Alignment rules

The ideal choice of conformers for 3D-QSAR would be the bioactive ones. Wherever experimental structural data exist concerning ligands bound to targets (i.e.. X-ray data from cocrystallized L-R complexes), the bioactive conformation of the ligand is available and should be used to derive an alignment rule. For the vast majority of cases, however, the bioactive conformation is unknown, but a variety of techniques have been developed over the years to generate bioactive conformations. 

When no structural data are available for the receptor, methods that explore conformational space using techniques such as simulated annealing and cluster analysis may find the best match between various ligands. During this procedure,low energy conformers are selected and minimized pairwise, and the best match obtained from all different conformations can be selected. This method is useful for structurally dissimilar ligands. 

An assortment of computational tools exist that allow one to force molecules into a conformation as similar as possible to that d a rigid template molecule that is presumably the bioactive conformation. In cases where phar- 

Electrostatic Descriptors and Choice ci Partial Atomic Charges 

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Waller, C. L., Oprea, T. I., Giolitti, A., and Marshall, G. R. (1993) Three-dimensional QSAR of human immunodeficiency virus (I) protease inhibitors. 1. A COMFA study employing experimentally-determined alignement rules../. Med. Chem. 36, 4152-4160. 

Figure 12. Alignment rule used in the prediction of antimalarial activity of racemic artemisinin analogues.

The pharmacophore concept plays a very important role in guiding the drug discovery process. Pharmacophore models help medicinal chemists gain an insight into the key interactions between ligand and receptor when the receptor structure has not been determined experimentally. A pharmacophore can be used as a basis for the alignment rules in 3D-QSAR analysis for the lead compound optimization... 

It must be noted that the invariance to rotation of G-WHIM descriptors, i.e. the independence of any molecular alignment rule, is obtained if the grid points are dense enough. In fact, a too sparse distribution of grid points represents an inadequate sampling of the ideal scalar field and is not able to guarantee that the calculated scalar field is representative of the ideal scalar field in such a way as to preserve rotational invariance. 

A number of - shape descriptors are defined in terms of principal moments of inertia. Moreover, principal moments of inertia are used to provide a unique reference framework for the calculation of the - shadow indices, and in general are used as - alignment rules of the molecules. They are encountered among - WHIM descriptors and used by the CoMMA method. 

This is 3D-QSAR technique proposed to overcome the drawbacks of the - grid-based QSAR techniques such as -> CoMFA related to the superimposition of the molecules. The descriptors produced by this method do not require - alignment rules and are not... 

Waller, C.L. and Marshall, G.R. (1993). Three Dimensional Quantitative Structure-Activity Relationship of Angiotesin Converting Enzyme and Thermolysin Inhibitors. 2. A Comparison of CoMFA Models Incorporating Molecular Orbital Fields and Desolvation Free Energies Based on Active Analog and Complementary Receptor Field Alignment Rules. JMeeLChem., 36,2390-2403. 

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