Biomedical subjects

Ling Xue

Publications and source records attributed to Ling Xue.

15 recordsLinked to original sources

PubMed2004

Identification of structurally diverse growth hormone secretagogue agonists by virtual screening and structure-activity relationship analysis of 2-formylaminoacetamide derivatives.

Two molecules with known growth hormone secretagogue (GHS) agonist activity were used as templates to computationally screen approximately 80000 compounds. A total of 108 candidate compounds were selected, and five of them were found to be active in the low-micromolar range in both cell-based and direct binding assays. These compounds were structurally diverse and significantly differed from known GHS agonists. The most active compound was subjected to SAR evaluation, which slightly increased its potency and identified molecular regions important for specific GHS agonist activity.

Acetamides↗

PubMed2004

Influence of serum from liver-damaged rats on differentiation tendency of bone marrow-derived stem cells.

AIM: Recent studies in both rodents and humans indicated that bone marrow (BM)-derived stem cells were able to home to the liver after they were damaged and demonstrated plasticity in becoming hepatocytes. However, the question remains as to how these stem cells are activated and led to the liver and where the signals initiating the mechanisms of activation and differentiation of stem cells originate. The aim of this study was to investigate the influence of serum from liver-damaged rats on differentiation tendency of bone marrow-derived stem cells. METHODS: Serum samples were collected from rats treated with a 2-acetylaminofluorene (2-AAF) /carbon tetrachloride (CCl(4)) program for varying time points and then used as stimulators of cultured BM stem cells. Expression of M(2)- and L-type isozymes of rat pyruvate kinase, albumin as well as integrin-beta1 were then examined by reverse transcription polymerase chain reaction (RT-PCR) to estimate the differentiation state of BM stem cells. RESULTS: Expression of M(2)-type isozyme of pyruvate kinase (M(2)-PK), a marker of immature hepatocytes, was detected in each group stimulated with experimental serum, but not in controls including mature hepatocytes, BM stem cells without serum stimulation, and BM stem cells stimulated with normal control serum. As a marker expressed in the development of liver, the expression signal of integrin-beta1 was also detectable in each group stimulated with experimental serum. However, expression of L-type isozyme of pyruvate kinase (L-PK) and albumin, marker molecules of mature hepatocytes, was not detected in groups stimulated with experimental serum. CONCLUSION: Under the influence of serum from rats with liver failure, BM stem cells begin to differentiate along a direction to hepatocyte lineage and to possess some features of immature hepatocytes.

Animals↗

PubMed2004

Is inhibition of cancer angiogenesis and growth by paclitaxel schedule dependent?

It has been speculated that weekly paclitaxel enhances antiangiogenesis and, hence, results in a greater inhibition of cancer growth than the 3-week schedule. We compared the weekly and 3-week schedules of paclitaxel in inhibiting angiogenesis, tumor growth and bone marrow hematopoiesis in a lung cancer model. Vehicle or paclitaxel was administered i.p. to three groups of nude mice bearing a human lung cancer. The vehicle was given weekly for six doses or every 3 weeks for two doses (Group A). Paclitaxel was administered at 20 mg/kg/week for six doses (Group B) or 60 mg/kg/3 weeks for two doses (Group C). The tumor growth rate was reduced by 50% equally in both the paclitaxel-treated groups. Intratumoral microvasculature was reduced by 70% in each paclitaxel-treated group. However, white blood cell count was significantly reduced in Group C in comparison with that of Group A or B. We conclude that in this model, angiogenesis and tumor growth were inhibited to the same extent when paclitaxel was administered on a weekly or 3-week schedule. Inhibition of tumor growth by paclitaxel was associated with suppression of angiogenesis. Weekly administration of paclitaxel resulted in a lower degree of leukopenia than with the 3-week schedule, mimicking the clinical setting.

Angiogenesis Inhibitors↗

PubMed2004

Cell-based partitioning.

Partitioning techniques are widely used to classify compound sets or databases according to specific chemical or biological criteria. Partitioning is conceptually related to, yet algorithmically distinct from, conventional clustering methods and is particularly suitable for efficient processing of very large compound sets. Currently, some of the most popular partitioning approaches in the chemoinformatics field involve dimension reduction of initially defined chemistry spaces and creation of subsections of low-dimensional space for molecular classification. These subsections are often called cells. Original chemical reference spaces are generated through selection of various descriptors of molecular structure and properties. Principles and methodological aspects of dimension reduction of chemical spaces and compound partitioning in low-dimensional space are described herein.

Information Services↗

PubMed2003

A selective tropism of transfused oval cells for liver.

AIM: To explore the biological behaviors of hepatic oval cells after transfused into the circulation of experimental animals. METHODS: Oval cells from male SD rat were transfused into the circulation of a female rat which were treated by a 2-AAF/CCl(4) program, through caudal vein. Sex-determining gene sry which located on Y chromosome was examined by PCR and in situ hybridization technique in liver, kidney and spleen of the experimental animals, respectively. RESULTS: The results of the cell-transplant experiment showed that the sry gene was detectable only in the liver but not in spleen and kidney of the experimental rats, and no signals could be detected in the control animals. It can be also morphologically proved that some exogenous cells had migrated into the parenchyma of the liver and settled there. CONCLUSION: The result means that there are exogenous cells located in the liver of the experimental animal and the localization is specific to the liver. This indicates that some "signal molecules" must exist in the circulation of the rats treated by 2-AAF/CCl(4). These "signal molecules" might play an important role in specific localization and differentiation of transfused oval cells.

Animals↗

PubMed2002

Methods for compound selection focused on hits and application in drug discovery.

In the context of virtual screening calculations, a multiple fingerprint-based metric is applied to generate focused compound libraries by database searching. Different fingerprints are used to facilitate a similarity step for database mining, followed by a diversity step to assemble the final library. The method is applied, for example, to build libraries of limited size for hit-to-lead development efforts. In studies designed to inhibit a therapeutically relevant protein-protein interaction, small molecular hits were initially obtained by combined fingerprint- and structure-based virtual screening and used for the design of focused libraries. We review the applied virtual screening approach and report the statistics and results of screening as well as focused library design. While the structures of lead compounds cannot be disclosed, the analysis is thought to provide an example of the interplay of different methods applied in practical lead identification.

Binding Sites↗

PubMed2002

[Studies on the anti-inflammation effect of the TCM prescription of a combination of monkshood root with peony root].

OBJECTIVE: To make a comparison between the single and combined use of Monkshood Root and Peony Root to observe the anti-inflammation effect in the experimental animals. METHOD: The experimental inflammatory models were adopted, i.e. adjuvant-induced polyarthritis carrageenan-induced or formaldehyde-induced rat paw edema, and cotton pellet-induced granuloma formation in rats xylene-induced mouse ear edema, exudation of abdominal blood capillaries of mice, etc. RESULT: The anti-inflammafion effect of Monkshood Root was weaker than that of Peony Root or Peony Root combined with Monkshood Root. It was found that anti-inflammation effect with the drug-cooperation was enhanced more significantly in the formaldehyde-induced or adjuvant-induceed arthritis models than in the carrageenan-induced rat paw edema and other inflammatory models either in the large dosage of 1:1 proportion or in the small dosage of 1:2 proportion. CONCLUSION: The drug-cooperation has a good selective and synergic effect on anti-inflammation.

Aconitum↗

PubMed1998

In situ hybridization assay of androgen receptor gene in hepatocarcinogenesis.

AIM:To determine the correlation between expression of androgen receptor (AR) gene and hepatocarcinogenesis.METHODS:Male SD rats were used as experimental animals and the animal model of experimental hepatocarcinoma was established by means of 3'-me-DAB administration. Androgen receptor mRNA was detected by a non-radioactive in situ hybridization assay in neoplastic and non-neoplastic liver tissues.RESULTS:The expression of androgen receptor mRNA was observed only in neoplastic cells and some atypical hyperplastic cells. In the liver tissue of control animal and the remaining normal liver cells adjacent to the carcinoma tissue, no positive signal was seen.CONCLUSION:Androgen has an important correlation with hepatocarcinogenesis and the expression of androgen receptor gene might be a mark event during hepatocarcinogenesis.

Journal Article↗

PubMedDate not supplied

Accurate partitioning of compounds belonging to diverse activity classes.

Diverse sets of compounds were classified according to biological activity by use of a partitioning approach based on principal component analysis in conjunction with a genetic algorithm for molecular descriptor evaluation. Combinations of 236 molecular property and structural key descriptors were explored for their performance in classifying 317 molecules belonging to 21 distinct biological activity classes from various sources. Preferred descriptor combinations were further explored by complete factorial analysis. In these calculations, compounds having similar specific activity were predicted with greater than 80% accuracy.

Journal Article↗

PubMedDate not supplied

Median Partitioning: a novel method for the selection of representative subsets from large compound pools.

A method termed Median Partitioning (MP) has been developed to select diverse sets of molecules from large compound pools. Unlike many other methods for subset selection, the MP approach does not depend on pairwise comparison of molecules and can therefore be applied to very large compound collections. The only time limiting step is the calculation of molecular descriptors for database compounds. MP employs arrays of property descriptors with little correlation to divide large compound pools into partitions from which representative molecules can be selected. In each of n subsequent steps, a population of molecules is divided into subpopulations above and below the median value of a property descriptor until a desired number of 2n partitions are obtained. For descriptor evaluation and selection, an entropy formulation was embedded in a genetic algorithm. MP has been applied here to generate a subset of the Available Chemicals Directory, and the results have been compared with cell-based partitioning.

Algorithms↗

PubMedDate not supplied

Classification of biologically active compounds by median partitioning.

The median partitioning (MP) method was originally developed for the selection of diverse subsets from compound databases. Following this approach, property descriptors are used in subsequent steps to divide compounds into defined partitions from which representative molecules are selected. For descriptor analysis, MP was coupled to a genetic algorithm. MP subset selection does not depend on pairwise comparison of molecules and is therefore applicable to very large compound pools. Here the MP approach was evaluated for the classification of molecules according to biological activity. A total of 317 molecules belonging to 21 different activity classes were studied. MP compound classification calculations were carried out both in the presence and absence of 2000 randomly selected "background" molecules. The performance of MP was compared to cell-based partitioning and found to be at least comparable, with up to approximately 82% of active molecules occurring in "pure" partitions consisting only of molecules sharing the same activity. Different from cell-based methods, MP classification is based on "direct" and "sequential" contributions of molecular property descriptors. Our results suggest that MP in not only an effective method for the selection of diverse subsets but also for the classification of active compounds and searching for molecules with desired activity.

Computer Simulation↗

PubMedDate not supplied

Design and evaluation of a molecular fingerprint involving the transformation of property descriptor values into a binary classification scheme.

A new fingerprint design concept is introduced that transforms molecular property descriptors into two-state descriptors and thus permits binary encoding. This transformation is based on the calculation of statistical medians of descriptor distributions in large compound collections and alleviates the need for value range encoding of these descriptors. For binary encoded property descriptors, bit positions that are set off capture as much information as bit positions that are set on, different from conventional fingerprint representations. Accordingly, a variant of the Tanimoto coefficient has been defined for comparison of these fingerprints. Following our design idea, a prototypic fingerprint termed MP-MFP was implemented by combining 61 binary encoded property descriptors with 110 structural fragment-type descriptors. The performance of this fingerprint was evaluated in systematic similarity search calculations in a database containing 549 molecules belonging to 38 different activity classes and 5000 background molecules. In these calculations, MP-MFP correctly recognized approximately 34% of all similarity relationships, with only 0.04% false positives, and performed better than previous designs and MACCS keys. The results suggest that combinations of simplified two-state property descriptors have predictive value in the analysis of molecular similarity.

Computing Methodologies↗

PubMedDate not supplied

Profile scaling increases the similarity search performance of molecular fingerprints containing numerical descriptors and structural keys.

The concept of compound class-specific profiling and scaling of molecular fingerprints for similarity searching is discussed and applied to newly designed fingerprint representations. The approach is based on the analysis of characteristic patterns of bits in keyed fingerprints that are set on in compounds having equivalent biological activity. Once a fingerprint profile is generated for a particular activity class, scaling factors that are weighted according to observed bit frequencies are applied to signature bit positions when searching for similar compounds. In systematic similarity search calculations over 23 diverse activity classes, profile scaling consistently increased the performance of fingerprints containing property descriptors and/or structural keys. A significant improvement of approximately 15% was observed for a new fingerprint consisting of binary encoded molecular property descriptors and structural keys. Under scaling conditions, this fingerprint, termed MP-MFP, correctly recognized on average close to 60% of all active test compounds, with only a few false positives. MP-MFP outperformed MACCS keys and other reference fingerprints. In general, optimum performance in scaling calculations was achieved at higher threshold values of the Tanimoto coefficient than in nonscaled calculations, thereby increasing the search selectivity. In general, putting relatively high weight on signature bit positions that were always, or almost always, set on was found to be the most effective scaling procedure. Analysis of class-specific search performance revealed that profile scaling of MP-MFP improved the similarity search results for each of the 23 activity classes.

Journal Article↗

PubMedDate not supplied

Molecular similarity analysis and virtual screening by mapping of consensus positions in binary-transformed chemical descriptor spaces with variable dimensionality.

A novel compound classification algorithm is described that operates in binary molecular descriptor spaces and groups active compounds together in a computationally highly efficient manner. The method involves the transformation of continuous descriptor value ranges into a binary format, subsequent definition of simplified descriptor spaces, identification of consensus positions of specific compound sets in these spaces, and iterative adjustments of the dimensionality of the descriptor spaces in order to discriminate compounds sharing similar activity from others. We term this approach Dynamic Mapping of Consensus positions (DMC) because the definition of reference spaces is tuned toward specific compound classes and their dimensionality is increased as the analysis proceeds. When applied to virtual screening, sets of bait compounds are added to a large screening database to identify hidden active molecules. In these calculations, molecules that map to consensus positions after elimination of most of the database compounds are considered hit candidates. In a benchmark study on five biological activity classes, hits for randomly assembled sets of bait molecules were correctly identified in 95% of virtual screening calculations in a source database containing more than 1.3 million molecules, thus providing a measure of the sensitivity of the DMC technique.

Journal Article↗

PubMedDate not supplied

Similarity search profiles as a diagnostic tool for the analysis of virtual screening calculations.

An analysis method termed similarity search profiling has been developed to evaluate fingerprint-based virtual screening calculations. The analysis is based on systematic similarity search calculations using multiple template compounds over the entire value range of a similarity coefficient. In graphical representations, numbers of correctly identified hits and other detected database compounds are separately monitored. The resulting profiles make it possible to determine whether a virtual screening trial can in principle succeed for a given compound class, search tool, similarity metric, and selection criterion. As a test case, we have analyzed virtual screening calculations using a recently designed fingerprint on 23 different biological activity classes in a compound source database containing approximately 1.3 million molecules. Based on our predefined selection criteria, we found that virtual screening analysis was successful for 19 of 23 compound classes. Profile analysis also makes it possible to determine compound class-specific similarity threshold values for similarity searching.

Databases, Factual↗