Related Experiment Video
Updated: Feb 16, 2026
06:26
Nano-Differential Scanning Fluorimetry for Screening in Fragment-based Lead Discovery
Published on: May 16, 2021
5.6K
Fragment-based discovery of a potent NAMPT inhibitor
Alla Korepanova1, Kenton L Longenecker1, Steve D Pratt1
1Research & Development, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, United States.
Bioorganic & Medicinal Chemistry Letters
|December 31, 2017
Summary
Researchers identified novel small molecule binders for NAMPT (Nicotinamide phosphoribosyltransferase), a protein targeted in cancer therapy. Elaboration of a key fragment led to a potent NAMPT inhibitor, offering new therapeutic strategies.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Structural Biology
Background:
- Nicotinamide phosphoribosyltransferase (NAMPT) is upregulated in various cancers, presenting it as a viable target for anticancer drug development.
- Identifying novel inhibitors of NAMPT is crucial for advancing cancer therapeutics.
Purpose of the Study:
- To discover and characterize novel small molecule binders of human NAMPT.
- To use structural information to develop potent NAMPT inhibitors for potential anticancer applications.
Main Methods:
- Fragment screening using Nuclear Magnetic Resonance (NMR) and Time-Resolved Förster Resonance Energy Transfer (TR-FRET).
- X-ray crystallography to determine co-crystal structures of NAMPT with bound fragments.
- Force-field driven molecular docking to predict fragment binding poses.
- Structure-based drug design for inhibitor elaboration.
Main Results:
- Six novel NAMPT binders were identified with varying potencies.
- Co-crystal structures were obtained for two binders, providing detailed structural insights.
- Docking studies generated plausible binding poses for the remaining four binders.
- One fragment was successfully elaborated into a potent NAMPT inhibitor based on structural analysis.
Conclusions:
- Novel chemical matter targeting NAMPT has been discovered.
- Structural insights facilitate the rational design of potent NAMPT inhibitors.
- The identified potent inhibitor represents a promising lead for anticancer drug development.
Related Concept Videos
02:31Habitat Fragmentation
21.5K
Habitat fragmentation describes the division of a more extensive, continuous habitat into smaller, discontinuous areas. Human activities such as land conversion, as well as slower geological processes leading to changes in the physical environment, are the two leading causes of habitat fragmentation. The fragmentation process typically follows the same steps: perforation, dissection, fragmentation, shrinkage, and attrition.
21.5K
01:52Eukaryotic Transcription Inhibitors
11.1K
Certain biochemical processes, such as embryonic development and cell growth regulation, depend on the repression of specific genes. DNA binding proteins known as eukaryotic transcription inhibitors regulate the repression of gene expression in eukaryotes. The presence of these inhibitors at the required location and time in the cell is triggered by the presence of hormones and additional signals from other cells.
Eukaryotic transcription inhibitors usually contain two distinct domains, a...
Eukaryotic transcription inhibitors usually contain two distinct domains, a...
11.1K
01:26Drug Discovery: Overview
12.0K
Drug discovery is a multifaceted process involving extensive screening, testing, and optimization of lead compounds to identify potential new drugs for therapeutic use. It combines several approaches, including screening large numbers of natural products, chemical modification of known active molecules, identification of new drug targets, and rational design based on biological mechanisms and drug-receptor structure. These approaches are carried out in both academic research laboratories and...
12.0K
00:59Mass Spectrometry: Alkene Fragmentation
3.7K
Alkenes lose one electron from the unsaturated π bond upon ionization and form stable molecular ions. Further fragmentation of alkenes occurs through three different reaction pathways. The most prominent fragmentation is the cleavage at the allylic position. The resultant allylic carbocation is resonance stabilized. In the mass spectra of terminal alkenes, this fragment appears at a mass-to-charge ratio of 41. In the internal alkenes, where there are two choices of allylic cleavage, the...
3.7K
00:55Mass Spectrometry: Amine Fragmentation
2.4K
Amines can be identified using mass spectroscopy based on their characteristic fragmentation patterns. The molecular ions of amines undergo fragmentation via ⍺-cleavage. The ⍺-cleavage of the carbon-carbon bonds in amines generates an alkyl radical and resonance-stabilized nitrogen-containing cation.
In amines, the number of nitrogen atoms affects the mass of the molecular ion, which is described by the nitrogen rule of mass spectrometry. This rule states that a compound containing a single...
In amines, the number of nitrogen atoms affects the mass of the molecular ion, which is described by the nitrogen rule of mass spectrometry. This rule states that a compound containing a single...
2.4K
01:05Mass Spectrometry: Cycloalkane Fragmentation
2.3K
In mass spectrometry, cycloalkanes exhibit distinct fragmentation patterns due to the inherent stability of their molecular ions compared to linear or branched alkanes. The ring structure of cycloalkanes provides additional stability to the molecular ions, often resulting in prominent ion peaks in the mass spectrum.
For example, cyclohexane molecular ions have a mass-to-charge ratio (m/z) of 84, which tends to produce a stronger signal than linear alkanes like hexane. This stability comes from...
For example, cyclohexane molecular ions have a mass-to-charge ratio (m/z) of 84, which tends to produce a stronger signal than linear alkanes like hexane. This stability comes from...
2.3K