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Scott Boyer

Publications and source records attributed to Scott Boyer.

11 recordsLinked to original sources
PubMed2006

Circular fingerprints: flexible molecular descriptors with applications from physical chemistry to ADME.

Circular fingerprints -- the representation of molecular structures by atom neighborhoods -- have been applied to a wide range of applications, such as similarity searching and the prediction of absorption, distribution, metabolism, excretion and toxicity properties. In recent years there has been a surge in applications resulting from the superior performance of circular fingerprints in comparative studies. This feature examines the nature of circular fingerprints as well as their applications, including virtual screening, metabolism prediction and the estimation of pK((a)) constants.

Algorithms↗
PubMed2005

Illuminating drug discovery with biological pathways.

Systems biology promises to impact significantly on the drug discovery process. One of its ultimate goals is to provide an understanding of the complete set of molecular mechanisms describing an organism. Although this goal is a long way off, many useful insights can already come from currently available information and technology. One of the biggest challenges in drug discovery today is the high attrition rate: many promising candidates prove ineffective or toxic owing to a poor understanding of the molecular mechanisms of biological systems they target. A "systems" approach can help identify pathways related to a disease and can suggest secondary effects of drugs that might cause these problems and thus ultimately improve the drug discovery pipeline.

Animals↗
PubMed2005

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. Analysis of NRacl has ultimately led to the identification of scaffolds with highly promiscuous nuclear receptor profiles and to the classification of nuclear receptor groups with similar scaffold promiscuity patterns. This information can be exploited in the design of probing libraries for deorphanization activities as well as for devising screening batteries to address selectivity issues.

Combinatorial Chemistry Techniques↗
PubMed2005

Practical Approaches to the Development of Biomedical Informatics: the INFOBIOMED Network of Excellence.

Biomedical Informatics (BMI) is the emerging discipline that aims to facilitate integration of Bioinformatics and Medical Informatics for the purpose of accelerating discovery and the generation of novel diagnostic and therapeutic modalities. Building on the success of the European Commission-funded BIOINFOMED Study, an INFOBIOMED Network of Excellence has been constituted with the main objective of setting a structure for a collaborative approach at a European level. Initially formed by fifteen European organizations, the main objective of the INFOBIOMED network is therefore to enable the reinforcement of European BMI at the forefront of these emergent interdisciplinary fields. The paper describes the structure of the network, the integration approaches regarding databases and four pilot applications.

Biomedical Research↗
PubMed2003

Generation and evaluation of a CYP2C9 heteroactivation pharmacophore.

Positive cooperativity (auto- and heteroactivation) of drug oxidation, a potential cause of drug interactions, is well established in vitro for cytochrome P450 (P450) 3A4 but to a much lesser extent for other drug-metabolizing P450 isoforms. Using a high throughput fluorescent-based CYP2C9 effector assay, we identified >30 heteroactivators from a set of 1504 structurally diverse compounds. Several potent heteroactivators of CYP2C9-mediated 7-methoxy-4-trifluoromethyl-coumarin metabolism are marketed drugs or endogenous compounds (amiodarone, niclosamide, liothyronine, meclofenemate, zafirlukast, estropipate, and dichlorphenamide, yielding 150% control reaction velocity at 0.04, 0.09, 0.5, 1, 1.2, 1.5, and 2.5 microM, respectively). Some heteroactivators are also known CYP2C9 substrates or inhibitors, suggesting potential multiple binding sites and substrate-dependent effects. v(150%), the concentration of effector giving 150% of control reaction velocity, was used as pharmacophore modeling parameter based on enzyme kinetic assumptions. The generated pharmacophore (training set: n = 36, v(150%) 0.04-150 microM) contains one hydrogen bond acceptor, one aromatic ring, and two hydrophobes. v(150%) values for 94% of the training set heteroactivators were predicted within 1 log unit for the residual (r [log observed v(150%)] versus [log predicted v(150%)] = 0.71; r2 0.50). The model also correctly identifies close to 70% of potent inhibitors (IC50 < 1 microM) as high-affinity CYP2C9 binders, suggesting that heteroactivators and inhibitors share some common structural CYP2C9 binding features, supporting the previously suggested hypothesis that CYP2C9 heteroactivators can bind within the active site.

Aryl Hydrocarbon Hydroxylases↗
PubMed2003

In vivo CYP3A4 heteroactivation is a possible mechanism for the drug interaction between felbamate and carbamazepine.

Atypical (non-Michaelis-Menten) kinetics are commonly observed with CYP3A4 substrates in vitro. If relevant in vivo, cytochrome P450 heteroactivation could give rise to increased drug clearance. To test the possible in vivo relevance of atypical cytochrome P450 kinetics, we investigated the role of heteroactivation in the therapeutically relevant drug interaction between the anti-epileptics felbamate and carbamazepine. Felbamate heteroactivates CYP3A4-mediated formation of carbamazepine-10,11-epoxide (carbamazepine-ep), the major metabolite of carbamazepine, in human liver microsomes and recombinant CYP3A4 at relevant in vivo concentrations of both drugs (maximum activation 98% at 10 microM carbamazepine, 1 mM felbamate). Felbamate (50-500 microM) did not induce CYP3A4, as based on mRNA measurements in human liver slices. The further metabolism of carbamazepine-ep was inhibited (38% by 500 microM felbamate) in human liver slices. We propose a methodology to predict changes in steady-state plasma concentrations (Css) of parent drug and metabolite from in vitro heteroactivation and inhibition data, including prediction of the increase in fraction metabolized. A meta-analysis of reported in vivo effects of felbamate on Csscarbamazepine was performed to allow evaluation of this approach. The predicted effect of in vitro heteroactivation on Csscarbamazepine corresponds well to that observed in vivo. Combining the effect of heteroactivation on the fraction metabolized to carbamazepine-ep, and inhibition of its further metabolism, predicts a change in Csscarbamazepine-ep that falls within the range observed in vivo. Our results strongly suggest that in vivo heteroactivation of CYP3A4 is a possible mechanism of the clinically observed drug interaction between felbamate and carbamazepine.

Carbamazepine↗
PubMed2002

Discovery and optimization of a series of carbazole ureas as NPY5 antagonists for the treatment of obesity.

The hypothesis that antagonists of the neuropeptide Y5 receptor would provide safe and effective appetite suppressants for the treatment of obesity has prompted vigorous research to identify suitable compounds. We discovered a series of acylated aminocarbazole derivatives (e.g., 3a) that are potent and selective Y5 antagonists, representing interesting starting points but suffering from poor bioavailability and concerns about potential toxicity as a consequence of the embedded aminocarbazole fragment. It proved relatively easy to improve the drug metabolism and pharmacokinetic (DMPK) properties by variation of the side chain (as in 4a) but difficult to eliminate the aminocarbazole fragment. For compounds in this series to have the potential to be drugs, we believed that both the compound itself and the component aniline must be free of mutagenic activity. Parallel structure-activity relationship studies looking at the effects of ring substitution have proved that it is possible by incorporation of a 4-methyl substituent to produce carbazole ureas with potent Y5 activity, comprised of carbazole anilines that in themselves are devoid of mutagenic activity in the Ames test. Compound 4o (also known as NPY5RA-972) is highly selective with respect to Y1, Y2, and Y4 receptors (and also to a diverse range of unrelated receptors and enzymes), with an excellent DMPK profile including central nervous system penetration. NPY5RA-972 (4o) is a highly potent Y5 antagonist in vivo but does not block neuropeptide Y-induced feeding nor does it reduce feeding in rats, suggesting that the Y5 receptor alone has no significant role in feeding in these models.

Aniline Compounds↗
PubMed2002

Selective antagonism of the NPY Y5 receptor does not have a major effect on feeding in rats.

Neuropeptide Y (NPY) is thought to play a key role in stimulating feeding, thus making NPY receptors attractive appetite suppressant drug targets for treating obesity. Because the orexigenic effects of NPY have been ascribed to actions at the NPY Y5 receptor, we have determined the role of this receptor in feeding in rats, using a small molecule antagonist of this receptor. NPY5RA-972 is a selective and potent (<10 nmol/l) NPY Y5 receptor antagonist. This compound is central nervous system (CNS) penetrant, and an oral dose of 10 mg/kg NPY5RA-972 to rats produced concentrations in cerebrospinal fluid that greatly exceeded the in vitro IC(50) (inhibitory concentration 50%). Indeed, at doses to rats as low as 1 mg/kg, NPY5RA-972 inhibited feeding induced by intracerebroventricular (ICV) administration of a selective NPY Y5 agonist ([cPP(1-7),NPY(19-23),Ala(31),Aib(32),Gln(34)]-hPP). However, in the dose range 1-10 mg/kg, NPY5RA-972 had no significant effect on food intake in Wistar rats induced to feed by either ICV NPY or 24 h fasting or in free-feeding Wistar or obese Zucker rats. Chronic administration of NPY5RA-972 (10 mg/kg twice daily) had no effect on food intake or body weight in either free-feeding Wistar rats or dietary obese rats. These data indicate that NPY5RA-972 is a potent, selective, orally active, and CNS-penetrant antagonist of the NPY Y5 receptor that prevents feeding driven by activation of this receptor. The data obtained with this antagonist indicate that the NPY Y5 receptor is not a major regulator of feeding in the rat.

Animals↗
PubMedDate not supplied

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. If the similarity of one molecule to any of the molecules annotated to one particular nuclear receptor is below that threshold, the molecule receives an alert on the probability of having affinity below 10 microM for that nuclear receptor. On this basis, a linkage map was constructed that reveals the interaction network of nuclear receptors from the perspective of their active ligands. This ligand-based approach to nuclear receptor profiling was subsequently applied to four external chemical libraries of 10,000 molecules targeted to proteases, kinases, ion channels, and G protein-coupled receptors. The percentage of each library that returned an alert on at least one nuclear receptor was reasonably low and varied between 4.4 and 9.7%. In addition, ligand-based nuclear receptor profiling of a set of 2944 drugs provided an alert for 153 drugs. For some of them, namely, acitretin, telmisartan, phenyltoloxamine, tazarotene, and flumazenil, bibliographical evidence could be found indicating that those drugs may indeed have some potential off-target residual affinity for the nuclear receptors annotated. Overall, the present findings suggest that ligand-based approaches to protein family profiling appear as a promising means toward the establishment of novel tools for in silico pharmacology.

Animals↗