3D-QSAR approaches

Additionally, computational chemists often use the resulting output alignment of the molecules as input for 3D-QSAR modeling. As already stated, most field-based 3D-QSAR approaches (such as CoMFA) need a pre-aligned set of molecules and the pharmacophore method is certainly one of the best ways to obtain an objective alignment of the compounds. Klabunde et al., for instance, have recently reported the use of a pharmacophore model of human liver glycogen phosphorylase inhibitors together with 3D information from inhibitor-enzyme complexes to derive a predictive CoMFA model [98]. 

Generally speaking, 3D QSAR approaches provide useful tools for drug design and virtual screening. However, in many cases they require one to go back to topology-based (2D or 2.5D) structure representation rather than analyze the 3D molecular models directly. 

Simon and his coworkers have developed (426) a quantitative 3D-QSAR approach, the minimal steric (topologic) difference (MTD) approach. Oprea et al. (452) compared MTD and CoMFA on affinity of steroids for their binding proteins and found similar results. Snyder and colleagues (453) developed an automated method for pharmacophore extraction that can provide a clear-cut distinction between agonist and antagonist pharmacophores. Klopman (404,454) developed a procedure for the automatic detection of common molecular structural features present in a training set of compounds. This has been used to produce candidate pharmacophores for a set of antiulcer compounds (404). Extensions (454)of this approach allow differentiation between substructures responsible for activity and those that modulate the activity. 

Belvisi, L., Bravi, G, Scolastico, C., Vulpetti, A., Salimbeni, A. and Todeschini, R. (1994). A 3D QSAR Approach to the Search for Geometrical Similarity in a Series of Nonpeptide Angiotensin II Receptor Anatagonists. J.Comput.Aid.Molec.Des., 8,211-220,... 

Thibaut, U. (1993), Applications of CoMFA and Related 3D QSAR Approaches. In 3D QSAR in Drug Design. Theory, Methods and Applications. (Kubinyi, H., ed.), ESCQM, Leiden (The Netherlands), pp. 661-696. [R]... 

Several series of novel chirality descriptors of chemical organic molecules were introduced by Golbraikh et al. [5, 6]. These descriptors have been implemented in a QSAR study with a high content of chiral and enantiomeric compounds. It was shown fhat for all data sets 2D-QSAR models that use a combination of chirahty descriptors wifh conventional topological descriptors afford better or similar predictive abihty when compared to models generated wifh 3D-QSAR approaches. 2D-QSAR mefhods enhanced by chirahty descriptors present a powerful alternative to popular 3D-QSAR approaches. 

In this chapter, only QSAR methods which use physicochemical or structural properties of molecules will be discussed, while in Chapter 29 so-called 3D-QSAR approaches will be presented. 3D-QSAR techniques, for example, comparative molecular field analysis (CoMEA), commonly... 

The pseudo-receptor concept has been applied in recent years to analyze crucial ligand-receptor interaction sites and to establish 3D-QS ARs for the prediction of biological activities of ligands. A variety of application studies have shown that the pseudo-receptor concept is a versatile tool to establish 3D-QSAR models, often better in their predictive behavior compared to results obtained from classical 3D-QSAR approaches (e.g. CoMFA). Several application studies have been published which have shown the value but also the limitations of this approach. ... 

The Comparative Molecular Surface Analysis (CoMSA) is a 3D-QSAR approach that makes use of the topological feature maps combined with PLS method to quantitatively predict... 

With the same purpose, QSAR or 3D QSAR approaches were often used in the past. However, this requires a series of compounds that have already been synthesized and tested and relies critically on the aligmnent and superposition of the compounds. Moreover, this approach is difficult if the structural variation within the test compounds is too high. 

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