Cross-pharmacology analysis of G protein-coupled receptors.

The degree of applicability of chemogenomic approaches to protein families depends on the accuracy and completeness of pharmacological data and the corresponding level of pharmacological similarity observed among their protein members. The recent public domain availability of pharmacological data for thousands of small molecules on 204 G protein-coupled receptors (GPCRs) provides a firm basis for an in-depth cross-pharmacology analysis of this superfamily. The number of protein targets included in the cross-pharmacology profile of the different GPCRs changes significantly upon varying the ligand similarity and binding affinity criteria.

Chemical probes for biological systems.

According to the latest definition in use by the NIH Molecular Libraries Screening Centers Network, a compound to be nominated as a chemical probe should have, on the one hand, an affinity below 100 nM for the primary target and, on the other hand, at least tenfold selectivity against related targets. Taking drugs as the ultimate product of an affinity and selectivity optimization process, it is found that only 14.4% of them would actually qualify as chemical probes under those criteria.

Ligand-based approaches to in silico pharmacology.

The development of computational methods that can estimate the various pharmacodynamic and pharmacokinetic parameters that characterise the interaction of drugs with biological systems has been a highly pursued objective over the last 50 years. Among all, methods based on ligand information have emerged as simple, yet highly efficient, approaches to in silico pharmacology. With the recent impact on the identification of new targets for known drugs, they are again the focus of attention in chemical biology and drug discovery.

A canonical cation-π interaction stabilizes the agonist conformation of estrogen-like nuclear receptors.

Representative crystal structures of the ligand-binding domain for the majority of nuclear receptors are currently available. A systematic comparative analysis of these structures identified an energetically favorable cation-π interaction that involves an amino acid located at the extreme C-terminal end and appears to form only in the agonist conformation of the estrogen receptor α, glucocorticoid, mineralocorticoid, progesterone, and androgen receptors. It is postulated that this cation-π interaction is used by members of the estrogen-like subfamily to provide additional stabilization to the transcriptional active conformation upon ligand binding.

iPHACE: integrative navigation in pharmacological space.

Summary: The increasing availability of experimentally determined binding affinities for drugs on multiple protein targets requires the design of specific mining and visualization tools that graphically integrate chemical and biological data in an efficient environment. With this aim, we developed iPHACE, an integrative web-based tool to navigate in the pharmacological space defined by small molecule drugs contained in the IUPHAR-DB, with additional interactions present in PDSP. Extending beyond traditional querying and filtering tools, iPHACE offers a means to extract knowledge from the target profile of drugs as well as from the drug profile of protein targets.

A chemogenomic approach to drug discovery: focus on cardiovascular diseases.

References to individual protein targets and bioactive small molecules associated with cardiovascular diseases can be found in multiple bibliographic sources. From mining these sources, a highly curated list of 214 cardiovascular targets was collected and organised using functional classification schemes for the main protein families of therapeutic relevance, namely, enzymes, G-protein-coupled receptors, ion channels, and nuclear receptors. This list was then used to interrogate annotated chemical libraries and extract a chemical space of 44032 small molecules connected to 160 targets.

A ligand-based approach to mining the chemogenomic space of drugs.

The practical implementation and validation of a ligand-based approach to mining the chemogenomic space of drugs is presented and applied to the in silico target profiling of 767 drugs against 684 targets of therapeutic relevance. The results reveal that drugs targeting aminergic G protein-coupled receptors (GPCRs) show the most promiscuous pharmacological profiles. The detection of cross-pharmacologies between aminergic GPCRs and the opioid, sigma, NMDA, and 5-HT3 receptors aggravate the potential promiscuity of those drugs, predominantly including analgesics, antidepressants, and antipsychotics.

Coverage and bias in chemical library design.

The design of chemical libraries directed to target classes is an activity that requires the availability of ligand pharmacological data and/or protein structural data. On the basis of the knowledge derived from these data, chemical libraries directed mainly to G protein-coupled receptors, kinases, proteases, and nuclear receptors have been assembled. However, current design strategies widely overlook assessing the potential ability of the compounds contained in a focused library to provide uniform ample coverage of the protein family they intend to target.

BioMoby web services to support clustering of co-regulated genes based on similarity of promoter configurations.

Unlabelled: Here we present a computational protocol to analyze the promoter regions of a given set of co-expressed genes, and its implementation through the use of Web services technologies. This protocol aims to cluster a set of co-regulated genes in subsets of genes showing similar configurations of transcription factor binding sites. All the steps of this protocol have been developed as web services that are compliant with BioMoby specifications.

Ligand-based approach to in silico pharmacology: nuclear receptor profiling.

Bioactive ligands are a valuable and increasingly accessible source of information about protein targets. On the basis of this statement, a list of 25 nuclear receptors was described by a series of bioactive ligands extracted directly from bibliographical sources, stored properly in an annotated chemical library, and mathematically represented using the recently reported SHED molecular descriptors. Analysis of this ligand information allowed for derivation of a threshold of nuclear receptor concern.

SHED: Shannon entropy descriptors from topological feature distributions.

A novel set of molecular descriptors called SHED (SHannon Entropy Descriptors) is presented. They are derived from distributions of atom-centered feature pairs extracted directly from the topology of molecules. The value of a SHED is then obtained by applying the information-theoretical concept of Shannon entropy to quantify the variability in a feature-pair distribution.

FCP: functional coverage of the proteome by structures.

Motivation: Tools and resources for translating the remarkable growth witnessed in recent years in the number of protein structures determined experimentally into actual gain in the functional coverage of the proteome are becoming increasingly necessary. We introduce FCP, a publicly accessible web tool dedicated to analyzing the current state and trends of the population of structures within protein families. FCP offers both graphical and quantitative data on the degree of functional coverage of enzymes and nuclear receptors by existing structures, as well as on the bias observed in the distribution of structures along their respective functional classification schemes.

Representativity of target families in the Protein Data Bank: impact for family-directed structure-based drug discovery.

Analysis of the population of enzyme structures in the Protein Data Bank across all levels of the functional classification based on enzyme commission (EC) numbers reveals that, in spite of the almost exponential growth in the number of structures deposited, progress in achieving complete occupancy at all EC levels is relatively slow. Moreover, inspection of the distribution of the population among the members of the different enzyme families uncovers a strong bias towards enzymes widely recognized as therapeutically relevant targets. The low representativity levels identified in some target families warn on the current scope and applicability of structure-based approaches to family-directed strategies in drug discovery.

Framework-based design of a new all-purpose molecular simulation application: the Adun simulator.

Here we present Adun, a new molecular simulator that represents a paradigm shift in the way scientific programs are developed. The traditional algorithm centric methods of scientific programming can lead to major maintainability and productivity problems when developing large complex programs. These problems have long been recognized by computer scientists; however, the ideas and techniques developed to deal with them have not achieved widespread adoption in the scientific community.

Chemical and biological profiling of an annotated compound library directed to the nuclear receptor family.

Nuclear receptors form a family of ligand-activated transcription factors that regulate a wide variety of biological processes and are thus generally considered relevant targets in drug discovery. We have constructed an annotated compound library directed to nuclear receptors (NRacl) as a means for integrating the chemical and biological data being generated within this family. Special care has been put in the appropriate storage of annotations by using hierarchical classification schemes for both molecules and nuclear receptors, which takes the ability to extract knowledge from annotated compound libraries to another level.

Guided docking approaches to structure-based design and screening.

With the number of protein-ligand complexes available in the Protein Data Bank constantly growing, structure-based approaches to drug design and screening have become increasingly important. Alongside this explosion of structural information, a number of molecular docking methods have been developed over the last years with the aim of maximally exploiting all available structural and chemical information that can be derived from proteins, from ligands, and from protein-ligand complexes. In this respect, the term 'guided docking' is introduced to refer to docking approaches that incorporate some degree of chemical information to actively guide the orientation of the ligand into the binding site.

Effects of asthma on cell components in peripheral blood among smokers and non-smokers.

Background: Eosinophils play a central role in asthma, but the interplay of the effects of smoking, eosinophils and asthma remains unclear.

Objective: The primary objective of our study was to investigate the extent to which smoking modifies the effect of asthma on circulating eosinophils, CD4+ and CD8+ T cell counts.

Methods: Data were collected semiannually between 1987 and 1994 from HIV-negative participants in the Multicenter AIDS Cohort Study.

Interrelationship of smoking, paraoxonase activity, and leisure time physical activity: a population-based study.

METHODS: We determined the effect of smoking on PON1 activity levels in a population-based sample of 1380 subjects and examined the possibility of regular physical activity modulating the effect of cigarette smoking on PON1 activity levels at a population level. RESULTS: Mean PON1 activity was significantly lower in smokers than in non- or ex-smokers (237.6+/-8.

The paraoxonase-1 codon 192 polymorphism is associated with fasting total cholesterol and LDL-cholesterol concentrations only in postmenopausal women. The REGICOR study.

Paraoxonase-1 (PON1) is a high-density lipoprotein (HDL)-linked enzyme which appears to protect low-density lipoproteins (LDL) from oxidation. PON1 activity is associated with variation at the PON1 gene locus, specifically the common amino acid polymorphism at codon 192, for which the Q192 allele specifies low activity and the R192 allele specifies high activity. We investigated the association between the PON1 codon 192 polymorphism and fasting concentrations of glucose, lipids, lipoproteins and PON1 activity in 1380 subjects (724 men and 656 women).

Physical activity modulates the combined effect of a common variant of the lipoprotein lipase gene and smoking on serum triglyceride levels and high-density lipoprotein cholesterol in men.

Physical activity has been identified as a protective factor against the occurrence and progression of coronary heart disease. The lipoprotein lipase (LPL) HindIII polymorphism has been associated with changes in triglyceride and high density lipoprotein (HDL)-cholesterol levels. We have investigated whether the association between the LPL HindIII genetic polymorphism and lipid levels is modified by physical activity.

Relationship of age-related myocardial infarction risk and Gln/Arg 192 variants of the human paraoxonase1 gene: the REGICOR study.

Paraoxonase1 (PON1) seems to exert a major antioxidant effect by removing lipid-peroxidation products. A common polymorphism of the PON1 gene, the PON1-192 genetic polymorphism, modulates PON1 activity and has been related in some studies to coronary heart disease. Oxidized LDL is believed to play a crucial role in the pathogenesis of atherosclerosis and there are studies providing support for the oxidative stress theory of aging.

Paraoxonase1-192 polymorphism modulates the nonfatal myocardial infarction risk associated with decreased HDLs.

Serum paraoxonase1 (PON1), a high density lipoprotein (HDL)-linked enzyme, appears to have a role in the protection of low density lipoproteins from oxidative stress. PON1 enzyme activity for paraoxon as a substrate is modulated, along with others at the PON1 locus, by the PON1-192 polymorphism, which contains low paraoxon-activity and high paraoxon-activity alleles (Q and R, respectively). The association of PON1 with HDL suggests that impaired serum concentrations of the lipoprotein could have consequences for the susceptibility to oxidative stress.

Mucins as differentiation markers in bronchial epithelium. Squamous cell carcinoma and adenocarcinoma display similar expression patterns.

Unlabelled: Highly glycosylated apomucins are important to maintain the viscoelastic properties of the mucus. Changes in their expression are frequently associated with inflammatory and neoplastic conditions. We analyzed the expression of apomucins in normal respiratory tract (n = 8) and compared it with distal, peritumoral, and tumoral epithelia from patients with squamous cell carcinoma (n = 20), adenocarcinoma (n = 13), and small cell carcinoma (n = 12).

Detection of HuD transcripts by means of reverse transcriptase and polymerase chain reaction: implications for the detection of minimal residual disease in patients with small cell lung cancer.

Small cell lung cancer (SCLC) expresses neuroectodermal markers including HuD, the best characterized member of the Hu gene family. The aim of this study is to optimize a simple and sensitive reverse transcriptase-polymerase chain reaction assay to detect circulating HuD-expressing cells for the early detection of SCLC recurrences. HuD-specific primers that selectively amplify the three HuD isoforms allowed the detection of one tumor cell/10(6) non-tumor cells.