4D QSAR models

There are two possible application strategies for the use of 4D-QSAR models as a VHTS. The first is to take a collection of (manifold) 4D-QSAR models and create a consensus 4D-QSAR model. The consensus model is evaluated for each molecule using all of the individual 4D-QSAR models ... 

Another way to form a VHTS from several 4D-QSAR models is to use all the distinct grid cell occupancy descriptors (GCODs) and the bioactivity (AG) values of the training set. This simple method of constructing a VHTS-QSAR model is likely to suffer from overfitting the data, but is useful in a VHTS... 

The use of manifold models as an aid to gauge the important descriptors of a 4D-QSAR model is an intriguing proposition. Methods such as CoMFA and SOMFA provide the user with a single, graphical QSAR model from which to harvest usable information. Traditional QSAR results are better, providing a model that can be dissected, but if an automated method was employed to... 

Fig. 11. (see facing page) Manifold 4D-QSAR models. Three separate models are illustrated for the same set of compounds for Alignment 2. The models are ordered based on Q2 values with (A) being the best (0.767) and (C) the worst (0.619). 

Ekins et al. (201) used the MS-WHIM descriptors to construct 3D and 4D QSAR models for the log(l/Aj) of 14 competitive inhibitors of CYP3A. The 3D QSAR of the CYP3A4-mediated midazolam l -hydroxylation was shown to be predictive yielding a leave-one-out (LOO) q2 value of 0.32. Although the 4D QSAR methodology includes conformational changes, it did not provide for a significant improvement over the 3D QSAR (LOO q2 0.44). Two other datasets (242,243) were used to create 3D and 4D QSAR models. In both datasets, it was not possible to build predictive 3D QSAR models however, 4D QSAR models were constructed (LOO q2 = 0.41-0.56). 

D-QSAR models can be used as a virtual high-throughput screen to identify further potent ligands. 

Comparison of the best 4D-QSAR models with the best CoMFA models revealed that they had similar r2 values, but that the q2 values are higher for the 4D-QSAR models. 

Kuz min VE, Artemenko AG, Polischuk PG et al (2005) Hierarchic system of QSAR models (ID D) on the base of simplex representation of molecular structure. JMol Model 11 457-467 Kuz min VE, Artemenko AG, Lozitsky VP et al (2002) The analysis of structure-anticancer and antiviral activity relationships for macrocyclic pyridinophanes and their analogues on the basis of 4D QSAR models (simplex representation of molecular structure). Acta Biochim Pol 49 157-168... 

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