Small molecules with potent and selective antitumor activity continue to be identified by screening in cellular assays and to be entered into clinical development, and in some cases small molecules are progressed despite the fact that the mechanism of action is unknown. Current examples of drugs with unknown mechanism of action include LY-573636 (Eli Lilly & Co), CHS-828 and SPC-595 (Sunesis Pharmaceutical Co Ltd). Early discovery and the elucidation of structure-activity relationships may be in part facilitated by the fact that the compounds must be relatively soluble and permeable to cells to demonstrate activity, although the challenges of optimizing absorption, distribution, metabolism and excretion/pharmacokinetic properties, toxicity and clinical activity remain similar to compounds developed under the 'targeted therapy' paradigm.
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J Proteome Res
January 2025
Discovery Research, AbbVie, Inc., 1 North Waukegan Rd., North Chicago, Illinois 60064, United States.
Affinity capture (AC) combined with mass spectrometry (MS)-based proteomics is highly utilized throughout the drug discovery pipeline to determine small-molecule target selectivity and engagement. However, the tedious sample preparation steps and time-consuming MS acquisition process have limited its use in a high-throughput format. Here, we report an automated workflow employing biotinylated probes and streptavidin magnetic beads for small-molecule target enrichment in the 96-well plate format, ending with direct sampling from EvoSep Solid Phase Extraction tips for liquid chromatography (LC)-tandem mass spectrometry (MS/MS) analysis.
View Article and Find Full Text PDFJ Mol Model
January 2025
College of Mechanical Engineering, Changzhou University, Changzhou, Jiangsu Province, China.
Context: The flow equations are derived for describing the two-dimensional hybrid molecular-scale and continuum flows in the very small surface separation with inhomogeneous solid surfaces and they can be applied for designing the specific bearings. The aim of the present study is to solve this specific flow problem in engineering with normal computational cost. The flow factor approach model describes the flow of the molecule layer adjacent to the solid surface and the Newtonian fluid model describes the flow of the intermediate continuum fluid.
View Article and Find Full Text PDFJ Chem Inf Model
January 2025
Industrial and Molecular Pharmaceutics, Purdue University, West Lafayette, Indiana 47907, United States.
Drug-drug interaction can lead to diminished therapeutic effects or increased toxicity, posing significant risks, especially in polypharmacy, and cytochrome P450 plays an indispensable role in this interaction. Cytochrome P450, responsible for the metabolism and detoxification of most drugs, metabolizes about 90% of Food and Drug Administration-approved drugs, making early detection of potential drug-drug interactions. Over the years, in-silico modeling has become a valuable tool for predicting drug-drug interactions.
View Article and Find Full Text PDFNaturwissenschaften
January 2025
Institute of Bioengineering and Biosciences, School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, USA.
While most dentate non-mammalian vertebrates possess simple conical teeth, some demonstrate complex tooth shapes. Lake Malawi cichlid fishes are an extreme example of this, exhibiting a myriad of tooth shapes driven by an ecologically derived rapid evolution of closely related but distinct species. Tooth shape in mammals is generally considered to be established by signaling centers called primary and secondary enamel knots, which are not believed to be present in non-mammalian vertebrates.
View Article and Find Full Text PDFAstrobiology
January 2025
Experimental Biophysics and Space Sciences, Department of Physics, Freie Universitaet Berlin, Berlin, Germany.
The (PSS) experiment was part of the European Space Agency's mission and was conducted on the International Space Station from 2014 to 2016. The PSS experiment investigated the properties of montmorillonite clay as a protective shield against degradation of organic compounds that were exposed to elevated levels of ultraviolet (UV) radiation in space. Additionally, we examined the potential for montmorillonite to catalyze UV-induced breakdown of the amino acid alanine and its potential to trap the resulting photochemical byproducts within its interlayers.
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