Current Drug Discovery Technologies

ISSN: 1570-1638

Current Drug Discovery Technologies
Volume 2, Number 3, September 2005

Contents


Reversible Covalent Chemistry in Drug Delivery Pp.123-160
Kevin R. West and Sijbren Otto
[Abstract]


Reverse Pharmacognosy: Application of Selnergy, a New Tool for Lead Discovery. The Example of ε-Viniferin Pp.161-167
Quoc-Tuan Do, Isabelle Renimel, Patrice Andre, Claire Lugnier,
Christian D. Muller and Philippe Bernard
[Abstract]


Macromolecular and Nanotechnological Modification of Camptothecin and its Analogs to Improve the Efficacy Pp.169-183
Hiraku Onishi and Yoshiharu Machida
[Abstract]


Application of the In Combo Screening Approach For the Discovery of Non-Alkaloid Acetylcholinesterase Inhibitors from Cichorium intybus Pp.185-193
J. M. Rollinger, P. Mock, C. Zidorn, E. P. Ellmerer, T. Langer and H. Stuppner
[Abstract]


Artificial Neural Networks to Optimize Formulation Components of a Fixed- Dose Combination of Rifampicin,Isoniazid and Pyrazinamide in a Microemulsion Pp.195-201
B. D.Glass, S. Agatonovic-Kustrin and M. H. Wisch
[Abstract]




Abstracts

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Reversible Covalent Chemistry in Drug Delivery
Kevin R. West and Sijbren Otto

The targeting of drugs specifically to their sites of action is an important strategy for increasing drug efficacy. Chemists have come up with many elegant schemes that aim to convert drugs into magic bullets. This review focuses on the chemistry that underlies these schemes, with particular emphasis on two types of cleavable covalent bonds that are frequently used to link drugs to their various carriers: disulfide bonds and hydrazone bonds. These linkages have been used to release drugs under specific conditions; in the case of disulfides, cleavage is triggered by the mildly reducing environment found in intracellular fluids, and in the case of hydrazones, the acidic conditions that prevail in endosomes cause release of the drug. The applications of these chemistries in drug delivery are reviewed.


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Reverse Pharmacognosy: Application of Selnergy,a New Tool for Lead Discovery. The Example of ε-Viniferin
Quoc-Tuan Do, Isabelle Renimel, Patrice Andre, Claire Lugnier, Christian D. Muller and Philippe Bernard

The aim of reverse pharmacognosy is to find new biological targets for natural compounds by virtual or real screening and identify natural resources that contain the active molecules. To demonstrate the applicability of this concept, we report here a study on ε-viniferin, an active ingredient for cosmetic development. Nevertheless, this natural substance is weakly defined in terms of biological properties. SELNERGY, an inverse docking computer software, was used to identify putative binding biological targets for ε-viniferin. Among the 400 screened proteins two targets were retained. For cosmetic application, cyclic nucleotide phosphodiesterase 4 (PDE4) was the most interesting candidate. Moreover, other PDE subtypes (1, 2, 3, 5 and 6) were not retained, indicating a selectivity for PDE4. The experimental binding tests on the 6 subtypes of PDE revealed a significant selectivity of ε-viniferin for the PDE4 subtype. This selectivity was confirmed by evaluation of ε-viniferin on the secretion of TNF-α and Interleukin-8. Our data demonstrated that ε-viniferin possesses anti-inflammatory properties by inhibiting PDE4 subtype. In conclusion, reverse pharmacognosy and its inverse docking component cannot only be integrated into a program for new lead discovery but is also a useful approach to find new applications for identified compounds.


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Macromolecular and Nanotechnological Modification of Camptothecin and its Analogs to Improve the Efficacy
Hiraku Onishi and Yoshiharu Machida

Camptothecin (CPT) and its analogs are some of the most potent antitumor agents known. However, their poor water-solubility and high toxicity require changes of their physicochemical and biological characteristics. Active lactone forms have provoked interest in the utility of CPT and its analogs again. Macromolecular chemical modifications and nanotechnological formulations have been used to obtain improved systems of CPT-related compounds. In these systems, one of the most important concepts is the enhanced permeability and retention (EPR) effect. The outcomes obtained by these approaches are displayed by introducing concrete examples.


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Application of the In Combo Screening Approach For the Discovery of Non-Alkaloid Acetylcholinesterase Inhibitors from Cichorium intybus
J. M. Rollinger, P. Mock, C. Zidorn, E. P. Ellmerer, T. Langer and H. Stuppner

Because of the direct correlation of cholinergic deficit and the severity of dementia, Alzheimer’s disease is preferentially treated with acetylcholinesterase (AChE) inhibitors to supplement the acetylcholine level. In this study we focused on non-alkaloid AChE inhibitors from natural sources in order to discover new lead structures.

In the course of in vitro extract screening of Tyrolean plants using an enzyme assay with Ellman’s reagent, the dichloromethane extract of chicory roots (Cichorium intybus L.) showed a pronounced inhibitory effect on AChE. At a concentration of 1 mg extract/ml an inhibition of 70% was measured. Based on a 3D multi-conformational molecular-structure database consisting of secondary metabolites from C. intybus known from the relevant literature, virtual screening filtering experiments were conducted using both a feature-based pharmacophore model and a docking procedure. Some low molecular weight sesquiterpenoids exhibited distinct interactions with the pharmacophore model.

In order to verify the applicability of this computer-aided strategy, an activity-guided fractionation of the chicory root extract was performed, which resulted in the isolation of two sesquiterpene lactones, 8-deoxylactucin and lactucopicrin, showing significant and dose-dependent inhibitory activity on AChE (IC₅₀ of 308.1 µM [CI₉₅ 243.9 - 405.3 µM] and 150.3 µM [CI₉₅ 100.8 - 188.1 µM], respectively). The two isolates were correctly predicted within the virtual screening process which corroborates the potential of the computer-assisted in combo screening approach for the discovery of the anti-cholinesterase compounds from C. intybus.


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Artificial Neural Networks to Optimize Formulation Components of a Fixed- Dose Combination of Rifampicin,
Isoniazid and Pyrazinamide in a Microemulsion
B. D.Glass, S. Agatonovic-Kustrin and M. H. Wisch

The aim of this study to design a stable microemulsion formulation to deliver a combination of rifampicin, isoniazid and pyrazinamide in quantities suitable for administration to a paediatric population. The chemical stability of rifampicin, isoniazid and pyrazinamide alone and in various combinations was investigated in different solvents, solubilizing agents and surfactants. An artificial neural network was used to model data from the stability studies and a sensitivity analysis was applied to optimize the selection of the formulation components. Imwitor 308 and Crillet 3, exhibiting the highest overall positive sensitivity were selected to formulate the stable microemulsion. Due to drug dose specifications and solubility limitations, the final formulation contained only rifampicin and isoniazid, since the solubility of pyrazinamide in the lipid and aqueous components of the microemulsion did not achieve the required dose. The stability and solubility of rifampicin were improved in the formulation. Solubilization of the rifampicin in the lipid droplets of the internal phase and lipophilic chains of the surfactants increased the quantity of rifampicin that can be incorporated, while protecting it from oxidative degradation and also limited its contact with isoniazid, which has been shown to affect its stability. The results of this study indicate that the Artificial Neural Network can be successfully used to optimize the choice of solvents, solubilizing agents and surfactants prior to formulation of the microemulsion, limiting the amount of experiments, thus reducing the costs during the preformulation study.