Pseudoreceptor approach

Although the orientations and calculated free binding energies of the sulfonamide ligands are not presented in the original paper, reconstruction of the receptor site via a pseudoreceptor approach was promising and stimulated further activities. 

Further additions to the 3D-QSAR arsenal include comparative molecular similarity indices analysis (CoMSIA) [15], 4D-QSAR [16], COMPASS [17], receptor surface models [18], the pseudoreceptor approach [19], ComPharm [20], and comparative molecular surface analysis (CoMSA) [21], 3-D-invariant, alignment-free descriptor systems such as comparative molecular moment analysis (CoMMA) [22], EVA [23], WHIM [24], and ALMOND [25], have also become available. A survey of the 3D-QSAR literature reveals 1154 entries in the Chemical Abstracts Plus database of these, 79% are journal publications, 19% are conference proceedings, and four are patents related to, or using, 3D-QSAR models. As the number of potential targets amenable to drug discovery is increasing exponentially, it is likely that 3D-QSAR models and methodologies will continue to be developed in the next decade. 

This chapter does not cover these classical approaches but rather focuses on basic principles, evolution and scientific applications based on specialized pseudoreceptor modeling software packages. 

Fig. 5.2 Flowchart of a typical PrCen pseudoreceptor model construction and validation approach.

The predictive powers of the two models are almost identical although, at first glance, deviation from experimental values is smaller making use of the classical pharmacophore-CoMFA approach [e.g. AAG° = 0.39 (PA) vs 0.70 kcal mol-1 (PrA)]. On closer inspection, one has to take into account that the pseudoreceptor-derived model shows a stronger internal correlation (higher r2 and r v values) and therefore the differences in the prediction are statistically not relevant. 

In a reversed type of approach, we used the pseudoreceptor modeling concept not to develop a tool for SAR predictions but to characterize two discrete ion channel modes on a molecular level [28]. For this purpose, a set of 13 well-characterized 1,4-dihydropyridine (DHP) derivatives with experimentally determined dissociation constants (Kf) for the voltage-gated calcium channel (VGCC) in the resting state (rs) and the open/inactivated state (is) were investigated (Table 5.2). 

Manetti F, Forli S, Maccari L, et al. 3D QSAR studies of the interaction between (3-tubulin and microtubule stabilizing antimitotic agents (MSAA). A combined pharmacophore generation and pseudoreceptor modeling approach applied to taxanes and epothilones. II Farmaco 2003 58 357-361... 

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