1,721,036 research outputs found
Proteolysis targeting chimeras in antiviral research
No full textAn editorial on the role of PROTACs in antiviral researc
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
Esterification of Unprotected α-Amino Acids in Ionic Liquids as Reaction Media
No full textIonic liquid 1,3-dimethylimidazolium methanesulfonate was used to prepare -amino acids benzylic esters from unprotected amino acids and benzyl chloride. Esterification of several amino acids was achieved with satisfactory yields: by-products can be removed by a simple work-up procedure to afford the pure product. The described method is simple, mild, rapid and save
Film Nanostrutturati di Poliammine Anfifile con Proprietà Chelanti all’Interfase Aria/Acqua
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BioGPS: Navigating biological space to predict polypharmacology, off-targeting, and selectivity
No full textThe structural comparison of protein binding sites is increasingly important in drug design; identifying structurally similar sites can be useful for techniques such as drug repurposing, and also in a polypharmacological approach to deliberately affect multiple targets in a disease pathway, or to explain unwanted off-target effects. Once similar sites are identified, identifying local differences can aid in the design of selectivity. Such an approach moves away from the classical “one target one drug” approach and toward a wider systems biology paradigm. Here, we report a semiautomated approach, called BioGPS, that is based on the software FLAP which combines GRID Molecular Interactions Fields (MIFs) and pharmacophoric fingerprints. BioGPS comprises the automatic preparation of protein structure data, identification of binding sites, and subsequent comparison by aligning the sites and directly comparing the MIFs. Chemometric approaches are included to reduce the complexity of the resulting data on large datasets, enabling focus on the most relevant information. Individual site similarities can be analyzed in terms of their Pharmacophoric Interaction Field (PIF) similarity, and importantly the differences in their PIFs can be extracted. Here we describe the BioGPS approach, and demonstrate its applicability to rationalize off-target effects (ERα and SERCA), to classify protein families and explain polypharmacology (ABL1 kinase and NQO2), and to rationalize selectivity between subfamilies (MAP kinases p38α/ERK2 and PPARδ/PPARγ). The examples shown demonstrate a significant validation of the method and illustrate the effectiveness of the approach. Proteins 2015; 83:517–532. © 2015 Wiley Periodicals, Inc
Use of ionic liquids in amidation reactions for proteolysis targeting chimera synthesis†
No full text<jats:p>Selective degradation of disease-causing proteins using proteolysis targeting chimeras (PROTACs) has gained great attention, thanks to its several advantages over traditional therapeutic modalities.</jats:p>
Refining the model to design α-chymotrypsin superactivators: the role of the binding mode of quaternary ammonium salts
No full textA number of quaternary ammonium salts with bulky hydrophobic moieties are known to provoke the superactivation of alfa-chymotrypsin (alfa-CT) in aqueous solution. In particular, benzyl-substituted
ammonium and dicationic ammonium-based salts have recently emerged as promising classes of compounds to induce a-CT superactivation and stabilization. Preliminary in silico modelling suggested the
alfa-CT residue tryptophan 215 to be the major anchor point of these additives. In order to achieve a broader knowledge of the enzyme–additive interactions and to validate the modelling studies, new ammonium- based additives were designed and tested. The hydrophobic interaction resulted in being critical to improving superactivation, with [(2,3,5,6-tetramethyl-p-phenylene)dimethylene]bis[triethylammonium bromide] (bisEDuEAB) resulting as the most effective quaternary ammonium superactivating agent studied so far. Finally, a general agreement between in silico outcomes and kinetic parameters was observed, and data interpretation is discussed based on the proposed alfa-CT/additive binding modes
Metabolism study and biological evaluation of bosentan derivatives
No full textBosentan, the first-in-class drug used in treatment of pulmonary arterial hypertension, is principally metabolized by the cytochromes P450, and it is responsible for cytochromes induction and drug-drug interaction events with moderate to severe consequences. A strategy to reduce drug-drug interactions consists of increasing the metabolic stability of the perpetrator, and fluorinated analogues are often designed to block the major sites of metabolism. In this paper bosentan analogues were synthesized, and their metabolism and biological activity were evaluated. All synthesized compounds showed an improved metabolic stability towards CYP2C9, with one maintaining a moderate antagonist effect towards the ETA receptor.
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