Current Drug Discovery Technologies - Volume 3, Issue 1, 2006

In today's drug discovery process, the very early consideration of ADME properties is aimed at a reduction of drug candidate drop out rate in later development stages. Apart from in vitro testing, in silico methods are evaluated as complementary screening tools for compounds with unfavorable ADME attributes. Especially members of the cytochrome P450 (P450) enzyme superfamily - e.g. P450 1A2, P450 2C9, P450 2C19, P450 2D6, and P450 3A4 - contribute to xenobiotic metabolism, and compound interaction with one of these enzymes is therefore critically evaluated. Pharmacophore models are widely used to identify common features amongst ligands for any target. In this study, both structure-based and ligand-based models for prominent drug-metabolizing members of the P450 family were generated employing the software packages LigandScout and Catalyst. Essential chemical ligand features for substrate and inhibitor activity for all five P450 enzymes investigated were determined and analyzed. Finally, a collection of 11 pharmacophores for substrates and inhibitors was evaluated as an in silico P450 profiling tool that could be used for early ADME estimation of new chemical entities.

Sequencing of the human genome along with developments in combinatorial synthesis and high-throughput biological screening provide unparallel opportunities to drug discovery. It has been noted that the increased number of synthesized and annotated compounds did not yield the expected increase in number of viable drug candidates. To address this problem, several novel computation technologies have emerged for making combinatorial library design costeffective. Of particular interest for the modern drug discovery are the structure-based or target-based methods that use structural information about target proteins and their small molecule ligands. In this work, we provide an overview of selected advances in computational algorithms for the rational selection of molecule libraries for the synthesis, with emphasis on structure-based approaches. These include a fusion of scaffold-linking method and combinatorial library design, pharmacophore matching and informative library design, and search by 3-D tree topological descriptors.

The anti-inflammatory activity of a new class of phenyl-pyrazolone derivatives, structurally related to phenidone, has been evaluated using the Croton oil ear test in mice as model of acute inflammation. Derivative 5h reduces the percentage of oedema similarly to indomethacin and more efficiently than phenylbutazone. The anti-inflammatory activity of these two reference drugs depends on their COX inhibition, but for the synthesized derivatives it has not been demonstrated a significant COX or LOX inhibition, as previously reported. While the anti-inflammatory activity of phenidone is correlated to its anti-oxidant properties, the redox potential of these compounds appears not decisive in the inflammatory process inhibition. In order to investigate the mechanism of action for these compounds, we quantified their anti-oxidant activity and the lipophilicity, and a relationship between the calculated logP and the percentage of oedema reduction was found. We hypothesize that the anti-inflammatory activity, recorded in vivo, could be related to lipophilic parameter of these compounds.

Modelling of drug targets requires the reliable selection of an accurate and representative structure from large ensembles of alternate models. Statistical potentials developed to discriminate native protein structures generally represent pairwise interactions between atoms, which are less sensitive to local conformational details. The discrimination of local distortions is therefore particularly difficult. Local interaction preferences, expressed through torsion angles, are rarely used, as some controversy exists in the literature regarding their discrimination power. The present study aims to benchmark the efficiency of different implementations of torsion angle propensities for selecting the native structure from ensembles of well-constructed decoys. Several statistical potentials derived from fine-grained discretisations of torsion angle space are constructed and evaluated. Results from a comparison with nine widely used statistical scoring functions show the torsion angle potentials to be more effective in recognising native structures and to improve with the number of torsion angles considered. These data suggest local structural propensities to be important for estimating the overall quality of native-like models.

Vascular complications are a leading cause of blindness, end-stage renal failure, a variety of neuropathies and accelerated atherosclerosis, which could account for disabilities and high mortality rates in patients with diabetes. There is a growing body of evidence that formation and accumulation of advanced glycation end products (AGEs) progress during normal aging, and at an extremely accelerated rate in diabetes, thus being involved in the pathogenesis of diabetic vascular complications. Furthermore, the interaction by AGEs of their receptor, RAGE, activates down-stream signaling and evokes inflammatory responses in vascular wall cells. Therefore, inhibition of AGE formation or blockade of the RAGE signaling may be a promising target for therapeutic intervention to prevent diabetic vascular complications. This review discusses the molecular mechanisms of diabetic retinopathy, especially focusing on the AGE-RAGE system. Several types of inhibitors of the AGE-RAGE system and their therapeutic implications are also reviewed here.

J. M. Rollinger*, P. Mock, C. Zidorn, E. P. Ellmerer, T. Langer and H. Stuppner: Application of the in combo screening approach for the discovery of non-alkaloid acetylcholinesterase inhibitors from Cichorium intybus Current Drug Discovery Technologies, 2005, 2, 185-193 Page 187: Some of the structures in Fig. 1 were incorrect or missing due to oversight of the authors. Thus, the figure should be replaced by the one depicted below. The authors apologize for any inconvenience caused by these errors.