Towards a partial order graph for interactive pharmacophore exploration: extraction of pharmacophores activity delta
Etienne Lehembre, Johanna Giovannini, Damien Geslin, Alban Lepailleur, Jean–Luc Lamotte, David Auber, Abdelkader Ouali, Bruno Crémilleux, Albrecht Zimmermann, Bertrand Cuissart, Ronan Bureau · Journal of Cheminformatics · 2023
This paper presents a novel approach called Pharmacophore Activity Delta for extracting outstanding pharmacophores from a chemogenomic dataset, with a specific focus on a kinase target known as BCR-ABL. The method involves constructing a Hasse diagram, referred to as the pharmacophore network, by utilizing the subgraph partial order as an initial step, leading to the identification of pharmacophores for further evaluation. A pharmacophore is classified as a 'Pharmacophore Activity Delta' if its capability to effectively discriminate between active vs inactive molecules significantly deviates (by at least δ standard deviations) from the mean capability of its related pharmacophores. Among the 1479 molecules associated to BCR-ABL binding data, 130 Pharmacophore Activity Delta were identified. The pharmacophore network reveals distinct regions associated with active and inactive molecules. The study includes a discussion on representative key areas linked to different pharmacophores, emphasizing structure-activity relationships.