Biomedical subjects

Yun Tang

Publications and source records attributed to Yun Tang.

16 recordsLinked to original sources

PubMed2006

Ampakines alleviate respiratory depression in rats.

RATIONALE: There is a need for improved therapeutic interventions to treat both drug- and sleep-induced respiratory depression. Increased understanding of the neurochemical control of respiration will help identify a basis for advances. Activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors positively modulates respiratory drive and rhythmogenesis in several brain regions including the pre-Bötzinger complex. Ampakines are a diverse group of small molecules that activate subsets of these receptors. OBJECTIVE: We determined whether the ampakine CX546 would enhance respiratory drive and rhythmogenesis across various stages of development and whether this ampakine could counter opioid- and barbiturate-induced respiratory depression. METHODS: Respiratory frequency and amplitude were measured in the following rat models: (1) perinatal in vitro brainstem-spinal cord, (2) neonatal in vitro medullary slice, (3) juvenile in situ perfused, working heart-brainstem preparation, and (4) newborn and adult in vivo. RESULTS: Administration of CX546 stimulated baseline respiratory frequency in perinatal in vitro preparations but not in older animals (greater than Postnatal Day 0). Furthermore, pharmacologic depression of respiratory frequency and amplitude was countered at all ages studied by the administration of CX546 in vitro, in situ, and in vivo. Significantly, CX546 countered opioid-induced breathing depression in all preparations, without altering analgesia as assessed by measuring the time to foot withdrawal in response to a thermal stimulus. CONCLUSIONS: CX546 effectively reverses opioid- and barbiturate-induced respiratory depression without reversing the analgesic response. These studies suggest that ampakines may be useful in preventing or reversing opioid-induced respiratory depression and identify the potential of ampakines for alleviating other forms of respiratory depression including sedative use and sleep apnea.

Analgesics, Opioid↗

PubMed2006

Structure-based 3D-QSAR studies on thiazoles as 5-HT3 receptor antagonists.

Structure-based 3D-QSAR studies were performed on 20 thiazoles against their binding affinities to the 5-HT(3) receptor with comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The thiazoles were initially docked into the binding pocket of a human 5-HT(3A) receptor homology model, constructed on the basis of the crystal structure of the snail acetylcholine binding protein (AChBP), using the GOLD program. The docked conformations were then extracted and used to build the 3D-QSAR models, with cross-validated r2omega values 0.785 and 0.744 for CoMFA and CoMSIA, respectively. An additional five molecules were used to validate the models further, giving satisfactory predictive r2 values of 0.582 and 0.804 for CoMFA and CoMSIA, respectively. The results would be helpful for the discovery of new potent and selective 5-HT(3) receptor antagonists.

Amino Acid Sequence↗

PubMed2006

Isolation and characterization of a novel thermophilic Bacillus strain degrading long-chain n-alkanes.

A thermophilic Bacillus strain NG80-2 growing within the temperature range of 45-73 degrees C (optimum at 65 degrees C) was isolated from a deep subterranean oil-reservoir in northern China. The strain was able to utilize crude oil and liquid paraffin as the sole carbon sources for growth, and the growth with crude oil was accompanied by the production of an unknown emulsifying agent. Further examination showed that NG80-2 degraded and utilized only long-chain (C15-C36) n-alkanes, but not short-chain (C8-C14) n-alkanes and those longer than C40. Based on phenotypic and phylogenic analyses, NG80-2 was identified as Geobacillus thermodenitrificans. The strain NG80-2 may be potentially used for oily-waste treatment at elevated temperature, a condition which greatly accelerates the biodegradation rate, and for microbial enhancing oil recovery process.

Alkanes↗

PubMed2006

3D-QSAR studies of orvinol analogs as kappa-opioid agonists.

Orvinols are potent analgesics that target opioid receptors. However, their analgesic mechanism remains unclear and no significant preference for subtype opioid receptor has been achieved. In order to find new orvinols that target the kappa-receptor, comparative 3D-QSAR studies were performed on 26 orvinol analogs using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The best predictions for the kappa-receptor were obtained with the CoMFA standard model (q2 = 0.686, r2 = 0.947) and CoMSIA model combined steric, electrostatic, hydrophobic, and hydrogen bond donor/acceptor fields (q2 = 0.678, r2 = 0.914). The models built were further validated by a test set made up of seven compounds, leading to predictive r2 values of 0.672 for CoMFA and 0.593 for CoMSIA. The study could be helpful for designing and prepare new category kappa-agonists from orvinols.

Analgesics, Opioid↗

PubMed2006

Investigation of the binding mode of (-)-meptazinol and bis-meptazinol derivatives on acetylcholinesterase using a molecular docking method.

Molecular docking has been performed to investigate the binding mode of (-)-meptazinol (MEP) with acetylcholinesterase (AChE) and to screen bis-meptazinol (bis-MEP) derivatives for preferable synthetic candidates virtually. A reliable and practical docking method for investigation of AChE ligands was established by the comparison of two widely used docking programs, FlexX and GOLD. In our hands, we had more luck using GOLD than FlexX in reproducing the experimental poses of known ligands (RMSD<1.5 A). GOLD fitness values of known ligands were also in good agreement with their activities. In the present GOLD docking protocol, (-)-MEP seemed to bind with the enzyme catalytic site in an open-gate conformation through strong hydrophobic interactions and a hydrogen bond. Virtual screening of a potential candidate compound library suggested that the most promising 15 bis-MEP derivatives on the list were mainly derived from (-)-MEP with conformations of (S,S) and (SR,RS) and with a 2- to 7-carbon linkage. Although there are still no biological results to confirm the predictive power of this method, the current study could provide an alternate tool for structural optimization of (-)-MEP as new AChE inhibitors. [Figure: see text].

Acetylcholinesterase↗

PubMed2006

QSAR study of 4-phenylpiperidine derivatives as mu opioid agonists by neural network method.

A nonlinear QSAR study was conducted on a series of 4-phenylpiperidine derivatives (4PPs) acting as mu opioid agonists by three-layer back-propagation neural network (NN) method. At first a variety of molecular descriptors were calculated and then selected with two-stage least squares combining partial least squares (PLS) method. The selected four molecular descriptors, out of 292 ones, were correlated with the known analgesic activities of 38 4PPs by NN method. The established QSAR model was further validated by five additional 4PPs, as an external testing set. Moreover, a pharmacophore model was hypothesized based on the results, which would be helpful for structural optimization of 4PPs.

Analgesics, Opioid↗

PubMed2006

Conformational re-analysis of (+)-meptazinol: an opioid with mixed analgesic pharmacophores.

AIM: To further investigate the analgesic pharmacophore of (+)-meptazinol. METHODS: Two different opioid pharmacophores, Pharm-I and Pharm-II, were established from structures of nine typical opiates and meperidine by using molecular modeling approaches according to their different structure activity relationship properties. They were further validated by a set of conformationally constrained arylpiperidines. Two conformers of (+)-meptazinol (Conformer-I and Conformer-II) detected in solution were then fitted into the pharmacophores, respectively, by Fit Atoms facilities available in SYBYL, a computational modeling tool kit for molecular design and analysis. RESULTS: Conformer-I fit Pharm-I from typical opiates well. However, Conformer-II fit none of these pharmacophores. Instead, it was found to be similar to another potent analgesic, benzofuro[2,3-c]pyridin-6-ol, whose pharmacophore was suggested to hold the transitional state between the two established pharmacophores. Unlike typical analgesics derived from 4-aryl piperidine (eg, meperidine) with one conformer absolutely overwhelming, the (+)-meptazinol exists in two conformers with similar amounts in solution. Furthermore, both conformers can not transform to each other freely in ordinary conditions based on our NMR results. CONCLUSION: (+)-meptazinol was suggested to be an opioid with mixed analgesic pharmacophores, which may account for the complicated pharmacological properties of meptazinol.

Analgesics, Opioid↗

PubMed2005

Molecular modeling and 3D-QSAR studies of indolomorphinan derivatives as kappa opioid antagonists.

Molecular modeling and 3D-QSAR studies were performed on 31 indolomorphinan derivatives to evaluate their antagonistic behaviors on kappa opioid receptor and provide information for further modification of this kind of compounds. Best predictions were obtained with CoMFA standard model (q2 = 0.693, N = 4, r2 = 0.900) and CoMSIA combined model (q2 = 0.617, N = 4, r2 = 0.904). Both models were further validated by an external test set of eight compounds with satisfactory predictions: r2 = 0.607 for CoMFA and r2 = 0.701 for CoMSIA. In addition, the 3D structure of human kappa opioid receptor was constructed based on the crystal structure of bovine rhodopsin, and the CoMSIA contour plots were then mapped into the structural model of kappa opioid receptor-GNTI complex to identify key residues, which might account for kappa antagonist potency and selectivity. The roles of nonconserved Glu297 and conserved Lys227 of human kappa opioid receptor were then discussed.

Amino Acid Sequence↗

PubMed2005

Model of full-length HIV-1 integrase complexed with viral DNA as template for anti-HIV drug design.

We report structural models of the full-length integrase enzyme (IN) of the human immunodeficiency virus type 1 (HIV-1) and its complex with viral and human DNA. These were developed by means of molecular modeling techniques using all available experimental evidence, including X-ray crystallographic and NMR structures of portions of the full-length protein. Special emphasis was placed on obtaining a model of the enzyme's active site with the viral DNA apposed to it, based on the hypothesis that such a model would allow structure-based design of inhibitors that retain activity in vivo. This was because bound DNA might be present in vivo after 3'-processing but before strand transfer. These structural models were used to study the potential binding modes of various diketo-acid HIV-1 IN inhibitors (many of them preferentially inhibiting strand transfer) for which no experimentally derived complexed structures are available. The results indicate that the diketo-acid IN inhibitors probably chelate the metal ion in the catalytic site and also prevent the exposure of the 3'-processed end of the viral DNA to human DNA.

Amino Acid Sequence↗

PubMed2005

Structural comparisons of meptazinol with opioid analgesics.

AIM: To investigate the mechanism of action of a potent analgesic, (+/-)-meptazinol. METHODS: The structures of meptazinol enantiomers were compared with opioid pharmacophore and tramadol. RESULTS: Neither enantiomer of meptazinol fitted any patterns among the opioid pharmacophore and tramadol, although they did share some structural and pharmacological similarities. However, the structure superpositions implied that both enantiomers of meptazinol might share some similar analgesic mechanisms with typical opiate analgesics. CONCLUSION: Meptazinol should have a different mechanism of action to known analgesics, which would be helpful in further investigations of meptazinol in the search for non-addictive analgesics.

Analgesics, Opioid↗

PubMed2005

Aligning multiple protein structures by deterministic annealing.

Protein structure alignment plays a key role in protein structure prediction and fold family classification. An efficient method for multiple protein structure alignment in a mathematical manner is presented, based on deterministic annealing technique. The alignment problem is mapped onto a nonlinear continuous optimization problem (NCOP) with common consensus chain, matching assignment matrices and atomic coordinates as variables. At each step in the annealing procedure, the NCOP is decomposed into as many sub-problems as the number of protein chains, each of which is actually an independent pairwise structure alignment between a protein chain and the consensus chain and hence can be efficiently solved by the parallel computation technique. The proposed method is robust with respect to choice of iteration parameters for a wide range of proteins, and performs well in both multiple and pairwise structure alignment cases, compared with existing alignment methods.

Algorithms↗

PubMed2004

Protein structure alignment by deterministic annealing.

MOTIVATION: Protein structure alignment is one of the most important computational problems in molecular biology and plays a key role in protein structure prediction, fold family classification, motif finding, phylogenetic tree reconstruction and so on. From the viewpoint of computational complexity, a pairwise structure alignment is also a NP-hard problem, in contrast to the polynomial time algorithm for a pairwise sequence alignment. RESULTS: We propose a method for solving the structure alignment problem in an accurate manner at the amino acid level, based on a mean field annealing technique. We define the structure alignment as a mixed integer-programming (MIP) problem. By avoiding complicated combinatorial computation and exploiting the special structure of the continuous partial problem, we transform the MIP into a reduced non-linear continuous optimization problem (NCOP) with a much simpler form. To optimize the reduced NCOP, a mean field annealing procedure is adopted with a modified Potts model, whose solution is generally identical to that of the MIP. There is no 'soft constraint' in our mean field model and all constraints are automatically satisfied throughout the annealing process, thereby not only making the optimization more efficient but also eliminating many unnecessary parameters that depend on problems and usually require careful tuning. A number of benchmark examples are tested by the proposed method with comparisons to several existing approaches.

Algorithms↗

PubMed2004

[A discussion on Zhang Cigong's materia medica].

Zhang Cigong's Materia Medica, being compiled by the author after learning and studying exogenous cold disease and herbology for several decades, printed in 1949 with a capacity of 150,000 Chinese characters, is a book of practical and clinical significance, featuring adoration on the theory of cold pathogenic disease, preferential practical use, integration of Chinese and western medicine, pursuit of origin and evolution, discussion on the compatibility of drug application. It emphasizes the application of drugs utilized in Shang han lun (Treatise on Cold Pathogenic Disease) and advocating the ideas of absorbing extensively ancient and modern theories from various schools, especially consulting the pharmacology of Chinese and the west, embodying the author's advocacy of "developing the classical ideas and integrating new knowledge", "overcoming one's weak points by learning from others' strong points and making effort in inheriting and developing the science of traditional Chinese medicine". However, this book also bears some incorrect points which are not overall and comprehensive enough in the understanding of drugs, and thus, should be properly accepted and rejected.

Books↗

PubMed2004

[Cloning and function analysis of L-lactate dehydrogenase gene from Lactobacillus sp. MD-1].

It was constructed that a genomic DNA library from Lactobacillus sp. MD-1 yielding D, L-lactic acid. The gene encoding L-lactate dehydrogenase (L-LDH) was cloned from the genomic library of strain MD-1 by complementation in E. coli FMJ144 which was lactate dehydrogenase and pyruvate-formate lyase double defective mutant. The nucleotide sequence of the ldhL gene predicted a protein of 316 amino acid starting with ATG. The putative molecular weight of the L-LDH amino acid sequence was 33.84kD. A putative typical promoter (-35 and -10 boxes) had been observed in the 5' noncoding region. An rho-independent transcriptional terminator has been observed in the 3' noncoding region. Three highly conserved regions (Gly13 approximately Asp50, Asp73 approximately Ileul00 and Asn123 approximately Arg154) with several conserved residues had been identified. Gly13 approximately Asp50 was NADH-binding site domain. Asp73 approximately Ileu100 and Asn123 approximately Arg154 were reported to be the active site domains. The ldhL and the L-LDH of Lactobacillus sp. MD-1 showed the low identity and similarity with other Lactobacilli, and the highest percentage were 61.9% and 68.9% respectively. All the above indicated this gene is a novel ldhL.

Amino Acid Sequence↗

PubMed2002

Structure activity of 3-aryl-1,3-diketo-containing compounds as HIV-1 integrase inhibitors.

The 4-aryl-2-hydroxy-4-oxo-2-butenoic acids and their isosteric tetrazoles are among an emerging class of aryl beta-diketo (ADK)-based agents which exhibit potent inhibition of HIV-1 integrase (IN)-catalyzed strand transfer (ST) processes, while having much reduced potencies against 3'-processing (3'-P) reactions. In the current study, L-708,906 (10e) and 5CITEP (13b), which are two examples of ADK inhibitors that have been reported by Merck and Shionogi pharmaceutical companies, served as model ADK leads. Structural variations to both the "left" and "right" sides of these molecules were made in order to examine effects on HIV-1 integrase inhibitory potencies. It was found that a variety of groups could be introduced onto the left side aryl ring with maintenance of good ST inhibitory potency. However, introduction of carboxylic acid-containing substituents onto the left side aryl ring enhanced 3'-P inhibitory potency and reduced selectivity toward ST reactions. Although both L-708,906 and 5CITEP show potent inhibition of IN in biochemical assays, there is a disparity of antiviral activity in cellular assays using HIV-1-infected cells. Neither 5CITEP nor any other of the indolyl-containing inhibitors exhibit significant antiviral effects in cellular systems. Alternatively, consistent with literature reports, L-708,906 does provide antiviral protection at low micromolar concentrations. Interestingly, several analogues of L-708,906 with varied substituents on the left side aryl ring, while having good inhibitory potencies against IN in extracellular assays, are not antiviral in whole-cell systems.

Acetoacetates↗

PubMed1997

A Computer Model for the Pore of Potassium Channel: Oxygen Cage Mechanism.

We have constructed a structural motif for the pore of voltage-gated K(+) channel by computer modeling. The model developed here predicts that the narrowest part of the pore is formed by the four carbonyl oxygens of Gly444 or Gly446, and that the ion selectivity is achieved through "oxygen cage" mechanism. Residues 447, 448 and 449 make the external entrance to the narrowest part of the pore. Of these residues, 449 and 447 are believed to interact directly with TEA. This model agrees well with many available experimental data.

Journal Article↗