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At least 955 records · Page 53Linked to original sources
PubMed2004

Hybridized particle swarm algorithm for adaptive structure training of multilayer feed-forward neural network: QSAR studies of bioactivity of organic compounds.

The multilayer feed-forward ANN is an important modeling technique used in QSAR studying. The training of ANN is usually carried out only to optimize the weights of the neural network and without paying attention to the network topology. Some other strategies used to train ANN are, first, to discover an optimum structure of the network, and then to find weights for an already defined structure. These methods tend to converge to local optima, and may also lead to overfitting. In this article, a hybridized particle swarm optimization (PSO) approach was applied to the neural network structure training (HPSONN). The continuous version of PSO was used for the weight training of ANN, and the modified discrete PSO was applied to find appropriate the network architecture. The network structure and connectivity are trained simultaneously. The two versions of PSO can jointly search the global optimal ANN architecture and weights. A new objective function is formulated to determine the appropriate network architecture and optimum value of the weights. The proposed HPSONN algorithm was used to predict carcinogenic potency of aromatic amines and biological activity of a series of distamycin and distamycin-like derivatives. The results were compared to those obtained by PSO and GA training in which the network architecture was kept fixed. The comparison demonstrated that the HPSONN is a useful tool for training ANN, which converges quickly towards the optimal position, and can avoid overfitting in some extent.

Journal Article↗
PubMed2007

Support vector machine based training of multilayer feedforward neural networks as optimized by particle swarm algorithm: application in QSAR studies of bioactivity of organic compounds.

Multilayer feedforward neural networks (MLFNNs) are important modeling techniques widely used in QSAR studies for their ability to represent nonlinear relationships between descriptors and activity. However, the problems of overfitting and premature convergence to local optima still pose great challenges in the practice of MLFNNs. To circumvent these problems, a support vector machine (SVM) based training algorithm for MLFNNs has been developed with the incorporation of particle swarm optimization (PSO). The introduction of the SVM based training mechanism imparts the developed algorithm with inherent capacity for combating the overfitting problem. Moreover, with the implementation of PSO for searching the optimal network weights, the SVM based learning algorithm shows relatively high efficiency in converging to the optima. The proposed algorithm has been evaluated using the Hansch data set. Application to QSAR studies of the activity of COX-2 inhibitors is also demonstrated. The results reveal that this technique provides superior performance to backpropagation (BP) and PSO training neural networks.

Algorithms↗
PubMed2005

Pharmacology and structure-activity relationships of bioactive polycyclic cage compounds: a focus on pentacycloundecane derivatives.

The chemistry of organic polycyclic cage compounds has intrigued medicinal chemists for over 50 years, yet little is published about their pharmacological profiles. Polycyclic cage compounds have important pharmaceutical applications, ranging from the symptomatic and proposed curative treatment of neurodegenerative diseases such as Parkinson's and Alzheimer's disease (e.g., amantadine and memantine), to use as anti-viral agents against influenza and the immunodeficiency virus (HIV). The polycyclic cage appears to be a useful scaffold to yield drugs with a wide scope of applications, and can be used also to modify and improve the pharmacokinetic and pharmacodynamic properties of drugs in current use. This review attempts to summarize the pharmacological profiles of polycyclic cage compounds with an emphasis on the lesser known pentacycloundecanes, homocubanes, and trishomocubanes.

Anti-Inflammatory Agents↗
PubMed1992

Quantitative bioassay using laser-monitored bacteria to assess toxicology and metabolism of bioactive Group IV compounds.

A new approach has been developed for assessing the toxicity and the metabolism of Group IV compounds and for other toxic substances that may interact with them at the molecular level. The approach is based upon the selective responses of sensitive biodetectors whose molecular interactions with a wide variety of toxic substances have been previously described and reported. Detection and quantitation of carbon, silicon, and tin-containing compounds has been accomplished using a laser-monitored bacterial bioassay. This system uses isogenic Bacillus subtilis strains that are genetically engineered to respond differentially to specific toxicants. The response of these biodetectors is monitored by differential light scattering of a laser that is integrated with a computerized system which collects and analyzes this data. The assay can routinely generate fully analyzed data for fixed time intervals, i.e. 60 or 90 min, or kinetic data so that the mechanisms of interactions can be elucidated.

Animals↗
PubMed2006

Boosting support vector regression in QSAR studies of bioactivities of chemical compounds.

In this paper, boosting has been coupled with SVR to develop a new method, boosting support vector regression (BSVR). BSVR is implemented by firstly constructing a series of SVR models on the various weighted versions of the original training set and then combining the predictions from the constructed SVR models to obtain integrative results by weighted median. The proposed BSVR algorithm has been used to predict toxicities of nitrobenzenes and inhibitory potency of 1-phenyl[2H]-tetrahydro-triazine-3-one analogues as inhibitors of 5-lipoxygenase. As comparisons to this method, the multiple linear regression (MLR) and conventional support vector regression (SVR) have also been investigated. Experimental results have shown that the introduction of boosting drastically enhances the generalization performance of individual SVR model and BSVR is a well-performing technique in QSAR studies superior to multiple linear regression.

Algorithms↗
PubMedDate not supplied

Piecewise hypersphere modeling by particle swarm optimization in QSAR studies of bioactivities of chemical compounds.

As the structural diversity in a quantitative structure-activity relationship (QSAR) model increases, constructing a good model becomes increasingly difficult, and simply performing variable selection might not be sufficient to improve the model quality to make it practically usable. To combat this difficulty, an approach based on piecewise hypersphere modeling by particle swarm optimization (PHMPSO) is developed in this paper. It treats the linear models describing the sought-for subsets as hyperspheres which have different radii in the data space. According to the attribute of each hypersphere, all compounds in the training set are allocated to hyperspheres to construct submodels, and particle swarm optimization (PSO) is applied to search the optimal hyperspheres for finding satisfactory piecewise linear models. A new objective function is formulated to determine the appropriate piecewise models. The performance is assessed using three QSAR data sets. Experimental results have shown the good performance of this technique in improving the QSAR modeling.

Angiotensin II↗
PubMed2006

Studies on the preparation, crystal structure and bioactivity of ginsenoside compound K.

Microbial transformation of Panaxnotoginseng saponins (PNS) using Aspergillus niger afforded, as the main metabolite, ginsenoside compound K (20-O-beta-glucopyranosyl-20(S)-protopanaxadiol). Its structure was determined spectroscopically and by X-ray analysis, and this is the first time the crystal structure of ginsenoside has been reported. In comparison with ginsenoside Rb1, the pro-drug for this metabolite, compound K exhibits potent cytotoxic activity against tumor cell lines. The mean concentrations of compound K needed to inhibit the proliferation of cells by 50% (IC50) were 12.7, 11.4, 8.5 and 9.7 microM for mouse high-metastatic melanoma (B16-BL6), human hepatoma (HepG2), human myeloid leukemia (K562) and human high-metastatic lung carcinoma (95-D) cell lines, respectively. The data show that ginsenoside compound K is a good antitumor drug candidate.

Animals↗
PubMed1979

Investigations with bioactivated polymethylmethacrylates.

Compound bone cement on a PMMA base with an additive of bioactive glass ceramic particles in different portions and different particle sizes are tested in animal experiments. The tissue reactions to extracorporal polymerized specimens and to in situ polymerized specimens are observed. The experiments with an implantation period up to six months demonstrate a tight bonding between the newly formed osseous tissue and the glass ceramic particles at the interface. The inflammatory reactions in the vicinity of the implant are small. It is the objective of the investigations to improve the adherance of the bone cement at the interface to achieve a more durable anchorage of bone cement in the tissue.

Animals↗
PubMed2005

Production of the potent antibacterial polyketide erythromycin C in Escherichia coli.

An Escherichia coli strain capable of producing the potent antibiotic erythromycin C (Ery C) was developed by expressing 17 new heterologous genes in a 6-deoxyerythronolide B (6dEB) producer strain. The megalomicin gene cluster was used as the source for the construction of two artificial operons that contained the genes encoding the deoxysugar biosynthetic and tailoring enzymes necessary to convert 6dEB to Ery C. The reconstructed mycarose operon contained the seven genes coding for the enzymes that convert glucose-1-phosphate (G-1-P) to TDP-L-mycarose, a 6dEB mycarosyl transferase, and a 6dEB 6-hydroxylase. The activity of the pathway was confirmed by demonstrating conversion of exogenous 6dEB to 3-O-alpha-mycarosylerythronolide B (MEB). The reconstructed desosamine operon contained the six genes necessary to convert TDP-4-keto-6-deoxyglucose, an intermediate formed in the mycarose pathway, to TDP-D-desosamine, a desosamine transferase, a 6dEB 12-hydroxylase, and the rRNA methyltransferase ErmE; the last was required to confer resistance to the host cell upon production of mature macrolide antibiotics. The activity of this pathway was demonstrated by conversion of MEB to Ery C. When the mycarose and desosamine operons were expressed in an E. coli strain engineered to synthesize 6dEB, Ery C and Ery D were produced. The successful production of Ery C in E. coli shows the potentiality of this model microorganism to synthesize novel 6-deoxysugars and to produce bioactive glycosylated compounds and also establishes the basis for the future use of E. coli both in the production of new glycosylated polyketides and for the generation of novel bioactive compounds through combinatorial biosynthesis.

Aminoglycosides↗
PubMed2002

[Studies on structure modification of (+)-praeruptorin A].

AIM: In order to look for new active compounds, the structure of (+)-praeruptorin A is modified. METHODS: (+)-Praeruptorin A was isolated from the root of Peucedanum praeruptorum, basic hydrolysis of (+)-praeruptorin A and acyled reactions of hydrolysis product of (+)-praeruptorin A were carried out. RESULTS: Eighteen compounds were semi-synthesized from (+)-praeruptorin A. CONCLUSION: Fourteen compounds (5-18) among them are new compounds. Preliminary bioactivity assay indicated that the new compounds show calcium antagonist activity, but they are not as strong as (+)-praeruptorin A.

Animals↗
PubMed2006

Bioactivation of carboxylic acid compounds by UDP-Glucuronosyltransferases to DNA-damaging intermediates: role of glycoxidation and oxidative stress in genotoxicity.

Nonenzymatic modification of proteins by acyl glucuronides is well documented; however, little is known about their potential to damage DNA. We have previously reported that clofibric acid undergoes glucuronidation-dependent bioactivation to DNA-damaging species in cultured mouse hepatocytes. The aim of this study was to investigate the mechanisms underlying such DNA damage, and to screen chemically diverse carboxylic acid drugs for their DNA-damaging potential in glucuronidation proficient murine hepatocytes. Cells were incubated with each aglycone for 18 h, followed by assessment of compound cytotoxicity using the MTT assay and evaluation of DNA damage using the Comet assay. Relative cytotoxic potencies were ketoprofen > diclofenac, benoxaprofen, nafenopin >> gemfibrozil, probenecid > bezafibrate > clofibric acid. At a noncytotoxic (0.1 mM) concentration, only benoxaprofen, nafenopin, clofibric acid, and probenecid significantly increased Comet moments (P < 0.05 Kruskal-Wallis). Clofibric acid and probenecid exhibited the greatest DNA-damaging potency, producing significant DNA damage at 0.01 mM concentrations. The two drugs produced maximal increases in Comet moment of 4.51 x and 2.57 x control, respectively. The glucuronidation inhibitor borneol (1 mM) abolished the induction of DNA damage by 0.5 mM concentrations of clofibric acid and probenecid. In an in vitro cell-free system, clofibric acid glucuronide was 10 x more potent than glucuronic acid in causing DNA strand-nicking, although both compounds showed similar rates of autoxidation to generate hydroxyl radicals. In cultured hepatocytes, the glycation inhibitor, aminoguanidine, and the iron chelator, desferrioxamine mesylate, inhibited DNA damage by clofibric acid, whereas the free radical scavengers Trolox and butylated hydroxytoluene, and the superoxide dismutase mimetic bis-3,5-diisopropylsalicylate had no effect. In conclusion, clinically relevant concentrations of two structurally unrelated carboxylic acids, probenecid and clofibric acid, induced DNA damage in isolated hepatocytes via glucuronidation- dependent pathways. These findings suggest acyl glucuronides are able to access and damage nuclear DNA via iron-catalyzed glycation/glycoxidative processes.

Animals↗
PubMed2000

Nitrogen bridgehead compounds, facile synthesis of bioactive cyanopyrimido[1,2-a]pyrimidinones.

Synthesis of some new cyanopyrimido[1,2-a]pyrimidinones 5-22 have been achieved via interaction of 2-amino-6-anisyl-5-cyano-4(3H)-pyrimidinone (1) with some heterocycles having a vicinal chloroester, chlorocyano or mercaptocyano group, dimethyl acetylenedicarboxylate, active methylene compounds, ethyl 2-acetyl-3-anisylpropenoate, ethyl 3-aryl-3-cyanopropenoates, ethyl 2-cyano-3-ethoxyacrylate and some enones or enals. Some of the isolated products were subjected to biological screening tests.

Absidia↗
PubMed1998

Prospects for the metabolic engineering of bioactive flavonoids and related phenylpropanoid compounds.

The successful engineering of complex metabolic pathways will require, in addition to availability of cloned genes and promoters, knowledge of the regulatory mechanisms that control metabolic flux into the pathway including post-translational phenomena such as metabolite channeling. We are interested in modifying pathways for the synthesis of isoflavonoids and other bioactive phenylpropanoid compounds in transgenic plants. We describe studies on flux control utilizing transgenic tobacco plants that under- and over-express key biosynthetic enzymes, and outline experimental approaches for the molecular dissection of potential metabolic channels in the synthesis of antimicrobial flavonoid derivatives in alfalfa and other species.

Flavonoids↗
PubMedDate not supplied

Marine pharmacology in 1999: antitumor and cytotoxic compounds.

During 1999 marine antitumor pharmacology research involved researchers in Austria, Australia, England, France, Germany, Greece, Holland, Italy, Japan, Spain, Taiwan and the United States. Thirty six papers were published in peer-reviewed journals describing the antitumor and cytotoxic properties of 30 marine natural products belonging to four structural types, namely polyketides, terpenes, nitrogen-containing compounds and polysaccharides. The organisms yielding these bioactive marine compounds comprised a diverse group of marine animals, algae, fungi and bacteria. A variety of antitumor pharmacological studies were conducted with 17 marine natural products with established mechanisms of action in a number of experimental and clinical models. Didemnin B, a tunicate-derived depsipeptide with potent antitumor effects, completed a Phase II anticancer clinical trial which resulted indeterminate in respect to activity against human melanoma due to anaphylactoid reactions. In vitro cytotoxicity data with murine and human cell lines were reported for 14 novel marine chemicals with as yet undetermined mechanisms of action. This 1999 literature overview thus highlights the fact that the multinational effort aimed at the discovery of novel marine antitumor agents remained at the same level of research activity as during 1998.

Animals↗
PubMed2004

Identification of an N-methyl-4-phenylpyridinium-like metabolite of the antidiarrheal agent loperamide in human liver microsomes: underlying reason(s) for the lack of neurotoxicity despite the bioactivation event.

In contrast with the Parkinson's-like effects associated with the mitochondrial neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and the neuroleptic agent haloperidol, there exist no reports on adverse central nervous system (CNS) effects with the structurally related N-substituted-4-arylpiperidin-4-ol derivative and antidiarrheal agent loperamide. Although this difference can be attributed to loperamide's P-glycoprotein substrate properties that prevent it from accessing the brain, an alternative possibility is that loperamide metabolism in humans is different from that of MPTP and haloperidol and does not involve bioactivation to a neurotoxic pyridinium species. In the current study, loperamide bioactivation was examined with particular focus on identification of pyridinium metabolites. A NADPH-dependent disappearance of loperamide was observed in both rat and human liver microsomes (human t(1/2) = 13 min; rat t(1/2) = 22 min). Loperamide metabolism was similar in human and rat and involved N-dealkylation to N-desmethylloperamide (M3) as the principal metabolic fate. Other routes of loperamide biotransformation included N- and C-hydroxylation to the loperamide-N-oxide (M4) and carbinolamide (M2) metabolites, respectively. Furthermore, the formation of an additional metabolite (M5) was also discernible in human and rat liver microsomes. The structure of M5 was assigned to the pyridinium species (LPP(+)) based on comparison of the liquid chromatography/tandem mass spectrometry characteristics to the pyridinium obtained from loperamide via a chemical reaction. Loperamide metabolism in human microsomes was sensitive to ketoconazole and bupropion treatment, suggesting P4503A4 and -2B6 involvement. Recombinant P4503A4 catalyzed all of the loperamide biotransformation pathways in human liver microsomes, whereas P4502B6 was only responsible for N-dealkylation and N-oxidation routes. The wide safety margin of loperamide (compared with MPTP and haloperidol) despite metabolism to a potentially neurotoxic pyridinium species likely stems from a combination of factors that include a therapeutic regimen normally restricted to a few days and the fact that loperamide and perhaps LPP(+) are P-glycoprotein substrates and are denied entry into the CNS. The differences in safety profile of haloperidol and loperamide despite a common bioactivation event supports the notion that not all compounds undergoing bioactivation in vitro will necessarily elicit a toxicological response in vivo.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗