Macrocyclic inhibitors of the malarial aspartic proteases plasmepsin I, II, and IV

Ersmark, Karolina; Nervall, Martin; Gutiérrez‐de‐Terán, Hugo; Hamelink, Elizabeth; Janka, Linda K.; Clemente, José C.; Dunn, Ben M.; Gogoll, Adolf; Samuelsson, Bertil; Åqvist, Johan; Hallberg, Anders

doi:10.1016/j.bmc.2005.11.003

Cited by 38 publications

(39 citation statements)

References 37 publications

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“…The excellent agreement between calculated and experimental affinities for the four compounds in the two enzymes (see Table 1) provided a strong argument for the reliability of the predicted binding modes [16]. Analysis of the MD simulations showed that the different experimental affinities observed between 18 and 19 in Plm IVoriginated from differences in the electrostatic interaction between the active site aspartates and the two hydroxyl groups in the transition state mimic core [16]. The introduction of the double bond in the macrocycle produced a constrained conformation of the cycle in the S1-S3 pocket for 18.…”

Section: Using the Md/lie Methods In The Design Of Plm II Inhibitorsmentioning

confidence: 77%

“…The 1,2-dihydroxyethylene-based inhibitors reported in Table 1 are the result of successful efforts to generate new lead compounds that inhibit the growth of P. falciparum [16,23,51,52]. These inhibitors were designed to obstruct the function of plasmepsins that are part of the catabolic pathway in the parasite.…”

Section: Discussionmentioning

confidence: 99%

“…The predicted conformation of the potent compound 13 is shown in Figure 7, illustrating the induced fit of the S2' pocket. Subsequently, the impact of cyclization was investigated in four compounds (18 -21 in Table 1) [16]. The general idea of cyclization is to preorganize the ligand in a bioactive conformation thereby reducing the entropy loss upon binding [89].…”

Section: Using the Md/lie Methods In The Design Of Plm II Inhibitorsmentioning

confidence: 99%

“…In projects like malaria treatment where budgets may be very limited, computational methods provide a very cost-effective approach for ligand design. A number of common problems in medicinal chemistry have been addressed in the present project: (i) the identification of a transition state mimetic [70,71], (ii) the selection of active stereoisomers in the process of lead scaffold identification [23], (iii) optimization of inhibitor side chains for improved binding [51], (iv) bioisostere replacement and macrocyclic protection of amide bonds, to improve pharmacokinetic properties [16,52] and (v) exploration of multiple enzyme inhibition and selectivity issues [54].…”

Section: Computational Approaches In Inhibitor Developmentmentioning

confidence: 99%

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Computational inhibitor design against malaria plasmepsins

Bjelic

Nervall

Gutiérrez‐de‐Terán

et al. 2007

Cell. Mol. Life Sci.

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Plasmepsins are aspartic proteases involved in the degradation of the host cell hemoglobin that is used as a food source by the malaria parasite. Plasmepsins are highly promising as drug targets, especially when combined with the inhibition of falcipains that are also involved in hemoglobin catabolism. In this review, we discuss the mechanism of plasmepsins I-IV in view of the interest in transition state mimetics as potential compounds for lead development. Inhibitor development against plasmepsin II as well as relevant crystal structures are summarized in order to give an overview of the field. Application of computational techniques, especially binding affinity prediction by the linear interaction energy method, in the development of malarial plasmepsin inhibitors has been highly successful and is discussed in detail. Homology modeling and molecular docking have been useful in the current inhibitor design project, and the combination of such methods with binding free energy calculations is analyzed.

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Section: Using the Md/lie Methods In The Design Of Plm II Inhibitorsmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: Using the Md/lie Methods In The Design Of Plm II Inhibitorsmentioning

confidence: 99%

Section: Computational Approaches In Inhibitor Developmentmentioning

confidence: 99%

See 2 more Smart Citations

Computational inhibitor design against malaria plasmepsins

Bjelic

Nervall

Gutiérrez‐de‐Terán

et al. 2007

Cell. Mol. Life Sci.

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“…PfPMT was found to be expressed in the clinical strain of the parasite and can be a potential point of therapeutic intervention. Plasmepsins I and IV, involved in hemoglobin degradation, are already present in the ring stages of Pf, indicating that hemoglobin degradation begins early in the parasite life cycle and is a promising step for therapeutic intervention [29,30]. Pf is also known to rely heavily on de novo polyamine biosynthesis [31].…”

Section: S-adenosyl Homocysteinasementioning

confidence: 99%

A glimpse into the clinical proteome of human malaria parasites Plasmodium falciparum and Plasmodium vivax

Acharya

Pallavi

Chandran

et al. 2009

Proteomics Clinical Apps

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Malaria causes a worldwide annual mortality of about a million people. Rapidly evolving drugresistant species of the parasite have created a pressing need for the identification of new drug targets and vaccine candidates. By developing fractionation protocols to enrich parasites from low-parasitemia patient samples, we have carried out the first ever proteomics analysis of clinical isolates of early stages of Plasmodium falciparum (Pf) and P. vivax. Patient-derived malarial parasites were directly processed and analyzed using shotgun proteomics approach using high-sensitivity MS for protein identification. Our study revealed about 100 parasitecoded gene products that included many known drug targets such as Pf hypoxanthine guanine phosphoribosyl transferase, Pf L-lactate dehydrogenase, and Plasmepsins. In addition, our study reports the expression of several parasite proteins in clinical ring stages that have never been reported in the ring stages of the laboratory-cultivated parasite strain. This proof-of-principle study represents a noteworthy step forward in our understanding of pathways elaborated by the parasite within the malaria patient and will pave the way towards identification of new drug and vaccine targets that can aid malaria therapy.

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Antimalarials

Smithson¹,

Guiguemde²,

Guy³

2010

Burger's Medicinal Chemistry and Drug Discovery

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While the treatment of malaria has until recently relied upon a small number of therapeutic agents with a few mechanisms of action, the past decade has seen a huge growth in the number of targets being addressed and new agents being pushed to the clinic. This chapter briefly reviews existing agents and close homologs in development and then carefully explores new targets and new chemotypes being developed.

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Macrocyclic inhibitors of the malarial aspartic proteases plasmepsin I, II, and IV

Cited by 38 publications

References 37 publications

Computational inhibitor design against malaria plasmepsins

Computational inhibitor design against malaria plasmepsins

A glimpse into the clinical proteome of human malaria parasites Plasmodium falciparum and Plasmodium vivax

Antimalarials

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