3D Pharmacophore, hierarchical methods, and 5-HT₄ receptor binding data

Abstract

5-Hydroxytryptamine subtype-4 (5-HT 4 ) receptors have stimulated considerable interest amongst scientists and clinicians owing to their importance in neurophysiology and potential as therapeutic targets. A comparative analysis of hierarchical methods applied to data from one thousand 5-HT 4 receptor -ligand binding interactions was carried out. The chemical structures were described as chemical and pharmacophore fingerprints. The definitions of indices, related to the quality of the hierarchies in being able to distinguish between active and inactive compounds, revealed two interesting hierarchies with the Unity (1 active cluster) and pharmacophore fingerprints (4 active clusters). The results of this study also showed the importance of correct choice of metrics as well as the effectiveness of a new alternative of the Ward clustering algorithm named Energy (Minimum E-Distance method). In parallel, the relationship between these classifications and a previously defined 3D 5-HT 4 antagonist pharmacophore was established.

Clustering files of chemical structures using the Székely–Rizzo generalization of Ward's method

“…This suggestion was developed by Varin et al in their study of ligands for the 5-HT 4 receptor: they used not just Euclidean distance but also six other similarity and distance coefficients [19]. They also used a range of clustering methods (single linkage, complete linkage, group average, Ward and energy methods) and structural descriptors (ChemAxon JChem fingerprints, Unity fingerprints and ChemAxon 2D pharmacophore fingerprints).…”

“…Four of these were created by CERMN (Centre d'Etudes de Recherche sur le Médicament de Normandie, see http://www.cermn.unicaen.fr/chimiotheque.html) as part of an ongoing project to develop ligands for a range of 5-HT receptors [19]. In addition, we have used ten datasets downloaded from the PubChem database at http://pubchem.ncbi.nlm.nih.gov/, with the bioassays selected to cover not just 5-HT receptors but also a range of other types of biological target.…”

“…Varin et al hence developed an alternative performance measure in which an active cluster is now defined as a non-singleton cluster for which the percentage of active molecules is greater than the percentage in the dataset as a whole [19]. Let p be the number of actives in active clusters, q the number of inactives in active clusters, r the number of actives in inactive clusters (i.e., clusters that are not active clusters) and s the number of singleton actives.…”

“…This method generalizes Ward's method by defining a cluster distance and objective function in terms of a power in the interval (0,2] of the Euclidean distance between cluster centres, with Ward's method being obtained as the limiting case when the power is 2. Varin et al have applied the Székely-Rizzo method to the clustering of chemical structures as part of a detailed study of ligands for the 5-hydroxytryptamine subtype-4 (5-HT 4 ) receptor, and found that this method led to better grouping of the actives than did conventional hierarchical agglomerative methods, including Ward's method [19]. In this paper, we report an extended evaluation of the Székely-Rizzo method, using a range of different distance metrics and using not just this data but also other 5-HT datasets from the Université de Caen and ten public PubChem datasets.…”

Combining multiple classifications of chemical structures using consensus clustering

“…Two evaluation measures were used: the Fmeasure, which was first devised to evaluate methods for document clustering in information retrieval 46 ; and the QPI-(for quality partition index) measure, which was devised by Varin et al to measure the separation between actives and inactives resulting from use of a clustering method 47 Assume that a cluster contains n compounds, that a of these are active and that there is a total of A compounds with the chosen activity. The precision, P, and the recall, R, for that cluster are then .…”