Topological ligand-based

Figure 12.10 Ligand-based virtual screening examples for ion channels, (a) Calcium antagonist clopimozid from topological pharmacophore searching, IC5o< 1 pM. (b) Pancreatic Kftjp channel openers obtained from three different methods EC50 >30 pM (left), 21 pM (middle), 15 pM (right).

Figure 12.11 Ligand-based virtual screening examples for kinases, (a) GSK-3 inhibitors from topological pharmacophore searching with IC50 1.2 iM (left) and from subsequent lead...

Ligand-based topological pharmacophores are a class of descriptors that attempt to simulate three-dimensional (3D) pharmacophoric representations by atomic abstraction and the application of through-graph distances as an adjunct for geometric distance through space. 

The CATS (chemically advanced template search) from Schneider et al. [23] was originally proposed as a ligand-based topological pharmacophore for scaffold hopping, a specific subset ofbioisosteric replacement, where the objective is to discover molecular scaffolds that are topologically different but retain the key functional requirements necessary for macromolecular recognition [24]. 

The work from Wagener and Lommerse [26] detailed a new ligand-based topological pharmacophore descriptor specifically for the identification of bioisosteres and can be seen as an approach to alleviate the issues of sensitivity to heteroatom replacement observed by Schuffenhauer et al. The descriptors applied in this work used an atom pair representation similar to that reported by Carhart et al. [28]. These descriptors are extracted from databases of known molecules by shredding the molecules at all deavable bonds with the attachment point being retained as a distinct atom type, X. 

D-ligand-based methods that create pharmacophore models capture the SAR by identifying common pharmacophoric features within a set of active molecules. These models are composed of the input molecules in a joint 3D-alignment that is based on those common features and not on 2D-topology. Hence, this approach enables the possibility to find compounds that share the same features, but are based on a different bioisosteric scaffold. This approach is being widely used in both academy and industry and has been extensively reviewed [144, 145]. 

L. H. Hall, L. B. Kier, and L. M. Hall, Topological QSAR applications Structure information representation in drug discovery, applications to drug discovery— Ligand-based lead optimization, in Comprehensive Medicinal Chemistry II, Vol. 4, D. J. Triggle and J. B. Taylor (Eds.), Elsevier, Oxford, UK, 2007, pp. 537-574. 

Ripphausen P, Nisius B, Wawer M, Bajorath J (2011) Rationalizing the role of SAR tolerance for ligand-based virtual sereening. J Chem Inf Model 51 837-842 Stumpfe D, Dimova D, Bajorath J (2014) Composition and topology of chemical spaces with network measures. J Chem InfModel 54 451-461... 

B and W J Howe 1991. Computer Design of Bioactive Molecules - A Method for Receptor-Based Novo Ligand Design. Proteins Structure, Function and Genetics 11 314-328. i H L 1965. The Generation of a Unique Machine Description for Chemical Structures - A hnique Developed at Chemical Abstracts Service. Journal of Chemical Documentation 5 107-113. J 1995. Computer-aided Estimation of Symthetic Accessibility. PhD thesis. University of Leeds, itan R, N Bauman, J S Dixon and R Venkataraghavan 1987. Topological Torsion A New )lecular Descriptor for SAR Applications. Comparison with Other Descriptors. Journal of emical Information and Computer Science 27 82-85. 

Abstract In general, asymmetric catalysts are based on the combination of a chiral organic ligand and a metal ion. Here we show that future research should also focus on complexes in which the chirality resides only at the metal center, as the result of a given topology of coordination of achiral ligands to the metal ion. Here we make a brief presentation of the methods available for preparing such compounds as well as the very few examples of enantioselective reactions catalyzed by chiral-at-metal complexes. 

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