4ZX8: X-ray Crystal Structure Of Pfa-m17 In Complex With Hydroxamic Acid- Based Inhibitor 9b

Citation:
Abstract
Malaria remains a global health problem, and though international efforts for treatment and eradication have made some headway, the emergence of drug-resistant parasites threatens this progress. Antimalarial therapeutics acting via novel mechanisms are urgently required. Plasmodium falciparum M1 and M17 are neutral aminopeptidases which are essential for parasite growth and development. Previous work in our group has identified inhibitors capable of dual inhibition of PfA-M1 and PfA-M17, and revealed further regions within the protease S1 pockets that could be exploited in the development of ligands with improved inhibitory activity. Herein, we report the structure-based design and synthesis of novel hydroxamic acid analogues that are capable of potent inhibition of both PfA-M1 and PfA-M17. Furthermore, the developed compounds potently inhibit Pf growth in culture, including the multi-drug resistant strain Dd2. The ongoing development of dual PfA-M1/PfA-M17 inhibitors continues to be an attractive strategy for the design of novel antimalarial therapeutics.
PDB ID: 4ZX8Download
MMDB ID: 137843
PDB Deposition Date: 2015/5/20
Updated in MMDB: 2017/10
Experimental Method:
x-ray diffraction
Resolution: 2.7  Å
Source Organism:
Similar Structures:
Biological Unit for 4ZX8: hexameric; determined by author and by software (PISA)
Molecular Components in 4ZX8
Label Count Molecule
Proteins (6 molecules)
6
Probable M17 Family Aminopeptidase
Molecule annotation
Chemicals (52 molecules)
1
6
2
12
3
6
4
5
5
1
6
15
7
7
* Click molecule labels to explore molecular sequence information.

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