Aminopiperazinone inhibitors of BACE were identified by rational design. Structure based design guided idea prioritization and initial racemic hit 18a showed good activity. Modification in decoration and chiral separation resulted in the 40 nM inhibitor, (-)-37, which showed in vivo reduction of amyloid beta peptides. The crystal structure of 18a showed a binding mode driven by interaction with the catalytic aspartate dyad and distribution of the biaryl amide decoration towards S1 and S3 pockets.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.bmcl.2011.10.050 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Rational design and synthesis of atomically precise nanocluster-based nanocomposites: a step towards environmental catalysis.
Chem Commun (Camb)
January 2025
School of Chemistry, Indian Institute of Science Education and Research Thiruvananthapuram, Thiruvananthapuram, Kerala, 695551, India.
Atomically precise metal nanoclusters (NCs) and metal-organic frameworks (MOFs) possess distinct properties that can present challenges in certain applications. However, integrating these materials to create new composite functional materials has gained significant interest due to their unique characteristics through a range of applications, particularly in catalysis. Considering MOFs as hosts and NCs as guests, several synergistic effects have been observed in composites, particularly in environmental catalytic reactions.
View Article and Find Full Text PDFFuture Directions for Quantitative Systems Pharmacology.
Handb Exp Pharmacol
January 2025
Genentech Inc, South San Francisco, CA, USA.
In this chapter, we envision the future of Quantitative Systems Pharmacology (QSP) which integrates closely with emerging data and technologies including advanced analytics, novel experimental technologies, and diverse and larger datasets. Machine learning (ML) and Artificial Intelligence (AI) will increasingly help QSP modelers to find, prepare, integrate, and exploit larger and diverse datasets, as well as build, parameterize, and simulate models. We picture QSP models being applied during all stages of drug discovery and development: During the discovery stages, QSP models predict the early human experience of in silico compounds created by generative AI.
View Article and Find Full Text PDFDetermination of the Negative Allosteric Binding Site of Cannabidiol at the CB1 Receptor: A Combined Computational and Site-Directed Mutagenesis Study.
ACS Chem Neurosci
January 2025
National Center for Natural Products Research, University of Mississippi, University, Mississippi 38677, United States.
Cannabinoid receptor 1 (CB1R) has been extensively studied as a potential therapeutic target for various conditions, including pain management, obesity, emesis, and metabolic syndrome. Unlike orthosteric agonists such as Δ-tetrahydrocannabinol (THC), cannabidiol (CBD) has been identified as a negative allosteric modulator (NAM) of CB1R, among its other pharmacological targets. Previous computational and structural studies have proposed various binding sites for CB1R NAMs.
View Article and Find Full Text PDFA High-Efficiency Autocatalysis-Oriented Cascade Circuit via Reciprocal Hug-Amplification for Assay-to-Treat Application.
Anal Chem
January 2025
Key Laboratory of Luminescence Analysis and Molecular Sensing (Southwest University), Ministry of Education; Chongqing Engineering Laboratory of Nanomaterials & Sensor Technologies; School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, PR China.
Developing a DNA autocatalysis-oriented cascade circuit (AOCC) via reciprocal navigation of two enzyme-free hug-amplifiers might be desirable for constructing a rapid, efficient, and sensitive assay-to-treat platform. In response to a specific trigger (), seven functional DNA hairpins were designed to execute three-branched assembly (TBA) and three isotropic hybridization chain reaction (3HCR) events for operating the AOCC. This was because three new inducers were reconstructed in TBA arms to initiate 3HCR (TBA-to-3HCR) and periodic repeats were resultantly reassembled in the tandem nicks of polymeric nanowires to rapidly activate TBA in the opposite direction (3HCR-to-TBA) without steric hindrance, thereby cooperatively manipulating sustainable AOCC progress for exponential hug-amplification (1:3).
View Article and Find Full Text PDFUnlocking Platelet Mechanisms through Multi-Omics Integration: A Brief Review.
Curr Cardiol Rev
January 2025
Laboratory of Chemoinformatics, Infochemistry Scientific Center, ITMO University, Saint-Petersburg, Russian Federation.
Platelets, tiny cell fragments measuring 2-4 μm in diameter without a nucleus, play a crucial role in blood clotting and maintaining vascular integrity. Abnormalities in platelets, whether genetic or acquired, are linked to bleeding disorders, increased risk of blood clots, and cardiovascular diseases. Advanced proteomic techniques offer profound insights into the roles of platelets in hemostasis and their involvement in processes such as inflammation, metastasis, and thrombosis.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!