Potent, Low-Molecular-Weight Non-Peptide Inhibitors of Malarial Aspartyl Protease Plasmepsin II

Haque, Tasir S.; Skillman, A. Geoffrey; Lee, C. E.; Habashita, Hiromu; Gluzman, Ilya Y.; Ewing, Todd; Goldberg, Daniel E.; Kuntz, Irwin D.; Ellman, Jonathan A.

doi:10.1021/jm980641t

Cited by 166 publications

(118 citation statements)

References 24 publications

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“…Inhibitors of PLM II that have low nanomolar inhibition constant values and are lethal against cultured malarial parasites have been identi®ed Carroll, Patel et al, 1998;Goldberg, 1992;Goldberg et al, 1991;Haque et al, 1999;Silva et al, 1996Silva et al, , 1998Westling et al, 1999). Furthermore, some aspartic and cysteine protease inhibitors demonstrate an apparent synergistic inhibition of hemoglobin degradation in both culture and a murine malaria model (Semenov et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Structures of Ser205 mutant plasmepsin II fromPlasmodium falciparumat 1.8 Å in complex with the inhibitors rs367 and rs370

Asojo

Afonina

Gulnik

et al. 2002

Acta Crystallogr D Biol Cryst

117

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Plasmepsin II is one of the four catalytically active plasmepsins found in the food vacuole of Plasmodium falciparum. These enzymes initiate hemoglobin degradation by cleavage at the -chain between Phe33 and Leu34. The crystal structures of Ser205 mutant plasmepsin II from P. falciparum in complex with two inhibitors have been re®ned at a resolution of 1.8 A Ê in the space group I222 and to R factors of 19.9 and 19.5%. Each crystal contains one monomer in the asymmetric unit. Both inhibitors have a Phe± Leu core and incorporate tetrahedral transition-state mimetic hydroxypropylamine. The inhibitor rs367 possesses a 2,6-dimethylphenyloxyacetyl group at the P2 position and 3-aminobenzamide at the P2 H position, while rs370 has the same P2 group but 4-aminobenzamide in the P2 H position. These complexes reveal key conserved hydrogen bonds between the inhibitor and the binding-cavity residues, notably with the¯ap residues Val78 and Ser79, the catalytic dyad Asp34 and Asp214 and the residues Ser218 and Gly36 that are in proximity to the catalytic dyad. The structures also show unexpected conformational variability of the binding cavity of plasmepsin II and may re¯ect the mode of binding of the hemoglobin -chain for cleavage.

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Section: Introductionmentioning

confidence: 99%

Structures of Ser205 mutant plasmepsin II fromPlasmodium falciparumat 1.8 Å in complex with the inhibitors rs367 and rs370

Asojo

Afonina

Gulnik

et al. 2002

Acta Crystallogr D Biol Cryst

117

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“…The inhibition of their activities by peptidomimetic compounds specific for aspartic proteases results in death of the parasites (12)(13)(14). The elucidation of structure-activity relationships for these enzymes will facilitate the development of potent, specific inhibitors.…”

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confidence: 99%

Active Site Contribution to Specificity of the Aspartic Proteases Plasmepsins I and II

Siripurkpong

Yuvaniyama

Wilairat

et al. 2002

Journal of Biological Chemistry

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Plasmepsins I and II (PM I and II) are aspartic proteases involved in the initial steps of Plasmodium hemoglobin degradation. They are attractive targets for antimalarial drug development. The two enzymes are 73% identical, yet have different substrate and inhibitor specificities. The x-ray structures of proform and mature PM II have been determined, but models of PM I do not adequately explain the selectivity of the two proteases. To better understand the basis of these recognition differences, we have identified nine residues of PM II that are in proximity to the inhibitor pepstatin in the crystal structure and differ in PM I. We mutated these residues in PM II to the cognate amino acids of PM I. Kinetic parameters for substrate and inhibitors for the PM II-mutant were similar to those of PM II-wild type (WT). Cleavage specificity was assessed using hemoglobin or a random decamer peptide library as substrate. Again, PM II-mutant behaved like PM II-WT rather than PM I-WT. These results indicate that differences in plasmepsin specificity depend more on conformational differences from distant sites than on specific active site variation.

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“…It is widespread in all parts of India except in areas, which are not favourable for transmission and multiplication of malaria parasites [1][2][3][4][5][6] . Quinine, the oldest known antimalarial, led to the discovery of chloroquine, the most widely used antimalarial drug for almost more than half a century.…”

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confidence: 99%

<i>In Vitro</i> Evaluation of the Antimalarial Activity of a Designed Novel Quinuclidine Derivative

Sharma¹,

Goswami²,

Rudrapal³

et al. 2016

Current Science

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A simple Schiff base, N-(pyridine-4-yl-methylene) quinuclidine-3-amine was synthesized from 3-aminoquinuclidine and 4-pyridine carboxaldehyde. The physico-chemical properties of the synthesized compound were studied. Molecular docking study was carried out and the quinuclidine derivative was evaluated for its in vitro antimalarial activity against chloroquine-sensitive Plasmodium falciparum strain. Although higher dose of synthesized compound was required for antimalarial activity (EC 50 = 13.125 g/ml) in comparison to chloroquine (EC 50 5.144 g/ml), the correlation coefficient confirmed good fit of the data. Furthermore, the result of the molecular docking provided insights into the ligand-protein interactions responsible for the inhibitory potency.Keywords: Antimalarial, docking, HPLC, Plasmodium falcipurum, quinuclidine, mass, NMR.MALARIA, a disease affecting large populations, has proved to be an obstacle in the cultural and socioeconomic progress of society in the tropical and subtropical world. It is widespread in all parts of India except in areas, which are not favourable for transmission and multiplication of malaria parasites [1][2][3][4][5][6] . Quinine, the oldest known antimalarial, led to the discovery of chloroquine, the most widely used antimalarial drug for almost more than half a century. However, chloroquine has lost its importance as an antimalarial due to widespread drug resistance 7,8 . Quinolines, however, are still considered as important lead structures and several researchers have been working on synthesis of their analogues 9 . Quinolines interact and form a non-covalent complex with heme and also inhibit the synthesis of hemozoin. On the other hand, quinuclidine(1-azabicyclo [2.2.2]octane), synthesized by Loffler and Stieze in 1909, is a structural component of some biomolecules, including quinine 10,11 . Although development of a new drug candidate against a specific disease is a difficult task, with the help of informatics-driven chemistry, it is now fairly easy. However, in silico prediction of biological activity is not always reflected in the biological system.In view of the resistance developed by malarial parasites and considering the biological activity of quinuclidine moiety-bearing biomolecules, a simple Schiff base carrying the quinuclidine structural component was designed 12 . Accordingly, N-(pyridine-4-yl-methylene) quinuclidine-3-amine (C) was synthesized (Scheme 1) from 3-aminoquinuclidine (A) and 4-pyridine carboxaldehyde (B). On the basis of the results of in silico antimalarial activity study, in vitro study was carried out for antimalarial activity of this Schiff base. The results of this study are promising and would help in the development of novel antimalarial drugs.All the reactions were carried out in borosilicate glassware with proper precautions. The solvents and reagents were synthesis-grade chemicals procured commercially and used as such without further tests and purification. Chemical structures have been drawn in ChemDraw version 7.0.1. Melting point ...

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Potent, Low-Molecular-Weight Non-Peptide Inhibitors of Malarial Aspartyl Protease Plasmepsin II

Cited by 166 publications

References 24 publications

Structures of Ser205 mutant plasmepsin II fromPlasmodium falciparumat 1.8 Å in complex with the inhibitors rs367 and rs370

Structures of Ser205 mutant plasmepsin II fromPlasmodium falciparumat 1.8 Å in complex with the inhibitors rs367 and rs370

Active Site Contribution to Specificity of the Aspartic Proteases Plasmepsins I and II

<i>In Vitro</i> Evaluation of the Antimalarial Activity of a Designed Novel Quinuclidine Derivative

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