HERG pharmacophore model

The 2 pharmacophore models were used to search a database of about 1.8 million compounds assembled from 12 commercial databases. Hypothesis 1 returned approximately 20,000 hits, which were aggressively filtered using the Catalyst scoring function, lack of hit to a hERG pharmacophore, clogP <5, fewer than five donors and ten acceptors. Fifteen compounds remained and were available for... 

Attempts to build predictive models based on common pharmacophoric elements have had some modest success. In the most general sense, a basic nitrogen atom which is substituted by aromatic or otherwise hydrophobic groups is a clearly problematic motif [73,74]. However, there are many compounds which interact with hERG which do not contain these features, and newer pharmacophore models have been proposed... 

Recanatini, M., Cavalli, A. and Masetti, M. (2005) In silico modelling-pharmacophores and hERG channel models. Novartis Foundation Symposium, 266171—181, discussion 181—175. 

The cover shows a model of the hERG ion channel in the lower left (chapter 4), a CYP structure, lower right (chapter 10), a pharmacophore model for the alphala adrenergic receptor, upper right (chapter 6) and a schematic of the intestinal epithelium with some transporters, upper left (chapter 15). 

Our studies also suggested that H-bond acceptors play an important role for compounds that bind the HERG channel (GRIND descriptors 13 and 34 in both the pharmacophoric models, as shown in Fig. 9.8). The statistical relevance of the MIFs generated by the hydrophobic probe confirmed the assumptions that were made in a previous CoMSiA model [17] regarding the presence of a hydrophobic feature. 

Pharmacophores have been used for many years to derive models for understanding the common interaction patterns of ligands or their subsets. These pharmacophores have, subsequently, been used not only to design new structures with better target properties or devoid of such activities if so being the desired case, for example, hERG pharmacophores [47], but also to search 3D databases for new interesting entities or core structures. For a recent review on pharmacophores, see Ref. [48]. 

A 2D topological similarity screen 186 utilizing atom pair descriptors and an amalgamated similarity metric termed TOPO was combined with a 3D pharmacophore ensemble procedure in a veto format to provide a single binary hERG classification model. A molecule flagged by either component of the method was considered hERG active. 

A widely used 3-D QSAR method that makes use of PLS is comparative molecular field analysis (CoMFA), in which a probe atom is used to calculate the steric and electronic fields at numerous points in a 3D lattice within which the molecules have been aligned. Poso et al. [56] used the technique to model the binding of coumarins to cytochrome P450 2A5, with similar results to those obtained by Bravi and Wikel [55]. Shi et al. [57] used it to model the estrogen receptor binding of a large diverse set of compounds, and Cavalli et al. [58] used it to develop a pharmacophore for hERG potassium... 

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