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Biomedical subjects

Kaixian Chen

Publications and source records attributed to Kaixian Chen.

At least 19 recordsLinked to original sources
PubMed2007

Hyrtiosal, a PTP1B inhibitor from the marine sponge Hyrtios erectus, shows extensive cellular effects on PI3K/AKT activation, glucose transport, and TGFbeta/Smad2 signaling.

Protein tyrosine phosphatase 1B (PTP1B) negatively regulates insulin signaling, and PTP1B inhibitors have been seen as promising therapeutic agents against obesity and type 2 diabetes. Here we report that the marine natural product hyrtiosal, from the marine sponge Hyrtios erectus, has been discovered to act as a PTP1B inhibitor and to show extensive cellular effects on PI3K/AKT activation, glucose transport, and TGFbeta/Smad2 signaling. This inhibitor wad able to inhibit PTP1B activity in dose-dependent fashion, with an IC(50) value of 42 microM in a noncompetitive inhibition mode. Further study with an IN Cell Analyzer 1000 cellular fluorescence imaging instrument showed that hyrtiosal displayed potent activity in abolishing the retardation of AKT membrane translocation caused by PTP1B overexpression in CHO cells. Moreover, it was found that this newly identified PTP1B inhibitor could dramatically enhance the membrane translocation of the key glucose transporter Glut4 in PTP1B-overexpressed CHO cells. Additionally, in view of our recent finding that PTP1B was able to modulate insulin-mediated inhibition of Smad2 activation, hyrtiosal was also tested for its capabilities in the regulation of Smad2 activity through the PI3K/AKT pathway. The results showed that hyrtiosal could effectively facilitate insulin inhibition of Smad2 activation. Our current study is expected to supply new clues for the discovery of PTP1B inhibitors from marine natural products, while the newly identified PTP1B inhibitor hyrtiosal might serve as a potential lead compound for further research.

Animals↗
PubMed2007

Discovering potassium channel blockers from synthetic compound database by using structure-based virtual screening in conjunction with electrophysiological assay.

Potassium ion (K+) channels are attractive targets for drug discovery because of the essential roles played in biological systems. However, high-throughput screening (HTS) cannot be used to screen K+ channel blockers. To overcome this disadvantage of HTS, we have developed a virtual screening approach for discovering novel blockers of K+ channels. On the basis of a three-dimensional model of the eukaryotic K+ channels, molecular docking-based virtual screening was employed to search the chemical database MDL Available Chemicals Directory (ACD). Compounds were ranked according to their relative binding energy, favorable shape complementarity, and potential to form hydrogen bonds with the outer mouth of the K+ channel model. Twenty candidate compounds selected from the virtual screening were examined using the whole-cell voltage-clamp recording in rat dissociated hippocampal neurons. Among them, six compounds (5, 6, 8, 18-20) potently blocked both the delayed rectifier (IK) and fast transient K+ currents (IA). When applied externally, these six compounds preferentially blocked IK with potencies 2- to 500-fold higher than that of tetraethylammonium chloride. Intracellular application of the six compounds had no effect on both K+ currents. In addition, the interaction models and binding free energy calculations demonstrated that hydrophobic interaction and solvent effects play important roles in the inhibitory activities of these compounds. The results demonstrated that structure-based computer screening strategy could be used to identify novel, structurally diverse compounds targeting the pore binding pocket of the outer mouth of voltage-gated K+ channels. This study provides an alternative way of finding new blockers of voltage-gated K+ channels, while the techniques for high-throughput screening of K+ channel drugs remain in development.

Animals↗
PubMed2007

A nonpeptidic agonist of glucagon-like peptide 1 receptors with efficacy in diabetic db/db mice.

Peptidic mimics of the gut hormone glucagon-like peptide (GLP) 1, exemplified by the recently approved drug exenatide, show promise as therapies for type 2 diabetes. Such "incretin mimetics" regulate glucose appearance in the plasma and can restore glucose-stimulated insulin secretion without excess risk of hypoglycemia. The need for injection, which may limit the use of peptidic GLP-1 receptor (GLP-1R) agonists, has driven largely unsuccessful efforts to find smaller molecules. The failure to identify orally effective agonists has instead promoted the indirect approach of inhibiting the GLP-1-degrading enzyme dipeptidyl peptidase IV. Here we report a nonpeptidic GLP-1R agonist with sufficient activity to evoke effects in whole animals, including antidiabetic efficacy in db/db mice. Two substituted cyclobutanes (S4P and Boc5) were developed after screening a compound library against a cell line stably cotransfected with GLP-1R and a cAMP-responsive reporter. Each bound to GLP-1R and increased intracellular cAMP. Agonist effects were blocked by the GLP-1R antagonist exendin(9-39). Boc5 amplified glucose-stimulated insulin secretion in isolated rat islets. Both i.p. and oral administration of Boc5 dose-dependently inhibited food intake in mice, an effect that could be blocked by pretreatment with exendin(9-39). Daily injections of Boc5 into db/db mice reduced HbA1c to nondiabetic values, an effect not observed in ad libitum-fed or pair-fed diabetic controls. Thus, Boc5 behaved as a full GLP-1 mimetic in vitro and in vivo. The chemical genus represented by Boc5 may prompt the exploration of orally available GLP-1R agonists with potential utility in diabetes and obesity.

Acute Disease↗
PubMed2006

Synthesis and antitumor evaluation of a novel series of triaminotriazine derivatives.

A series of triaminotriazine derivatives (compounds 5a-f, 6a-x, and 7a-g) was designed, synthesized, and evaluated for their inhibition activities to colorectal cancer (CRC) cell lines (HCT-116 and HT-29). Most of the synthesized compounds demonstrated moderate anti-proliferatory effects on both HCT-116 and HT-29 cell lines at the concentration of 10 microM. The inhibitory activities against HCT-116 and HT-29 cell lines were discussed to develop the structure-activity relationships of this new series. Compounds 6l and 6o exhibited prominent inhibition activities toward HCT-116, with IC50s of 0.76 and 0.92 microM, respectively. The in vivo antitumor studies and pharmacokinetics of compound 6l showed that it might be a promising new hit for further development of antitumor agents.

Antineoplastic Agents↗
PubMed2006

QSAR analyses on avian influenza virus neuraminidase inhibitors using CoMFA, CoMSIA, and HQSAR.

The recent wide spreading of the H5N1 avian influenza virus (AIV) in Asia, Europe and Africa and its ability to cause fatal infections in human has raised serious concerns about a pending global flu pandemic. Neuraminidase (NA) inhibitors are currently the only option for treatment or prophylaxis in humans infected with this strain. However, drugs currently on the market often meet with rapidly emerging resistant mutants and only have limited application as inadequate supply of synthetic material. To dig out helpful information for designing potent inhibitors with novel structures against the NA, we used automated docking, CoMFA, CoMSIA, and HQSAR methods to investigate the quantitative structure-activity relationship for 126 NA inhibitors (NIs) with great structural diversities and wide range of bioactivities against influenza A virus. Based on the binding conformations discovered via molecular docking into the crystal structure of NA, CoMFA and CoMSIA models were successfully built with the cross-validated q (2) of 0.813 and 0.771, respectively. HQSAR was also carried out as a complementary study in that HQSAR technique does not require 3D information of these compounds and could provide a detailed molecular fragment contribution to the inhibitory activity. These models also show clearly how steric, electrostatic, hydrophobicity, and individual fragments affect the potency of NA inhibitors. In addition, CoMFA and CoMSIA field distributions are found to be in well agreement with the structural characteristics of the corresponding binding sites. Therefore, the final 3D-QSAR models and the information of the inhibitor-enzyme interaction should be useful in developing novel potent NA inhibitors.

Amino Acid Sequence↗
PubMed2006

Detailed mechanism for AmtB conducting NH4+/NH3: molecular dynamics simulations.

The mechanism by which the ammonium transporter, AmtB, conducts NH4+/NH3 into the cytoplasm was investigated using conventional molecular dynamics (MD) simulations. These simulations revealed that the neutral molecule, NH3, passes automatically through the channel upon its arrival at the Am2 site and that the function of the channel as a one-way valve for passage of NH3 is not determined by the cytoplasmic exit gate but, rather, by the periplasmic entrance gate of the channel. The NH3, produced by deprotonation of NH4+ at the entrance gate, is spontaneously conveyed to the central region of the channel via a hydrogen-bond network comprising His-168, His-318, Tyr-32, and the NH3 molecule. Finally, the NH3 molecule exits the channel through the exit gate formed by Phe-31, Ile-266, Val-314, and His-318. In addition, Ser-263 is shown to play a critical role in the final stages, acting as a pivoting arm to shunt the NH3 molecule from the cytoplasmic exit gate of the channel out into the cytoplasm. This finding is further supported by another simulation which shows that NH3 fails to be translocated through the channel formed by the Ser-263-Ala mutation. Thus, this study casts new insights on the mechanism of AmtB-mediated passage of NH3 across cellular membranes.

Cation Transport Proteins↗
PubMed2006

Induction of an aromatic six-membered nitrogen ring via cation-pi interaction.

Nitrogen clusters have been intensively studied for their potential application as high-energy density materials, but a six-membered nitrogen ring (N6) was not found to be stable and aromatic. To explore the possibility of inducing an aromatic N6 ring via cation-pi interaction, quantum chemistry calculations were performed on the systems of Ca2N6, CaN6, CaN6(2-), N6, and N6(4-) at the B3LYP/6-311+G level. The optimized geometries reveal that the planar structure of the N6 ring is stable only in the Ca2N6 complex. The computed NBO and CHelpG charges demonstrate that the planar N6 moiety in the Ca2N6 complex is almost a 10pi-electron system. The predicted nucleus-independent chemical shift (NICS) values demonstrate that the N6 moiety is aromatic in comparison with the NICS values of benzene. The estimated enthalpy of formation for the Ca2N6 complex is 100.4 kcal/mol for the reaction of 2Ca and 3N2. The binding energy between the Ca2+ cation and the N6(4-) moiety is -1928.8 kcal/mol, with electrostatic interaction serving as the predominant component. When all the calculated results are taken into account, including the planar structure, 10pi-electron system, identical bond length, and negative NICS value of the N6(4-) moiety in the Ca2N6 complex, it is deduced that the alkaline earth metal Ca is capable of inducing an aromatic N6 ring through the cation-pi interaction formed by electron transfer from the Ca atom to the N6 ring.

Benzene↗
PubMed2006

Discovery of Helicobacter pylori shikimate kinase inhibitors: bioassay and molecular modeling.

Shikimate kinase (SK) is the fifth enzyme in the shikimate pathway and catalyzes the phosphate transfer from ATP to shikimate in generating shikimate 3-phosphate and ADP. SK has been developed as a promising target for the discovery of antibacterial agents. In this report, two small molecular inhibitors (compound 1, 3-methoxy-4-{[2-({2-methoxy-4-[(4-oxo-2-thioxo-1,3-thiazolidin-5-ylidene)methyl]phenoxy}methyl)benzyl]oxy}benzaldehyde; compound 2, 5-bromo-2-(5-{[1-(3,4-dichlorophenyl)-3,5-dioxo-4-pyrazolidinylidene]methyl}-2-furyl)benzoic acid) against Helicobacter pylori SK (HpSK) were successfully identified with IC(50) values of 5.5+/-1.2 and 6.4+/-0.4 microM, respectively. The inhibition kinetics shows that compound 1 is a noncompetitive inhibitor with respect to both shikimate and MgATP, and compound 2 is a competitive inhibitor toward shikimate and noncompetitive inhibitor with respect to MgATP. The surface plasmon resonance (SPR) technology based analysis reveals that the equilibrium dissociation constants (K(D)s) of compounds 1 and 2 with HpSK enzyme are 4.39 and 3.74 microM, respectively. The molecular modeling and docking of two inhibitors with HpSK reveals that the active site of HpSK is rather roomy and deep, forming an L-shape channel on the surface of the protein, and compound 1 prefers the corner area of L-shape channel, while compound 2 binds the short arm of the channel of SK in the binding interactions. It is expected that our current work might supply useful information for the development of novel SK inhibitors.

Algorithms↗
PubMed2006

Blocking of the nicotinic acetylcholine receptor ion channel by chlorpromazine, a noncompetitive inhibitor: A molecular dynamics simulation study.

A large series of pharmacological agents, distinct from the typical competitive antagonists, block in a noncompetitive manner the permeability response of the nicotinic acetylcholine receptor (nAChR) to the neurotransmitter acetylcholine. Taking the neuroleptic chlorpromazine (CPZ) as an example of such agents, the blocking mechanism of noncompetitive inhibitors to the ion channel pore of the nAChR has been explored at the atomic level using both conventional and steered molecular dynamics (MD) simulations. Repeated steered MD simulations have permitted calculation of the free energy (approximately 36 kJ/mol) of CPZ binding and identification of the optimal site in the region of the serine and leucine rings, at approximately 4 A from the pore entrance. Coulomb and the Lennard-Jones interactions between CPZ and the ion channel as well as the conformational fluctuations of CPZ were examined to assess the contribution of each to the binding of CPZ to the nAChR. The MD simulations disclose a dynamic interaction of CPZ binding to the nAChR ionic channel. The cationic ammonium head of CPZ forms strong hydrogen bonds with Glu262 (alpha), Asp268 (beta), Glu272 (beta), Ser276 (beta), Glu280 (delta), Gln271 (gamma), Glu275 (gamma), and Asn279 (gamma) nAChR residues. Finally, the conventional MD simulation of CPZ at its identified binding site demonstrates that the binding of CPZ not only blocks ion transport through the channel but also markedly inhibits the conformational transitions of the channel, necessary for nAChR to carry out its biological function.

Acetylcholine↗
PubMed2006

Carboxyl terminus of severe acute respiratory syndrome coronavirus nucleocapsid protein: self-association analysis and nucleic acid binding characterization.

Coronavirus nucleocapsid (N) protein envelops the genomic RNA to form long helical nucleocapsid during virion assembly. Since N protein oligomerization is usually a crucial step in this process, characterization of such an oligomerization will help in the understanding of the possible mechanisms for nucleocapsid formation. The N protein of severe acute respiratory syndrome coronavirus (SARS-CoV) was recently discovered to self-associate by its carboxyl terminus. In this study, to further address the detailed understanding of the association feature of this C-terminus, its oligomerization was systematically investigated by size exclusion chromatography and chemical cross-linking assays. Our results clearly indicated that the C-terminal domain of SARS-CoV N protein could form not only dimers but also trimers, tetramers, and hexamers. Further analyses against six deletion mutants showed that residues 343-402 were necessary and sufficient for this C-terminus oligomerization. Although this segment contains many charged residues, differences in ionic strength have no effects on its oligomerization, indicating the absence of electrostatic force in SARS-CoV N protein C-terminus self-association. Gel shift assay results revealed that the SARS-CoV N protein C-terminus is also able to associate with nucleic acids and residues 363-382 are the responsible interaction partner, demonstrating that this fragment might involve genomic RNA binding sites. The fact that nucleic acid binding could promote the SARS-CoV N protein C-terminus to form high-order oligomers implies that the oligomeric SARS-CoV N protein probably combines with the viral genomic RNA in triggering long nucleocapsid formation.

Amino Acid Sequence↗
PubMed2006

Biochemical characterization and inhibitor discovery of shikimate dehydrogenase from Helicobacter pylori.

Shikimate dehydrogenase (SDH) is the fourth enzyme involved in the shikimate pathway. It catalyzes the NADPH-dependent reduction of 3-dehydroshikimate to shikimate, and has been developed as a promising target for the discovery of antimicrobial agent. In this report, we identified a new aroE gene encoding SDH from Helicobacter pylori strain SS1. The recombinant H. pylori shikimate dehydrogenase (HpSDH) was cloned, expressed, and purified in Escherichia coli system. The enzymatic characterization of HpSDH demonstrates its activity with k(cat) of 7.7 s(-1) and K(m) of 0.148 mm toward shikimate, k(cat) of 7.1 s(-1) and K(m) of 0.182 mm toward NADP, k(cat) of 5.2 s(-1) and K(m) of 2.9 mm toward NAD. The optimum pH of the enzyme activity is between 8.0 and 9.0, and the optimum temperature is around 60 degrees C. Using high throughput screening against our laboratory chemical library, five compounds, curcumin (1), 3-(2-naphthyloxy)-4-oxo-2-(trifluoromethyl)-4H-chromen-7-yl 3-chlorobenzoate (2), butyl 2-{[3-(2-naphthyloxy)-4-oxo-2-(trifluoromethyl)-4H-chromen-7-yl]oxy}propanoate (3), 2-({2-[(2-{[2-(2,3-dimethylanilino)-2-oxoethyl]sulfanyl}-1,3-benzothiazol-6-yl)amino]-2-oxoethyl}sulfanyl)-N-(2-naphthyl)acetamide (4), and maesaquinone diacetate (5) were discovered as HpSDH inhibitors with IC(50) values of 15.4, 3.9, 13.4, 2.9, and 3.5 microm, respectively. Further investigation indicates that compounds 1, 2, 3, and 5 demonstrate noncompetitive inhibition pattern, and compound 4 displays competitive inhibition pattern with respect to shikimate. Compounds 1, 4, and 5 display noncompetitive inhibition mode, and compounds 2 and 3 show competitive inhibition mode with respect to NADP. Antibacterial assays demonstrate that compounds 1, 2, and 5 can inhibit the growth of H. pylori with MIC of 16, 16, and 32 microg.mL(-1), respectively. This current work is expected to favor better understanding the features of SDH and provide useful information for the development of novel antibiotics to treat H. pylori-associated infection.

Alcohol Oxidoreductases↗
PubMed2006

Inhibitor discovery targeting the intermediate structure of beta-amyloid peptide on the conformational transition pathway: implications in the aggregation mechanism of beta-amyloid peptide.

Abeta peptides cleaved from the amyloid precursor protein are the main components of senile plaques in Alzheimer's disease. Abeta peptides adopt a conformation mixture of random coil, beta-sheet, and alpha-helix in solution, which makes it difficult to design inhibitors based on the 3D structures of Abeta peptides. By targeting the C-terminal beta-sheet region of an Abeta intermediate structure extracted from molecular dynamics simulations of Abeta conformational transition, a new inhibitor that abolishes Abeta fibrillation was discovered using virtual screening in conjunction with thioflavin T fluorescence assay and atomic force microscopy determination. Circular dichroism spectroscopy demonstrated that the binding of the inhibitor increased the beta-sheet content of Abeta peptides either by stabilizing the C-terminal beta-sheet conformation or by inducing the intermolecular beta-sheet formation. It was proposed that the inhibitor prevented fibrillation by blocking interstrand hydrogen bond formation of the pleated beta-sheet structure commonly found in amyloid fibrils. The study not only provided a strategy for inhibitor design based on the flexible structures of amyloid peptides but also revealed some clues to understanding the molecular events involved in Abeta aggregation.

Amyloid↗
PubMed2006

Protein tyrosine phosphatase 1B regulates TGF beta 1-induced Smad2 activation through PI3 kinase-dependent pathway.

Insulin is known to modulate transforming growth factor-beta (TGFbeta) signaling. In this report, by using the IN Cell Analyzer 1000, the fluorescence cell imaging instrument, we demonstrated that protein tyrosine phosphatase 1B (PTP1B) could regulate TGFbeta1-induced Smad2 activation in a PI3 kinase-dependent manner. By using the CHO cells stably expressing EGFP-Smad2, we showed that TGFbeta1 effectively stimulated Smad2 nuclear translocation in CHO cells. When pretreated with insulin, TGFbeta1-induced Smad2 nuclear entry was dramatically decreased. Furthermore, both the PI3K inhibitor LY294002 and the dominant negative AKT (DN-AKT) abolished the inhibitory effects of insulin, demonstrating that the inhibition of Smad2 activation by insulin was PI3K/AKT dependent. Since PTP1B negatively modulates insulin signaling, we further addressed the effects of PTP1B on insulin-mediated inhibition of Smad2 activation. Our data showed that overexpression of PTP1B effectively attenuated insulin-induced inhibition of Smad2 stimulation. Moreover, the PTP1B inhibitor, 3-(3,5-dibromo-4-hydroxy-benzoyl)-2-ethyl-benzofuran-6-sulfonicacid-(4-(thiazol-2-ylsulfamyl)-phenyl)-amide (Compound-2), recovered insulin inhibition of Smad2 activation. In conclusion, our data revealed the insulin inhibitory effects on TGFbeta1-induced Smad2 activation and the regulation role of PTP1B in the inhibition events.

Animals↗
PubMed2006

Conformational transition pathway in the allosteric process of human glucokinase.

Glucokinase (GK) is an important enzyme for regulating blood glucose levels and a potentially attractive target for diabetes of the young type 2 and persistent hyperinsulinemic hypoglycemia of infancy. To characterize the conformational transition of GK from the closed state to the superopen state, a series of conventional molecular dynamics (MD) and target MD (TMD) simulations were performed on both the wild-type enzyme and its mutants. Two 10-ns conventional MD simulations showed that, although the allosteric site of GK is approximately 20 A away from the active site, the activator is able to enhance the activity of the enzyme through conformational restriction. Fourteen TMD simulations on GK and five of its mutants revealed a reliably conformational transition pathway. The overall conformational transition includes three stages, and three likely stable intermediate states were identified by free energy scanning for the snapshots throughout the pathway. The conformational transition feature revealed by our TMD simulations rationalized several important mutagenesis and kinetic data. Remarkably, the TMD simulations predicted that Y61S, I159A, A201R, V203E, and V452S mutations, which have not been investigated so far, may facilitate the opening process of GK. These predictions also have been verified by mutagenesis and kinetic analyses in this study. These observations are beneficial to understanding the mechanism of GK regulation and designing the compounds for treating metabolic diseases.

Allosteric Regulation↗
PubMed2006

Quantitative characterization of 15-deoxy-delta(12,14)-prostaglandin J2 in regulating EGFPSmad2 translocation in CHO cells through PPARgamma/TGFbeta/Smad2 pathway.

Smad2 is an important factor in TGFbeta/Smad2 signal transduction pathway with ability for signal propagation, it could translocate from cytoplasm to nucleus after the TGFbeta receptor-mediated phosphorylation. 15-deoxy-delta(12,14)-prostaglandin J2 (15d-PGJ2), a natural agonist of the peroxisome proliferator-activated receptor gamma (PPARgamma), is found recently to be able to function in the regulation of Smad2 activity. However, no quantification data have been yet reported, and it still keeps suspenseful whether or not 15d-PGJ2 could regulate Smad2 activity by depending on PPARgamma through PPAR gamma/TGFbeta/ Smad2 pathway. In this work, by analyzing the EGFP-Smad2 location in CHO cells according to the Nucleus Trafficking Analysis Module based on IN Cell Analyzer 1000 platform, TGFbeta stimulated EGFP-Smad2 translocation regulated by 15d-PGJ2 was quantitatively investigated. The results showed that TGFbeta could induce EGFP-Smad2 translocation from cytoplasm to nucleus by EC50 of 8.83 pM, and 15d-PGJ2 could impede the TGFbeta-stimulated Smad2 translocation by IC50 of 0.68 microM. Moreover, GW9662, a PPARgamma antagonist, could attenuate such a 15d-PGJ2 inhibitory activity by almost one order of magnitude. This result thereby implies that 15d-PGJ2 might inhibit Smad2 translocation through PPARgamma/TGFbeta/Smad2 pathway. Further investigation discovered that different from the case for 15d-PGJ2, rosiglitazone, another PPARgamma agonist, could enhance Smad2 translocation to nucleus, suggesting that rosiglitazone and 15d-PGJ(2) might take different modes in the activation of PPARgamma within the signaling pathway.

Anilides↗
PubMed2006

Peptide deformylase is a potential target for anti-Helicobacter pylori drugs: reverse docking, enzymatic assay, and X-ray crystallography validation.

Colonization of human stomach by the bacterium Helicobacter pylori is a major causative factor for gastrointestinal illnesses and gastric cancer. However, the discovery of anti-H. pylori agents is a difficult task due to lack of mature protein targets. Therefore, identifying new molecular targets for developing new drugs against H. pylori is obviously necessary. In this study, the in-house potential drug target database (PDTD, http://www.dddc.ac.cn/tarfisdock/) was searched by the reverse docking approach using an active natural product (compound 1) discovered by anti-H. pylori screening as a probe. Homology search revealed that, among the 15 candidates discovered by reverse docking, only diaminopimelate decarboxylase (DC) and peptide deformylase (PDF) have homologous proteins in the genome of H. pylori. Enzymatic assay demonstrated compound 1 and its derivative compound 2 are the potent inhibitors against H. pylori PDF (HpPDF) with IC50 values of 10.8 and 1.25 microM, respectively. X-ray crystal structures of HpPDF and the complexes of HpPDF with 1 and 2 were determined for the first time, indicating that these two inhibitors bind well with HpPDF binding pocket. All these results indicate that HpPDF is a potential target for screening new anti-H. pylori agents. In addition, compounds 1 and 2 were predicted to bind to HpPDF with relatively high selectivity, suggesting they can be used as leads for developing new anti-H. pylori agents. The results demonstrated that our strategy, reverse docking in conjunction with bioassay and structural biology, is effective and can be used as a complementary approach of functional genomics and chemical biology in target identification.

Amidohydrolases↗
PubMed2006

Mutagenic probability estimation of chemical compounds by a novel molecular electrophilicity vector and support vector machine.

MOTIVATION: Mutagenicity is among the toxicological end points that pose the highest concern. The accelerated pace of drug discovery has heightened the need for efficient prediction methods. Currently, most available tools fall short of the desired degree of accuracy, and can only provide a binary classification. It is of significance to develop a discriminative and informative model for the mutagenicity prediction. RESULTS: Here we developed a mutagenic probability prediction model addressing the problem, based on datasets covering a large chemical space. A novel molecular electrophilicity vector (MEV) is first devised to represent the structure profile of chemical compounds. An extended support vector machine (SVM) method is then used to derive the posterior probabilistic estimation of mutagenicity from the MEVs of the training set. The results show that our model gives a better performance than TOPKAT (http://www.accelrys.com) and other previously published methods. In addition, a confidence level related to the prediction can be provided, which may help people make more flexible decisions on chemical ordering or synthesis. AVAILABILITY: The binary program (ZGTOX_1.1) based on our model and samples of input datasets on Windows PC are available at http://dddc.ac.cn/adme upon request from the authors.

Algorithms↗
PubMed2006

TarFisDock: a web server for identifying drug targets with docking approach.

TarFisDock is a web-based tool for automating the procedure of searching for small molecule-protein interactions over a large repertoire of protein structures. It offers PDTD (potential drug target database), a target database containing 698 protein structures covering 15 therapeutic areas and a reverse ligand-protein docking program. In contrast to conventional ligand-protein docking, reverse ligand-protein docking aims to seek potential protein targets by screening an appropriate protein database. The input file of this web server is the small molecule to be tested, in standard mol2 format; TarFisDock then searches for possible binding proteins for the given small molecule by use of a docking approach. The ligand-protein interaction energy terms of the program DOCK are adopted for ranking the proteins. To test the reliability of the TarFisDock server, we searched the PDTD for putative binding proteins for vitamin E and 4H-tamoxifen. The top 2 and 10% candidates of vitamin E binding proteins identified by TarFisDock respectively cover 30 and 50% of reported targets verified or implicated by experiments; and 30 and 50% of experimentally confirmed targets for 4H-tamoxifen appear amongst the top 2 and 5% of the TarFisDock predicted candidates, respectively. Therefore, TarFisDock may be a useful tool for target identification, mechanism study of old drugs and probes discovered from natural products. TarFisDock and PDTD are available at http://www.dddc.ac.cn/tarfisdock/.

Databases, Protein↗