There was a greater than 50% decline in central nervous system (CNS) drug discovery and development programs by major pharmaceutical companies from 2009 to 2014. This decline was paralleled by a rise in the number of university led drug discovery centers, many in the CNS area, and a growth in the number of public-private drug discovery partnerships. Diverse operating models have emerged as the academic drug discovery centers adapt to this changing ecosystem.
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http://dx.doi.org/10.1021/acschemneuro.7b00040 | DOI Listing |
JACS Au
January 2025
Center for Biopharmaceuticals and Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 160, DK-2100, Copenhagen, Denmark.
Cysteine thioesters are involved in a myriad of central biological transformations due to their unique reactivity. Despite their well-studied properties, we discovered an unexpected transamidation reaction of cysteine thioesters that leads to peptide backbone cleavage. -Acylcysteine-containing peptides were found to spontaneously fragment by cleavage of the amide bond in the -1 position to the acylated cysteine residue at pH 8-10.
View Article and Find Full Text PDFJACS Au
January 2025
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India.
The 'escape from flatland' concept has gained significant traction in modern drug discovery, emphasizing the importance of three-dimensional molecular architectures, which serve as saturated bioisosteres of benzenoids. Bicyclo[1.1.
View Article and Find Full Text PDFComput Struct Biotechnol J
January 2025
Ph.D. Program in Computer Science, The Graduate Center, The City University of New York, New York, NY, USA.
Despite the wealth of single-cell multi-omics data, it remains challenging to predict the consequences of novel genetic and chemical perturbations in the human body. It requires knowledge of molecular interactions at all biological levels, encompassing disease models and humans. Current machine learning methods primarily establish statistical correlations between genotypes and phenotypes but struggle to identify physiologically significant causal factors, limiting their predictive power.
View Article and Find Full Text PDFBiocompatible covalent reactive groups (CRGs) play pivotal roles in several areas of chemical biology and the life sciences, including targeted covalent inhibitor design and preparation of advanced biologic drugs, such as antibody-drug conjugates. In this study, we present the discovery that the small, chlorinated polyketide natural product cyclohelminthiol II (CHM-II) acts as a new type of cysteine/thiol-targeting CRG incorporating both reversible and irreversible reactivity. We devise the first syntheses of four simple cyclohelminthols, (±)-cyclohelminthol I-IV, with selective chlorinations (at C and C) and a Ni-catalyzed reductive cross coupling between an enone, a vinyl bromide and triethylsilyl chloride as the key steps.
View Article and Find Full Text PDFTheranostics
January 2025
Department of Physiology & Medical Physics, RCSI University of Medicine & Health Sciences, Dublin D02 YN77, Ireland.
Post-traumatic epilepsy (PTE) is one of the most common life-quality reducing consequences of traumatic brain injury (TBI). However, to date there are no pharmacological approaches to predict or to prevent the development of PTE. The P2X7 receptor (P2X7R) is a cationic ATP-dependent membrane channel that is expressed throughout the brain.
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