Pharmacophores published models

A series of 2-amino-3/4-dihydro quinazolines have been extensively explored as selective T-type calcium channel antagonists. A recent disclosure included KYS05090 (9) with an IC50 of 41 nM on the Cav3.1 subtype of the T-type channel and 120-fold selectivity versus the N-type calcium channel Cav2.2 [55]. A pharmacophore model was recently published based on this and related structures [56], but no other selectivity or in vivo activity have been disclosed since the original report. 

Figure 5.1 Superimposition of the pharmacophoric schemes derived from the 3D QSAR models published by Ekins et al. [14] (vertical lines filling), Cavalli etal. [15] (horizontal lines filling) and Pearlstein etal. [17] (dotfilling). The central black circle represents the...

In a paper published in 2000 by Norinder [30], Catalyst was used for the first time to build a common feature pharmacophore hypothesis for HIV-1 protease inhibitors, which was then refined using in-house software (HypoOpt), after having added to it some hundreds of excluded volume spheres. These were actually derived from the X-ray structure of an inhibitor complexed to the enzyme. The aim of the approach was to obtain a computational model with some improved predictive power with respect to the corresponding hypothesis derived without receptor information. 

The BCRP is an ABC transporter similar to P-gp whose expression results in resistance to anticancer therapeutics and may limit intestinal absorption of drugs. However, there have been limited studies to elucidate the selectivities of dmgs for P-gp and BCRP (Brooks et al. 2004). We used a published dataset of seven topoisomerase inhibitors (Maliepaard et al. 2001) to construct a HipHop model for BCRP. We then mapped the potent tyrosine kinase inhibitor Gleevec to this pharmacophore as this compound has been suggested experimentally in conflicting studies as both a substrate and inhibitor of BCRP (Burger et al. 2004 Houghton et al. 2004). 

Figure 3 Development of the number of new crystal structures and homology models published over the years. The overall steady increase is clearly visible, as is the increase in homology and pharmacophore models during (temporary) declines in number of crystal structures, illustrating the complementary nature of experimental structure determination and model building. Publication of structures for isoforms that have been extensively used for homology model building are indicated at the top.

The earliest discussion of a common pharmacophore in the tubulin literature was presented by Winkler and Axelsen [70], who employed the second strategy of simultaneous alignment while fitting only three points of S AR. Without a published 3D reference, we were not able to test their hypothesis. However, as pointed out by others [71], the predictions made based upon this earliest model were not supported by subsequent SAR studies. 

Despite the large variety of molecules recently described as desirable Kvl.5 inhibitors, there has been limited success in predicting ligand-based Kvl.5 pharmacophores. Recently, a pharmacophore model was derived from several members of the bisaryl series (see Table 1) and another series. The model consists of three hydrophobic centers in a triangular arrangement, and it was used to identify anthranilic amides as novel Kvl.5 inhibitors [43]. A similar paucity of published data exists with regard to pharmacophores based on the Kvl.5 channel structure [59]. 

Pharmacophores are intrinsically three-dimensional - what, then, is topological pharmacophore supposed to mean This chapter highlights the key aspects of this topic along with some published studies. Its goal is to convey a general introduction to the main concepts and issues in 2D pharmacophore modeling, and was not conceived as an exhaustive literature review. This section briefly introduces key topics that are then detailed later on. 

---