The relationship of physico-chemical properties and structure to the differential antiplasmodial activity of the cinchona alkaloids

Warhurst, David C.; Craig, J. Cymerman; Adagu, I. S.; Meyer, David J.; Lee, Sylvia Y

doi:10.1186/1475-2875-2-26

Cited by 107 publications

(95 citation statements)

References 78 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…When superimposing VUF5300 onto FUB836, the imidazole moiety of VUF5300 (pK a (imidazole)~6.5, K i = 8.05 nM) [43] could be superimposed onto the 4-aminoquinoline group of FUB836 (expected pK a -value based upon the similarity to the compound amodiaquine = 7.53 [44], K i = 10.04 nM [45]). As an ionic interaction was predicted between the less basic imidazole moiety of VUF5300 and E5.46, the same was assumed for the interaction between the more basic 4-aminoquinoline moiety of FUB836 with E5.46.…”

Section: Resultsmentioning

confidence: 99%

Generation of a homology model of the human histamine H3 receptor for ligand docking and pharmacophore-based screening

Schlegel

Laggner

Meier

et al. 2007

J Comput Aided Mol Des

View full text Add to dashboard Cite

The human histamine H 3 receptor (hH 3 R) is a G-protein coupled receptor (GPCR), which modulates the release of various neurotransmitters in the central and peripheral nervous system and therefore is a potential target in the therapy of numerous diseases. Although ligands addressing this receptor are already known, the discovery of alternative lead structures represents an important goal in drug design. The goal of this work was to study the hH 3 R and its antagonists by means of molecular modelling tools. For this purpose, a strategy was pursued in which a homology model of the hH 3 R based on the crystal structure of bovine rhodopsin was generated and refined by molecular dynamics simulations in a dipalmitoylphosphatidylcholine (DPPC)/water membrane mimic before the resulting binding pocket was used for high-throughput docking using the program GOLD. Alternatively, a pharmacophore-based procedure was carried out where the alleged bioactive conformations of three different potent hH 3 R antagonists were used as templates for the generation of pharmacophore models. A pharmacophore-based screening was then carried out using the program Catalyst. Based upon a database of 418 validated hH 3 R antagonists both strategies could be validated in respect of their performance. Seven hits obtained during this screening procedure were commercially purchased, and experimentally tested in a [ 3 H]N a -methylhistamine binding assay. The compounds tested showed affinities at hH 3 R with K i values ranging from 0.079 to 6.3 lM.

show abstract

Section: Resultsmentioning

confidence: 99%

Generation of a homology model of the human histamine H3 receptor for ligand docking and pharmacophore-based screening

Schlegel

Laggner

Meier

et al. 2007

J Comput Aided Mol Des

View full text Add to dashboard Cite

show abstract

“…Indeed, halofantrine covalently binds to hematin in vitro [21]. Furthermore, quinine, an anti-malarial drug with some similarity to halofantrine, is capable of inhibiting the dimerization of hematin to the non-toxic dimer β-hematin by plasmodia [22]. However, stereoisomers of quinine did not significantly inhibit β-hematin formation but showed antiplasmodial activity at µM concentrations [22], suggesting that a different mechanism of action is involved.…”

Section: Inhibitor Discovery By Fragment-based Docking and Consensus mentioning

confidence: 99%

“…Furthermore, quinine, an anti-malarial drug with some similarity to halofantrine, is capable of inhibiting the dimerization of hematin to the non-toxic dimer β-hematin by plasmodia [22]. However, stereoisomers of quinine did not significantly inhibit β-hematin formation but showed antiplasmodial activity at µM concentrations [22], suggesting that a different mechanism of action is involved. Therefore, the docking results imply that halofantrine acts as PM inhibitor in addition to its interference on hematin dimerization.…”

Section: Inhibitor Discovery By Fragment-based Docking and Consensus mentioning

confidence: 99%

Discovery of Plasmepsin Inhibitors by Fragment‐Based Docking and Consensus Scoring

Friedman

Caflisch

2009

ChemMedChem

View full text Add to dashboard Cite

Plasmepsins (PMs) are essential proteases of the plasmodia parasites and are therefore promising targets for developing drugs against malaria. We have discovered six inhibitors of PM II by high‐throughput fragment‐based docking of a diversity set of ∼40 000 molecules, and consensus scoring with force field energy functions. Using the common scaffold of the three most active inhibitors (IC50=2–5 μM), another seven inhibitors were identified by substructure search. Furthermore, these 13 inhibitors belong to at least three different classes of compounds. The in silico approach was very effective since a total of 13 active compounds were discovered by testing only 59 molecules in an enzymatic assay. This hit rate is about one to two orders of magnitude higher than those reported for medium‐ and high‐throughput screening techniques in vitro. Interestingly, one of the inhibitors identified by docking was halofantrine, an antimalarial drug of unknown mechanism. Explicit water molecular dynamics simulations were used to discriminate between two putative binding modes of halofantrine in PM II.

show abstract

“…Once the aliphatic ring is open, the system is much more flexible since the two resulting side chains (HC-NH 2 and H 2 C-CHOH) can adopt many different conformations. The potential becomes much richer with several minima close in energy and separated by low barriers.…”

Section: Protonated Ai Molecules (H + Ai)mentioning

confidence: 99%

Diastereo-specific conformational properties of neutral, protonated and radical cation forms of (1R,2S)-cis- and (1R,2R)-trans-amino-indanol by gas phase spectroscopy

Bouchet

Klyne

Piani

et al. 2015

Phys. Chem. Chem. Phys.

View full text Add to dashboard Cite

Chirality effects on the intramolecular interactions strongly depend on the charge and protonation states. Here, the influence of chirality on the structure of the neutral, protonated, and radical cation forms of (1R,2S)-cis-and (1R,2R)-trans-1-amino-2-indanol diastereomers, prototypical molecules with two chiral centers, is investigated in a molecular beam by laser spectroscopy coupled with quantum chemical calculations. The neutral systems are structurally characterised by double resonance IR-UV spectroscopy, while IR-induced dissociation spectroscopy is employed for the charged molecules. The sterical constraints due to the cyclic nature of the molecule emphasise the chirality effects, which manifest themselves by the formation of an intramolecular hydrogen bond in neutral or protonated (1R,2S)-cis-amino-indanol. In contrast, this interaction is not possible in (1R,2R)-trans-amino-indanol. In the protonated species, chirality also influences the spectroscopic probes in the NH/OH stretch range by fine-tuning subtle effects such as the hyperconjugation between the s(OH) orbital and s* orbitals localised on the alicyclic ring. The radical cation undergoes opening of the alicyclic ring, which results in an ionisation-induced loss of the chirality effects.

show abstract

The relationship of physico-chemical properties and structure to the differential antiplasmodial activity of the cinchona alkaloids

Cited by 107 publications

References 78 publications

Generation of a homology model of the human histamine H3 receptor for ligand docking and pharmacophore-based screening

Generation of a homology model of the human histamine H3 receptor for ligand docking and pharmacophore-based screening

Discovery of Plasmepsin Inhibitors by Fragment‐Based Docking and Consensus Scoring

Diastereo-specific conformational properties of neutral, protonated and radical cation forms of (1R,2S)-cis- and (1R,2R)-trans-amino-indanol by gas phase spectroscopy

Contact Info

Product

Resources

About