Towards a systematic characterization of the antiprotozoal activity landscape of benzimidazole derivatives

Consensus Models of Activity Landscapes

“…Current graphical and numerical methods of activity landscape modeling are reviewed in several excellent publications [3,10,11] and are summarized in Table 11.1. These methods include the structure-activity relationship index (SARI) [29,30], structure-activity landscape index (SALI) and SALI graphs [13,14], structure-activity similarity (SAS) maps [23,31,32], netowork-like similarity graphs (NSG) [30,33], and combinatorial analog graphs (CAG) [34]. SARI and NSG have been used to detect molecules with small changes in structure but large changes in selectivity (selectivity cliffs) [33].…”

“…Such landscapes are common in lead optimization. It can also happen that structurally diverse compounds have similar activity, which is the basis of scaffold or R-hopping [19][20][21][22][23]. Additionally, active regions with wide variations in chemical structure but small variations in biological activity may suggest different binding modes or sites or may reveal the effect of additional mechanisms such as the interaction with membranes that are not typically considered in several modeling approaches [13].…”

“…Figure 11.1a shows an example of a pair of compounds with similar biological activity and very similar chemical structure, for example, continuous SAR. Figure 11.1b shows an example of a pair of molecules with similar activity but different chemical structure, for example, scaffold or R-hopping [23]. Figure 11.1c illustrates an example of an activity cliff: compounds with very different biological activity (more than three orders of magnitude) but very similar chemical structure (the only difference is a CF 2 group).…”

Discovery and Optimization of Inhibitors of DNA Methyltransferase as Novel Drugs for Cancer Therapy

“…While predictive SAR methods, such as pharmacophore modelling and traditional QSAR, focus on specific molecular descriptors or arrangements of substructures or functional groups associated with activity, descriptive activity landscape models rely on the "similarity property principle," i.e., similar structures should have similar biological properties (Bender and Glen, 2004;Maggiora and Shanmugasundaram, 2011) and employ whole-molecular similarity measures (Wawer et al, 2010). Systematic approaches to model activity landscapes and to detect "activity cliffs" using multiple representations are published elsewhere Pérez-Villanueva et al, 2010;Pérez-Villanueva et al, 2011).…”

In silicoscreening strategies for novel inhibitors of parasitic diseases

“…90 Inhibitors of the enzymes cruzain and glyceraldehydes-3-phosphate dehydrogenase (GAPDH) from Trypanosoma cruzi, molecular targets for Chagas disease, have been investigated by 2D and 3D quantitative structure-activity relationship (QSAR) methods [7,[18][19][20]. Additionally, studies based on 95 2D and 3D molecular similarity have been used to investigate the biological activity underlying a series of benzimidazoles against Trichomona vaginalis and Giardia intestinalis [21].…”