538 research outputs found
Metabolites: structure determination and prediction
No full textStructure determination and prediction of metabolites are essential to modern drug discovery. Experimental investigation of the metabolism of drug molecules is particularly resource demanding and therefore computational methods are of considerable interest to complement experimental approaches
Metamorphic evolution and petrogenesis of some migmatites from the axial zone of the Variscan chain of Sardinia
No full text
Continuous vs. discontinuous garnet growth in mylonitic micaschists from northeastern Sardinia, Italy: Evidence from LA-ICPMS trace element mapping
No full textGarnet with complex, discontinuous zoning is a common occurrence in metamorphic terrains, and the rela tionship between major and trace element zoning can provide insight into the metamorphic evolution of the host rock. Mylonitic micaschists along the Posada-Asinara Shear Zone in the Axial Zone of the Sardinia Variscan chain contain garnet porphyroblasts, enveloped by the S2 schistosity, with distinct core and rim domains. A large garnet porphyroblasts was investigated by laser ablation-inductively coupled plasma-mass spectrometry (LA ICPMS) mapping. The major element compositional variation follows a bell-shaped zoning, with Ca and Mn contents progressively decreasing, and Fe and Mg increasing, from the core to the outer rim. LA-ICPMS mapping revealed a thin and sharp annular enrichment zone in Y, Sc, Dy, Ho, Er, Tm at the mantle-rim boundary. The trace element (TE) compositional profiles show a central enrichment area for HREE (Tm, Yb, Lu). This enrich ment decreases progressively, as a function of atomic number, for Er, Ho and Dy. Elements with even lower atomic number (Tb, Gd, Eu and Sm), are depleted in this central domain, but their content increases in broad shoulders towards the garnet rim. The position of these lateral shoulders migrates progressively rimwards with decreasing atomic number. The REE distribution, trend and behavior in the growth zones of the garnet is an example of TE control during a continuous growth ruled by diffusion-limited REE uptake. The Y + HREE annular enrichment zone, interpreted as resulting from a decrease in the garnet growth rate, reflects a short-lived episode in the garnet growth history
Amphibole-bearing migmatite from NE Sa rdinia (Italy) and its constraints on Variscan partial melting
No full textFragExplorer: GRID-Based Fragment Growing and Replacement
No full textUnderstanding which chemical modifications can be made to known ligands is a key aspect of structure-based drug design and one that was pioneered by the software GRID. We developed FragExplorer with the explicit aim of showing GRID users which fragments would best match the GRID molecular interaction fields in a protein binding site, given a bound ligand as a starting point. Users can grow ligands or replace existing moieties; the R-Group Exploration mode identifies all potential R-Groups and searches for replacements automatically; the Scaffold Exploration mode does the same for all potential scaffolds. For a ligand with three points of variation, R-Group Exploration will typically explore a chemical space of 1016 potential molecules; including Scaffold Exploration increases this to 1022. FragExplorer was designed to be integrated within an interactive 3D Editor/Designer; therefore, the speed of computation was an important consideration; a typical fragment search takes 20 seconds. In a fragment reprediction test, FragExplorer demonstrates an overall fragment retrieval rate of 55%, increasing to 69% for smaller fragments. At a 90% substructural match, the retrieval rate increases to ∼80%. We also show how the approach could have been used to hop from olmesartan to azilsartan or to optimize a p38 MAP kinase lead to a compound that bears similarity to a known nanomolar inhibitor
40Ar-39Ar results on amphibole and biotite of an anatectic amphibole-bearing migmatite from the Variscan basement of NE Sardinia, Italy
No full textMolecular fields in drug discovery: getting old or reaching maturity?
No full textWith GRID first published 23 years ago, and CoMFA 20 years ago, the two most widely known methods
that apply molecular fields to drug discovery are now into their third decade. Are molecular-field-based
methods still applicable to modern drug discovery? Are they old and outdated? Or are they maturing into
their full potential
CHAPTER 18. Drug-induced Phospholipidosis
No full textIn the past decades, rising safety concerns about drug-induced phospholipidosis (DIPL) have induced scientists to develop novel strategies to detect the risk of DIPL early in drug discovery and drug development. An early detection of phospholipidosis (PL)-inducing potential of new chemical entities will contribute to the release of safer drugs, also reducing associated investments and time. This chapter focuses on concisely summarizing the current knowledge on DIPL, from the chemical features that are compatible with warnings to the proposed mechanisms behind phospholipid accumulation. In addition, strategies to mitigate the risk of DIPL are discusse
- …
