4ZX5

X-ray crystal structure of PfA-M1 in complex with hydroxamic acid-based inhibitor 10q

Summary for 4ZX5

• Entry DOI: 10.2210/pdb4zx5/pdb
• Related: 3EBG 4ZW3 4ZW5 4ZW6 4ZW7 4ZW8 4ZX3 4ZX4 4ZX6
• Descriptor: M1 family aminopeptidase, ZINC ION, N-{(1R)-2-(hydroxyamino)-2-oxo-1-[4-(thiophen-3-yl)phenyl]ethyl}-2,2-dimethylpropanamide, ... (7 entities in total)
• Functional Keywords: m1 alanyl-aminopeptidase, protease, inhibitor, hydroxamic acid, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Plasmodium falciparum
• Total number of polymer chains: 1
• Total formula weight: 104455.51

Authors

Drinkwater, N.,McGowan, S. (deposition date: 2015-05-20, release date: 2016-03-30, Last modification date: 2023-09-27)

Primary citation

Drinkwater, N.,Vinh, N.B.,Mistry, S.N.,Bamert, R.S.,Ruggeri, C.,Holleran, J.P.,Loganathan, S.,Paiardini, A.,Charman, S.A.,Powell, A.K.,Avery, V.M.,McGowan, S.,Scammells, P.J.
Potent dual inhibitors of Plasmodium falciparum M1 and M17 aminopeptidases through optimization of S1 pocket interactions.
Eur.J.Med.Chem., 110:43-64, 2016

PubMed 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.

PubMed: 26807544
DOI: 10.1016/j.ejmech.2016.01.015

Experimental method

X-RAY DIFFRACTION (1.95 Å)