ABSTRACT
Bioassay-guided fractionation of the methanol extract of the Australian sponge Neopetrosia exigua led to the isolation of exiguaquinol (2), a new pentacyclic hydroquinone that inhibited Helicobacter pylori glutamate racemase (MurI) with an IC(50) of 4.4 microM. Its structure and relative configuration were assigned on the basis of spectroscopic data. Exiguaquinol (2), bearing a novel pentacyclic ring skeleton, is the first natural product to show inhibition of H. pylori MurI. Its protein-ligand modeling is also discussed.
Subject(s)
Amino Acid Isomerases/antagonists & inhibitors , Anti-Bacterial Agents/isolation & purification , Anti-Bacterial Agents/pharmacology , Helicobacter pylori/drug effects , Helicobacter pylori/enzymology , Hydroquinones/isolation & purification , Hydroquinones/pharmacology , Porifera/chemistry , Animals , Anti-Bacterial Agents/chemistry , Crystallography, X-Ray , Hydroquinones/chemistry , Ligands , Molecular Structure , Protein ConformationABSTRACT
Fourteen natural products, known to inhibit other proteins of the Zincin-like fold class, were screened for inhibition of the Zincin-like fold metalloprotease thermolysin using mass spectrometry. Fourier Transform Mass Spectrometry was successful in identifying actinonin, a known inhibitor of astacin and stromelysin, to be an inhibitor of thermolysin. Molecular modelling studies have shown that specificity within the Zincin-like fold is determined by Protein Fold Topology.
Subject(s)
Metalloproteases/antagonists & inhibitors , Protease Inhibitors/chemistry , Protein Folding , Proteins/chemistry , Chemistry, Pharmaceutical/methods , Hydroxamic Acids/chemistry , Hydroxamic Acids/metabolism , Mass Spectrometry/methods , Protease Inhibitors/analysis , Proteins/analysis , Spectroscopy, Fourier Transform Infrared/methods , Thermolysin/chemistry , Thermolysin/metabolismABSTRACT
Natural products have withstood the test of time as therapeutics, but new lead-generation strategies have focussed away from natural products. A new approach that uses natural-product recognition to drive an understanding of biological space might provide an impetus for renewed focus on natural-product starting points. Protein fold topology (PFT) has been shown to be an underlying factor for natural-product recognition. An investigation of natural product inhibitors of the Zincin-like fold has demonstrated their capacity also to inhibit targets of different fold types. Analysis of crystal structure complexes for natural products cocrystallised within different fold types has shown similarity at the PFT level. Two new PFT(T) (where subscript T denotes PFT shared between therapeutic targets) relationships have been established: the Zincin-like- metallohydrolase/oxidoreductase PFT(T) and the Zincin-like-phosphorylase/hydrolase PFT(T). The PFT relationship between a natural product's biosynthetic enzyme and therapeutic target, and now between different fold targets of the same natural product, suggests that PFT is the simplest descriptor of biological space. This fundamental factor for recognition could facilitate a rational approach to drug development guided by natural products.
Subject(s)
Biological Products/pharmacology , Protein Folding , Crystallography, X-Ray , Models, MolecularABSTRACT
The relationship between a natural product's biosynthetic enzyme and its therapeutic target is unknown. The concept of protein fold topologies, as a determining factor in recognition, has been developed through molecular modeling techniques. We have shown that biosynthetic enzymes and the therapeutic targets of three classes of natural products that inhibit protein kinases share a common protein fold topology (PFT) and cavity recognition points despite having different fold type classifications. The clinical agent flavopiridol would have been identified by this new approach.
