A novel series of 2-aminobenzimidazole inhibitors of BACE1 has been discovered using fragment-based drug discovery (FBDD) techniques. The rapid optimization of these inhibitors using structure-guided medicinal chemistry is discussed.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.bmcl.2010.06.089 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Development of an G Protein-Coupled Receptor Fragment Molecule Screening Approach with High-Resolution Magic Angle Spinning Nuclear Magnetic Resonance.
ACS Chem Biol
January 2025
Department of Chemistry, University of Florida, Gainesville Florida 32611, United States.
Small molecules are essential for investigating the pharmacology of membrane proteins and remain the most common approach for therapeutically targeting them. However, most experimental small molecule screening methods require ligands containing radiolabels or fluorescent labels and often involve isolating proteins from their cellular environment. Additionally, most conventional screening methods are suited for identifying compounds with moderate to higher affinities ( < 1 μM) and are less effective at detecting lower affinity compounds, such as weakly binding molecular fragments.
View Article and Find Full Text PDFThermal Titration Molecular Dynamics: The Revenge of the Fragments.
J Chem Inf Model
January 2025
Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via Marzolo 5, Padova 35131, Italy.
During the last 20 years, the fragment-based drug discovery approach gained popularity in both industrial and academic settings due to its efficient exploration of the chemical space. This bottom-up approach relies on identifying high-efficiency small ligands (fragments) that bind to a target binding site and then rationally evolve them into mature druglike compounds. To achieve such a task, researchers rely on accurate information about the ligand binding mode, usually obtained through experimental techniques, such as X-ray crystallography or computer simulations.
View Article and Find Full Text PDFDesign, Synthesis, and Screening of an RNA Optimized Fluorinated Fragment Library.
SLAS Discov
January 2025
DTU Chemistry, Technical University of Denmark, Kgs. Lyngby, 2800, Denmark. Electronic address:
Fragment-based screening is an efficient method for early-stage drug discovery. In this study, we aimed to create a fragment library optimized for producing high hit rates against RNA targets. RNA has historically been an underexplored target, but recent research suggests potential for optimizing small molecule libraries for RNA binding.
View Article and Find Full Text PDFDifferent applications and differentiated libraries for crystallographic fragment screening.
Curr Opin Struct Biol
January 2025
Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Newcastle University, Paul O'Gorman Building, Newcastle Upon Tyne, NE2 4HH, UK; Cancer Research Horizons Therapeutic Innovation, Newcastle Drug Discovery Group, Translational and Clinical Research Institute, Newcastle University, Paul O'Gorman Building, Newcastle Upon Tyne, NE2 4HH, UK. Electronic address:
Macromolecular X-ray crystallography allows detection and characterisation of the binding of small, low-affinity chemical fragments. Here we review the utility of fragment screening for drug discovery, its potential for use in discovery science, as well as some of the distinct types of fragments that have been compiled into libraries.
View Article and Find Full Text PDFNovel starting points for fragment-based drug design against human heat-shock protein 90 identified using crystallographic fragment screening.
IUCrJ
March 2025
Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai 201800, People's Republic of China.
Heat-shock protein 90 (HSP90) is a highly active molecular chaperone that plays a crucial role in cellular function. It facilitates the folding, assembly and stability of various oncogenic proteins, particularly kinases and transcription factors involved in regulating tumor growth and maintenance signaling pathways. Consequently, HSP90 inhibitors are being explored as drugs for cancer therapy.
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!