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Structure-activity characterization of molecular databases plays a central role in drug discovery. However, the characterization of large databases containing structurally diverse molecules with several end-points represents a major challenge. For this purpose, the use of chemoinformatic methods plays an important role to elucidate structure-activity relationships. Herein, a general methodology, namely Chemotype Activity and Selectivity Enrichment plots, is presented. Chemotype Activity and Selectivity Enrichment plots provide graphical information concerning the activity and selectivity patterns of particular chemotypes contained in structurally diverse databases. As a case study, we analyzed a set of 658 compounds screened against cyclooxygenase-1 and cyclooxygenase-2. Chemotype Activity and Selectivity Enrichment plots analysis highlighted chemotypes enriched with active and selective molecules against cyclooxygenase-2; all this in a simple 2D graphical representation. Additionally, the most active and selective chemotypes detected in Chemotype Activity and Selectivity Enrichment plots were analyzed separately using the previously reported dual activity-difference maps. These findings indicate that Chemotype Activity and Selectivity Enrichment plots and dual activity-difference maps are complementary chemoinformatic tools to explore the structure-activity relationships of structurally diverse databases screened against two biological end-points.Key words: chemotypes, cyclooxygenases, dual activity-difference maps, selectivity, structure-activity relationships, visualization Abbreviations: CASE, chemotype activity and selectivity enrichment; COX-1, cyclooxygenase-1; COX-2, cyclooxygenase-2; DAD, dual activity-difference; SAR, structure-activity relationships. Structure-activity relationships (SAR) play a central role in drug discovery (1). To this end, a number of predictive and descriptive methods can be employed. Among them, some of the commonly used methodologies include quantitative SAR, rule-based methods, neural networks and pharmacophore modeling (2-5). However, the application of these methodologies is highly dependent of the structural nature of the database and the experimental information.The chemotype-based classification of structurally diverse databases, associated with one or multiple targets, requires a robust and flexible strategy (6). An approach developed by Xu and Johnson (7,8) shows a considerable promise in this regard. Their method decomposes molecules in terms of characteristic structural patterns of variable resolution and complexity called chemotypes and provides tools for a hierarchical classification based on these chemotypes (6-9).Chemotype-enrichment plots were previously designed to identify chemotype classes of active molecules with activity against one biological end-point in compound databases. The main goal of that approach is to characterize the relationship of occupancy to activity enrichment for a set of chemotypes at a given level of structural resolution (9). Hence, thi...

The present study evaluated the possible antiallodynic effect induced by [6]-gingerol in rats with L5-L6 spinal nerve ligation (SNL). Moreover, we determined the possible mechanism underlying the antiallodynic effect induced by [6]-gingerol in neuropathic rats. The animals underwent L5-L6 SNL for the purpose of developing tactile allodynia. Tactile allodynia was measured with von Frey filaments. Intrathecal administration of [6]-gingerol reversed SNL-induced tactile allodynia. The [6]-gingerolinduced antiallodynic effect was prevented by the intrathecal administration of methiothepin (30 μg per rat; nonselective 5-hydroxytryptamine [5-HT] antagonist), WAY-100635 (6 μg per rat; selective 5-HT 1A receptor antagonist), SB-224289 (5 μg per rat; selective 5-HT 1B receptor antagonist), BRL-15572 (4 μg per rat; selective 5-HT 1D receptor antagonist), and SB-659551 (6 μg per rat; selective 5-HT 5A receptor antagonist), but naloxone (50 μg per rat; nonselective opioid receptor antagonist) did not prevent the [6]-gingerol-induced antiallodynic effect. Moreover, intrathecal administration of Nω-nitro-L-arginine methyl ester (100 μg per rat; nonselective nitric oxide [NO] synthase inhibitor), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (10 μg per rat; inhibitor of guanylate cyclase), and glibenclamide (50 μg per rat; channel blocker of adenosine triphosphate [ATP]-sensitive K + channels) prevented the [6]-gingerol-induced antiallodynic effect. These data suggest that the antiallodynic effect induced by [6]-gingerol is mediated by the serotoninergic system involving the activation of 5-HT 1A/1B/1D/5A receptors, as well as the NO-cyclic guanosine monophosphate-ATP-sensitive K + channel pathway but not by the opioidergic system.