Abstract
ABSTRACT Introduction: Fragment-based drug discovery can identify relatively simple compounds with low binding affinity due to fewer binding interactions with protein targets. FBDD reduces the library size and provides simpler starting points for subsequent chemical optimization of initial hits. A much greater proportion of chemical space can be sampled in fragment-based screening compared to larger molecules with typical molecular weights (MWs) of 250–500 g mol−1 used in high-throughput screening (HTS) libraries. Areas covered: The authors cover the role of natural products in fragment-based drug discovery against parasitic disease targets. They review the approaches to develop fragment-based libraries either using natural products or natural product-like compounds. The authors present approaches to fragment-based drug discovery against parasitic diseases and compare these libraries with the 3D attributes of natural products. Expert opinion: To effectively use the three-dimensional properties and the chemical diversity of natural products in fragment-based drug discovery against parasitic diseases, there needs to be a mind-shift. Library design, in the medicinal chemistry area, has acknowledged that escaping flat-land is very important to increase the chances of clinical success. Attempts to increase sp3 richness in fragment libraries are acknowledged. Sufficient low molecular weight natural products are known to create true natural product fragment libraries.
Highlights
Fragment-based drug discovery can identify relatively simple compounds with low binding affinity due to fewer binding interactions with protein targets
A much greater proportion of chemical space can be sampled in fragment-based screening compared to larger molecules with typical molecular weights (MWs) of 250–500 g mol−1 used in high-throughput screening (HTS) libraries
Areas covered: The authors cover the role of natural products in fragment-based drug discovery against parasitic disease targets
Summary
We explore approaches to using natural products to build fragment libraries and identify examples of natural products that have been reported in other fragmentbased libraries. The various techniques in fragment-based discovery were, in highest to lowest order, X-ray crystallography, surface plasmon resonance, nuclear magnetic resonance, thermal shift assay, isothermal titration calorimetry, mass spectrometry [12]. ● Natural products are pre-validated both by the chemical space explored by nature in evolution and an embedded recognition of protein binding sites captured during their biosynthesis. ● The efforts to develop natural product-based libraries have been few and far between, in contrast to the recognition of 3D-space and Fsp being important in drug leads and candidate drugs. ● The use of natural products and natural product-like libraries has had limited application to parasitic diseases. ● The malaria proteome has been investigated by fragment-based screening using low MW natural products This box summarizes key points contained in the article. 2. Approaches to develop fragment-based libraries either using natural products or natural product-like compounds
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
