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Published on: May 25, 2018
Identification, biochemical and structural evaluation of species-specific inhibitors against type I methionine
Chandan Kishor1, Tarun Arya, Ravikumar Reddi
1Center for Chemical Biology, CSIR-Indian Institute of Chemical Technology , Tarnaka, Hyderabad AP-500 007, India.
Abstract:
Methionine aminopeptidases (MetAPs) are essential enzymes that make them good drug targets in cancer and microbial infections. MetAPs remove the initiator methionine from newly synthesized peptides in every living cell. MetAPs are broadly divided into type I and type II classes. Both prokaryotes and eukaryotes contain type I MetAPs, while eukaryotes have additional type II MetAP enzyme. Although several inhibitors have been reported against type I enzymes, subclass specificity is scarce. Here, using the fine differences in the entrance of the active sites of MetAPs from Mycobacterium tuberculosis , Enterococcus faecalis , and human, three hotspots have been identified and pyridinylpyrimidine-based molecules were selected from a commercial source to target these hotspots. In the biochemical evaluation, many of the 38 compounds displayed differential behavior against these three enzymes. Crystal structures of four selected inhibitors in complex with human MetAP1b and molecular modeling studies provided the basis for the binding specificity.
Insights
Researchers identified specific hotspots in methionine aminopeptidases (MetAPs) to develop targeted inhibitors. Pyridinylpyrimidine compounds showed differential activity, offering potential for new cancer and microbial infection therapies.
Area of Science:
- Biochemistry
- Enzymology
- Drug Discovery
Background:
- Methionine aminopeptidases (MetAPs) are crucial enzymes for protein synthesis, removing the N-terminal methionine.
- MetAPs are classified into type I and type II, present in prokaryotes and eukaryotes.
- Targeting MetAPs is a promising strategy for cancer and microbial infection treatments, but subclass specificity remains a challenge.
Purpose of the Study:
- To identify specific hotspots in the active sites of MetAPs from different organisms.
- To design and evaluate pyridinylpyrimidine-based inhibitors targeting these hotspots for subclass specificity.
Main Methods:
- Comparative analysis of active site structures of MetAPs from *Mycobacterium tuberculosis*, *Enterococcus faecalis*, and human.
- Screening of 38 pyridinylpyrimidine compounds for differential enzyme inhibition.
- Biochemical evaluation and crystal structure determination of inhibitor-enzyme complexes.
- Molecular modeling studies to understand binding specificity.
Main Results:
- Three distinct hotspots were identified in the active sites of the studied MetAPs.
- Many of the tested pyridinylpyrimidine compounds exhibited differential inhibitory activity against the three enzymes.
- Crystal structures revealed the binding mode of inhibitors to human MetAP1b, elucidating specificity.
Conclusions:
- Pyridinylpyrimidine-based molecules can be tailored to achieve subclass specificity against MetAPs.
- The identified hotspots and inhibitors provide a foundation for developing novel therapeutics against MetAP-related diseases.
- This study advances the development of selective MetAP inhibitors for clinical applications.
