suggests that PT-262 interacts with the ATP-binding site of ROCK protein. Together, these findings demonstrate that PT-262 is a new ROCK inhibitor. (C) 2011 Elsevier Inc. All rights reserved.
A cross-layer signaling and middleware platform for multi-interface mobile devices
(2007)
Shih, Yung-Chien
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Hsu, Kai-Cheng
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Tseng, Chien-Chao
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資訊工程學系
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Department of Computer Science
This paper presents a middleware platform approach to provide Cross-layer Signaling and Network Event Notification mechanisms for network-aware applications. Because a mobile device may be equipped with multiple network interfaces to attach different network as it moves, a network-aware application running on the mobile device must react promptly to the changes of network environment. In order for the applications to detect network changes, the proposed middleware platform provides APIs for setting up network configuration and acquiring low-layer statuses. Therefore, an application can detect network changes promptly via Network Event Notification mechanism. We also use two network-aware applications, namely a Mobility Manager and a Modified Kphone, as examples to demonstrate the effectiveness of our middleware platform.
A Novel Selective JAK2 Inhibitor Identified Using Pharmacological Interactions
(2018-12-04)
Lin, Tony Eight
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HuangFu, Wei-Chun
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Chao, Min-Wu
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Sung, Tzu-Ying
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Chang, Chao-Di
The JAK2/STAT signaling pathway mediates cytokine receptor signals that are involved in cell growth, survival and homeostasis. JAK2 is a member of the Janus kinase (JAK) family and aberrant JAK2/STAT is involved with various diseases, making the pathway a therapeutic target. The similarity between the ATP binding site of protein kinases has made development of specific inhibitors difficult. Current JAK2 inhibitors are not selective and produce unwanted side effects. It is thought that increasing selectivity of kinase inhibitors may reduce the side effects seen with current treatment options. Thus, there is a great need for a selective JAK inhibitor. In this study, we identified a JAK2 specific inhibitor. We first identified key pharmacological interactions in the JAK2 binding site by analyzing known JAK2 inhibitors. Then, we performed structure-based virtual screening and filtered compounds based on their pharmacological interactions and identified compound NSC13626 as a potential JAK2 inhibitor. Results of enzymatic assays revealed that against a panel of kinases, compound NSC13626 is a JAK2 inhibitor and has high selectivity toward the JAK2 and JAK3 isozymes. Our cellular assays revealed that compound NSC13626 inhibits colorectal cancer cell (CRC) growth by downregulating phosphorylation of STAT3 and arresting the cell cycle in the S phase. Thus, we believe that compound NSC13626 has potential to be further optimized as a selective JAK2 drug.
A site-moiety map and virtual screening approach for discovery of novel 5-LOX inhibitors
(2020-06-29)
Hsu, Kai-Cheng
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HuangFu, Wei-Chun
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Lin, Tony Eight
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Chao, Min-Wu
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Sung, Tzu-Ying
The immune system works in conjunction with inflammation. Excessive inflammation underlies various human diseases, such as asthma, diabetes and heart disease. Previous studies found that 5-lipoxygenase (5-LOX) plays a crucial role in metabolizing arachidonic acid into inflammatory mediators and is a potential therapeutic target. In this study, we performed an in silico approach to establish a site-moiety map (SiMMap) to screen for new 5-LOX inhibitors. The map is composed of several anchors that contain key residues, moiety preferences, and their interaction types (i.e., electrostatic (E), hydrogen-bonding (H), and van der Waals (V) interactions) within the catalytic site. In total, we identified one EH, one H, and five V anchors, within the 5-LOX catalytic site. Based on the SiMMap, three 5-LOX inhibitors (YS1, YS2, and YS3) were identified. An enzyme-based assay validated inhibitory activity of YS1, YS2, and YS3 against 5-LOX with an IC50 value of 2.7, 4.2, and 5.3 mu M, respectively. All three inhibitors significantly decrease LPS-induced TNF-alpha and IL-6 production, which suggests its potential use an anti-inflammatory agent. In addition, the identified 5-LOX inhibitors contain a novel scaffold. The discovery of these inhibitors presents an opportunity for designing specific anti-inflammatory drugs.
Alternative splicing in human cancer cells is modulated by the amiloride derivative 3,5-diamino-6-chloro-N-(N-(2,6-dichlorobenzoyl)carbamimidoyl)pyrazine-2-carboxide
(1970-01-01)
Lee, Chien-Chin
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Chang, Wen-Hsin
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Chang, Ya-Sian
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Yang, Jinn-Moon
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Chang, Chih-Shiang
Alternative splicing (AS) is a process that enables the generation of multiple protein isoforms with different biological properties from a single mRNA. Cancer cells often use the maneuverability conferred by AS to produce proteins that contribute to growth and survival. In our previous studies, we identified that amiloride modulates AS in cancer cells. However, the effective concentration of amiloride required to modulate AS is too high for use in cancer treatment. In this study, we used computational algorithms to screen potential amiloride derivatives for their ability to regulate AS in cancer cells. We found that 3,5-diamino-6-chloro-N-(N-(2,6-dichlorobenzoyl)carbamimidoyl)pyrazine-2-carboxamide (BS008) can regulate AS of apoptotic gene transcripts, including HIPK3, SMAC, and BCL-X, at a lower concentration than amiloride. This splicing regulation involved various splicing factors, and it was accompanied by a change in the phosphorylation state of serine/arginine-rich proteins (SR proteins). RNA sequencing was performed to reveal that AS of many other apoptotic gene transcripts, such as AATF, ATM, AIFM1, NFKB1, and API5, was also modulated by BS008. In vivo experiments further indicated that treatment of tumor-bearing mice with BS008 resulted in a marked decrease in tumor size. BS008 also had inhibitory effects in vitro, either alone or in a synergistic combination with the cytotoxic chemotherapeutic agents sorafenib and nilotinib. BS008 enabled sorafenib dose reduction without compromising antitumor activity. These findings suggest that BS008 may possess therapeutic potential for cancer treatment.
Anchor-based classification and type-C inhibitors for tyrosine kinases
(2015-06-16)
Hsu, Kai-Cheng
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Sung, Tzu-Ying
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Lin, Chih-Ta
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Chiu, Yi-Yuan
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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.
ATRIPPI: AN ATOM-RESIDUE PREFERENCE SCORING FUNCTION FOR PROTEIN-PROTEIN INTERACTIONS
(2010-06-01)
Liu, Kang-Ping
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Hsu, Kai-Cheng
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Huang, Jhang-Wei
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Chang, Lu-Shian
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Yang, Jinn-Moon
We present an ATRIPPI model for analyzing protein-protein interactions. This model is a 167-atom-type and residue-specific interaction preferences with distance bins derived from 641 co-crystallized protein-protein interfaces. The ATRIPPI model is able to yield physical meanings of hydrogen bonding, disulfide bonding, electrostatic interactions, van der Waals and aromatic-aromatic interactions. We applied this model to identify the native states and near-native complex structures on 17 bound and 17 unbound complexes from thousands of decoy structures. On average, 77.5% structures (155 structures) of top rank 200 structures are closed to the native structure. These results suggest that the ATRIPPI model is able to keep the advantages of both atom-atom and residue-residue interactions and is a potential knowledge-based scoring function for protein-protein docking methods. We believe that our model is robust and provides biological meanings to support protein-protein interactions.
Core Site-Moiety Maps Reveal Inhibitors and Binding Mechanisms of Orthologous Proteins by Screening Compound Libraries
(2012-02-29)
Hsu, Kai-Cheng
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Cheng, Wen-Chi
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Chen, Yen-Fu
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Wang, Hung-Jung
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Li, Ling-Ting
Members of protein families often share conserved structural subsites for interaction with chemically similar moieties despite low sequence identity. We propose a core site-moiety map of multiple proteins (called CoreSiMMap) to discover inhibitors and mechanisms by profiling subsite-moiety interactions of immense screening compounds. The consensus anchor, the subsite-moiety interactions with statistical significance, of a CoreSiMMap can be regarded as a "hot spot" that represents the conserved binding environments involved in biological functions. Here, we derive the CoreSiMMap with six consensus anchors and identify six inhibitors (IC50 < 8.0 mu M) of shikimate kinases (SKs) of Mycobacterium tuberculosis and Helicobacter pylori from the NCI database (236,962 compounds). Studies of site-directed mutagenesis and analogues reveal that these conserved interacting residues and moieties contribute to pocket-moiety interaction spots and biological functions. These results reveal that our multi-target screening strategy and the CoreSiMMap can increase the accuracy of screening in the identification of novel inhibitors and subsite-moiety environments for elucidating the binding mechanisms of targets.
Crowning Proteins: Modulating the Protein Surface Properties using Crown Ethers
(2014-11-24)
Lee, Cheng-Chung
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Maestre-Reyna, Manuel
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Hsu, Kai-Cheng
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Wang, Hao-Ching
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Liu, Chia-I
Crown ethers are small, cyclic polyethers that have found wide-spread use in phase-transfer catalysis and, to a certain degree, in protein chemistry. Crown ethers readily bind metallic and organic cations, including positively charged amino acid side chains. We elucidated the crystal structures of several protein-crown ether co-crystals grown in the presence of 18-crown-6. We then employed biophysical methods and molecular dynamics simulations to compare these complexes with the corresponding apoproteins and with similar complexes with ring-shaped low-molecular-weight polyethylene glycols. Our studies show that crown ethers can modify protein surface behavior dramatically by stabilizing either intra- or intermolecular interactions. Consequently, we propose that crown ethers can be used to modulate a wide variety of protein surface behaviors, such as oligomerization, domain-domain interactions, stabilization in organic solvents, and crystallization.
Design and synthesis of 1,2,3-triazole-containing N-acyl zanamivir analogs as potent neuraminidase inhibitors
(2016-11-10)
Das, Anindya
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Adak, Avijit K.
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Ponnapalli, Kalyankumar
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Lin, Chien-Hung
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Hsu, Kai-Cheng
The design of potent metabolically stable neuraminidase (NA) inhibitors represents an attractive approach for treating influenza virus infection. In this study, we describe the exploitation of the 150-cavity in the active site of group 1 NA for the design, synthesis, and in vitro evaluation of new triazole-containing N-acyl derivatives related to Zanamivir. Inhibition studies with influenza virus NAs of group 1 (H1N1) and group 2 (H3N2) revealed that several of them are good inhibitors, with IC50 values in the low nanomolar (2.3 nM-31 nM) range. Substituents that form stable van der Waals interaction with the 150-cavity residues play crucial roles in NA inhibition as demonstrated by the potency of 6a (H1N1 IC50 = 23 nM, and H3N2 IC50 = 2.9 nM). Docking studies indicated that the cyclohexane-substituted triazole ring extended toward the hydrophobic region in the active site of group 1 NA in open form. The high potency observed for inhibitor 6a may be attributable to the highly favorable hydrophobic interactions in this region. (C) 2016 Elsevier Masson SAS. All rights reserved.
DNA Mimic Proteins: Functions, Structures, and Bioinformatic Analysis
(2014-05-13)
Wang, Hao-Ching
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Ho, Chun-Han
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Hsu, Kai-Cheng
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Yang, Jinn-Moon
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Wang, Andrew H. -J.
DNA mimic proteins have DNA-like negative surface charge distributions, and they function by occupying the DNA binding sites of DNA binding proteins to prevent these sites from being accessed by DNA. DNA mimic proteins control the activities of a variety of DNA binding proteins and are involved in a wide range of cellular mechanisms such as chromatin assembly, DNA repair, transcription regulation, and gene recombination. However, the sequences and structures of DNA mimic proteins are diverse, making them difficult to predict by bioinformatic search. To date, only a few DNA mimic proteins have been reported. These DNA mimics were not found by searching for functional motifs in their sequences but were revealed only by structural analysis of their charge distribution. This review highlights the biological roles and structures of 16 reported DNA mimic proteins. We also discuss approaches that might be used to discover new DNA mimic proteins.
Functional analysis of Clostridium difficile sortase B reveals key residues for catalytic activity and substrate specificity
(2020-03-13)
Kang, Chia-Yu
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Huang, I-Hsiu
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Chou, Chi-Chi
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Wu, Tsai-Yu
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Chang, Jyun-Cyuan
Most of Gram-positive bacteria anchor surface proteins to the peptidoglycan cell wall by sortase, a cysteine transpeptidase that targets proteins displaying a cell wall sorting signal. Unlike other bacteria, Clostridium difficile, the major human pathogen responsible for antibiotic-associated diarrhea, has only a single functional sortase (SrtB). Sortase's vital importance in bacterial virulence has been long recognized, and C. difficile sortase B (Cd-SrtB) has become an attractive therapeutic target for managing C. difficile infection. A better understanding of the molecular activity of Cd-SrtB may help spur the development of effective agents against C. difficile infection. In this study, using site-directed mutagenesis, biochemical and biophysical tools, LC-MS/MS, and crystallographic analyses, we identified key residues essential for Cd-SrtB catalysis and substrate recognition. To the best of our knowledge, we report the first evidence that a conserved serine residue near the active site participates in the catalytic activity of Cd-SrtB and also SrtB from Staphylococcus aureus. The serine residue indispensable for SrtB activity may be involved in stabilizing a thioacyl-enzyme intermediate because it is neither a nucleophilic residue nor a substrate-interacting residue, based on the LC-MS/MS data and available structural models of SrtB?substrate complexes. Furthermore, we also demonstrated that residues 163?168 located on the ?6/?7 loop of Cd-SrtB dominate specific recognition of the peptide substrate PPKTG. The results of this work reveal key residues with roles in catalysis and substrate specificity of Cd-SrtB.
GemAffinity: a scoring function for predicting binding affinity and Virtual Screening
(2012)
Hsu, Kai-Cheng
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Chen, Yen-Fu
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Yang, Jinn-Moon
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生物科技學系
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生物資訊及系統生物研究所
Prediction of protein-ligand binding affinities plays an essential role for molecular recognition and virtual screening. We have developed a scoring function, namely GemAffinity, to predict binding affinities by using a stepwise regression method and 88 descriptors from 891 complex structures. GemAffinity consists of five descriptors, including van der Waals contacts; metal-ligand interactions; water effects; ligand deformation penalty; and conserved hydrogen-bonded residues. Experimental results indicate that GemAffinity is the best among 13 methods on a test set and can enrich screening accuracies on four sets. We believe that GemAffinity is useful for virtual screening and drug discovery.
GemAffinity: A Scoring Function for Predicting Binding Affinity and Virtual Screening
(2009)
Hsu, Kai-Cheng
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Chen, Yen-Fu
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Yang, Jinn-Moon
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生物資訊及系統生物研究所
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Institude of Bioinformatics and Systems Biology
Prediction of protein-ligand binding affinities is an important issue in molecular recognition and virtual screening. We have developed a scoring function, namely GemAffinity, to predict binding affinities by analyzing 88 descriptors derived from 891 protein-ligand structures selected from the Protein Data Bank (PDB). Based on these 88 descriptors, we derived GemAffinity using a stepwise regression method to identify five descriptors, including van der Waals contact; metal-ligand interactions; water effects; ligand deformation penalties; and highly conserved residues interacting to a bound ligand with hydrogen bonds. GemAffinity was evaluated on an independent set, and the correlation between predicted and experimental values is 0.572. GemAffinity is the best among 13 methods on this set. Our GemAffinity was then applied to virtual screening for thymidine kinase (TIC), human carbonic anhydrase II (HCAII), estrogen receptor of antagonists (ER) and agonists (ERA). Experimental results indicate that GemAffinity is able to reduce the disadvantages (i.e. preferring highly polar or high molecular weight compounds) of energy-based scoring functions. In addition, GemAffinity easily combined with other scoring functions to enrich screening accuracies. We believe that GemAffinity is useful to predict binding affinity and virtual screening.
Homopharma: A new concept for exploring the molecular binding mechanisms and drug repurposing
(2014-12-08)
Chiu, Yi-Yuan
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Tseng, Jen-Hu
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Liu, Kuan-Hsiu
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Lin, Chih-Ta
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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.
Identification of Inhibitors for the DEDDh Family of Exonucleases and a Unique Inhibition Mechanism by Crystal Structure Analysis of CRN-4 Bound with 2-Morpholin-4-ylethanesulfonate (MES)
(2016-09-08)
Huang, Kuan-Wei
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Hsu, Kai-Cheng
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Chu, Lee-Ya
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Yang, Jinn-Moon
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Yuan, Hanna S.
The DEDDh family of exonucleases plays essential roles in DNA and RNA metabolism in all kingdoms of life. Several viral and human, DEDDh exonucleases can serve as antiviral drug targets due to their critical roles virus replication. Here using RNase T and CRN-4 as the model systems, we identify potential inhibitors for DEDDh exonucleases. We further show that two of the inhibitors, ATA and PV6R, indeed inhibit the exonuclease activity of the viral protein NP exonuclease of Lassa fever virus in vitro. Moreover, we determine the crystal structure of CRN-4 in complex with MES that reveals a unique inhibition Mechanism, by inducing the general base His179 to shift out of the active site. Our results not only provide the structural basis for the inhibition mechanism but also suggest potential lead inhibitors for the DEDDh exonucleases that may pave the way for designing nuclease inhibitors for biochemical and biomedical applications.
Identification of inhibitors for the DEDDh family of exonucleases and a unique inhibition mechanism revealed by crystal structure analysis of CRN-4 bound with MES
(2016-01-01)
Hsiao, Yu-Yuan
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Huang, Kuan-Wei
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Hsu, Kai-Cheng
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Chu, Lee-Ya
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Yang, Jinn-Moon
Identification of neuraminidase inhibitors against dual H274Y/I222R mutant strains
(2017-09-26)
Hsu, Kai-Cheng
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Hung, Hui-Chen
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HuangFu, Wei-Chun
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Sung, Tzu-Ying
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Lin, Tony Eight
Influenza is an annual seasonal epidemic that has continually drawn public attentions, due to the potential death toll and drug resistance. Neuraminidase, which is essential for the spread of influenza virus, has been regarded as a valid target for the treatment of influenza infection. Although neuraminidase drugs have been developed, they are susceptible to drug-resistant mutations in the sialic-binding site. In this study, we established computational models (site-moiety maps) of H1N1 and H5N1 to determine properties of the 150-cavity, which is adjacent to the drug-binding site. The models reveal that hydrogen-bonding interactions with residues R118, D151, and R156 and van der Waals interactions with residues Q136, D151, and T439 are important for identifying 150-cavitiy inhibitors. Based on the models, we discovered three new inhibitors with IC50 values <10 mu M that occupies both the 150-cavity and sialic sites. The experimental results identified inhibitors with similar activities against both wild-type and dual H274Y/I222R mutant neuraminidases and showed little cytotoxic effects. Furthermore, we identified three new inhibitors situated at the sialic-binding site with inhibitory effects for normal neuraminidase, but lowered effects for mutant strains. The results suggest that the new inhibitors can be used as a starting point to combat drug-resistant strains.
iGEMDOCK: a graphical environment of enhancing GEMDOCK using pharmacological interactions and post-screening analysis
(2011-02-15)
Hsu, Kai-Cheng
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Chen, Yen-Fu
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Lin, Shen-Rong
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Yang, Jinn-Moon
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生物科技學系
Background: Pharmacological interactions are useful for understanding ligand binding mechanisms of a therapeutic target. These interactions are often inferred from a set of active compounds that were acquired experimentally. Moreover, most docking programs loosely coupled the stages (binding-site and ligand preparations, virtual screening, and post-screening analysis) of structure-based virtual screening (VS). An integrated VS environment, which provides the friendly interface to seamlessly combine these VS stages and to identify the pharmacological interactions directly from screening compounds, is valuable for drug discovery. Results: We developed an easy-to-use graphic environment, iGEMDOCK, integrating VS stages (from preparations to post-screening analysis). For post-screening analysis, iGEMDOCK provides biological insights by deriving the pharmacological interactions from screening compounds without relying on the experimental data of active compounds. The pharmacological interactions represent conserved interacting residues, which often form binding pockets with specific physico-chemical properties, to play the essential functions of a target protein. Our experimental results show that the pharmacological interactions derived by iGEMDOCK are often hot spots involving in the biological functions. In addition, iGEMDOCK provides the visualizations of the protein-compound interaction profiles and the hierarchical clustering dendrogram of the compounds for post-screening analysis. Conclusions: We have developed iGEMDOCK to facilitate steps from preparations of target proteins and ligand libraries toward post-screening analysis. iGEMDOCK is especially useful for post-screening analysis and inferring pharmacological interactions from screening compounds. We believe that iGEMDOCK is useful for understanding the ligand binding mechanisms and discovering lead compounds. iGEMDOCK is available at http://gemdock.life.nctu.edu.tw/dock/igemdock.php.