Identification of plasmepsin inhibitors as selective anti-malarial agents using ligand based drug design

McKay, Paul B.; Peters, Martin; Carta, Giorgio; Flood, Christopher T.; Dempsey, Enda; Bell, Angus; Berry, Colin; Lloyd, David G.; Fayne, Darren

doi:10.1016/j.bmcl.2011.04.015

Cited by 17 publications

(8 citation statements)

References 22 publications

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“…Plasmepsins have a varying degree of identity and similarity with human aspartic proteases, with the highest degree of similarity with Cathepsin D (catD) a lysosomal enzyme . Thus, catD is often used as a marker for cross inhibition when designing inhibitors of plasmepsins . The mature forms of plasmepsins fold into two topologically related N‐ and C‐terminal domains.…”

Section: Introductionmentioning

confidence: 99%

Flap flexibility amongst plasmepsins I, II, III, IV, and V: Sequence, structural, and molecular dynamics analyses

McGillewie

Soliman

2015

Proteins

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Herein, for the first time, we comparatively report the opening and closing of apo plasmepsin I - V. Plasmepsins belong the aspartic protease family of enzymes, and are expressed during the various stages of the P. falciparum lifecycle, the species responsible for the most lethal and virulent malaria to infect humans. Plasmepsin I, II, IV and HAP degrade hemoglobin from infected red blood cells, whereas plasmepsin V transport proteins crucial to the survival of the malaria parasite across the endoplasmic reticulum. Flap-structures covering the active site of aspartic proteases (such as HIV protease) are crucial to the conformational flexibility and dynamics of the protein, and ultimately control the binding landscape. The flap-structure in plasmepsins is made up of a flip tip in the N-terminal lying perpendicular to the active site, adjacent to the flexible loop region in the C-terminal. Using molecular dynamics, we propose three parameters to better describe the opening and closing of the flap-structure in apo plasmepsins. Namely, the distance, d1, between the flap tip and the flexible region; the dihedral angle, ϕ, to account for the twisting motion; and the TriCα angle, θ1. Simulations have shown that as the flap-structure twists, the flap and flexible region move apart opening the active site, or move toward each other closing the active site. The data from our study indicate that of all the plasmepsins investigated in the present study, Plm IV and V display the highest conformational flexibility and are more dynamic structures versus Plm I, II, and HAP.

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Section: Introductionmentioning

confidence: 99%

Flap flexibility amongst plasmepsins I, II, III, IV, and V: Sequence, structural, and molecular dynamics analyses

McGillewie

Soliman

2015

Proteins

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“…The efficacy of these compounds against parasites remains to be determined. The vast structural data available to the PM field also produced a rationally designed virtual screening protocol that identified 15 novel small-molecule inhibitors of the PM enzymes that were also active against P. falciparum [182]. The authors of this study state that these new compound scaffolds can now enter a SBDD pipeline.…”

Section: Plasmepsins and An Hap (Histo-aspartic Protease)mentioning

confidence: 99%

From crystal to compound: structure-based antimalarial drug discovery

Drinkwater

McGowan

2014

Biochemical Journal

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Despite a century of control and eradication campaigns, malaria remains one of the world's most devastating diseases. Our once-powerful therapeutic weapons are losing the war against the Plasmodium parasite, whose ability to rapidly develop and spread drug resistance hamper past and present malaria-control efforts. Finding new and effective treatments for malaria is now a top global health priority, fuelling an increase in funding and promoting open-source collaborations between researchers and pharmaceutical consortia around the world. The result of this is rapid advances in drug discovery approaches and technologies, with three major methods for antimalarial drug development emerging: (i) chemistry-based, (ii) target-based, and (iii) cell-based. Common to all three of these approaches is the unique ability of structural biology to inform and accelerate drug development. Where possible, SBDD (structure-based drug discovery) is a foundation for antimalarial drug development programmes, and has been invaluable to the development of a number of current pre-clinical and clinical candidates. However, as we expand our understanding of the malarial life cycle and mechanisms of resistance development, SBDD as a field must continue to evolve in order to develop compounds that adhere to the ideal characteristics for novel antimalarial therapeutics and to avoid high attrition rates pre- and post-clinic. In the present review, we aim to examine the contribution that SBDD has made to current antimalarial drug development efforts, covering hit discovery to lead optimization and prevention of parasite resistance. Finally, the potential for structural biology, particularly high-throughput structural genomics programmes, to identify future targets for drug discovery are discussed.

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“…The in vitro antiplasmodial activity revealed three promising hits with IC 50 ≤ 20 μM. The LBVS in combination with pharmacophore modeling has been used by Paul B. M. et al [ 8 ] in the discovery of novel small molecule inhibitors of the plasmepsin aspartyl proteases, active against P. falciparum . V.K.…”

Section: Introductionmentioning

confidence: 99%

A Novel Series of [1,2,4]Triazolo[4,3-a]Pyridine Sulfonamides as Potential Antimalarial Agents: In Silico Studies, Synthesis and In Vitro Evaluation

et al. 2020

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For the development of new and potent antimalarial drugs, we designed the virtual library with three points of randomization of novel [1,2,4]triazolo[4,3-a]pyridines bearing a sulfonamide fragment. The library of 1561 compounds has been investigated by both virtual screening and molecular docking methods using falcipain-2 as a target enzyme. 25 chosen hits were synthesized and evaluated for their antimalarial activity in vitro against Plasmodium falciparum. 3-Ethyl-N-(3-fluorobenzyl)-N-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine-6-sulfonamide and 2-(3-chlorobenzyl)-8-(piperidin-1-ylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one showed in vitro good antimalarial activity with inhibitory concentration IC50 = 2.24 and 4.98 μM, respectively. This new series of compounds may serve as a starting point for future antimalarial drug discovery programs.

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Identification of plasmepsin inhibitors as selective anti-malarial agents using ligand based drug design

Cited by 17 publications

References 22 publications

Flap flexibility amongst plasmepsins I, II, III, IV, and V: Sequence, structural, and molecular dynamics analyses

Flap flexibility amongst plasmepsins I, II, III, IV, and V: Sequence, structural, and molecular dynamics analyses

From crystal to compound: structure-based antimalarial drug discovery

A Novel Series of [1,2,4]Triazolo[4,3-a]Pyridine Sulfonamides as Potential Antimalarial Agents: In Silico Studies, Synthesis and In Vitro Evaluation

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