3D alignment

Flexible 3D alignment of a set of ligands binding to the same target and/or CoMFA analysis allowing the perception of a pharmacophore for this target. 

At the other extreme, a three-dimensional (3D) model of the molecule itself can be considered as a descriptor. In order to compare them, the molecules have to be aligned in 3D space, which is a difficult task, mostly owing to the conformational flexibility of most compounds of interest. Such 3D alignment-based comparisons of molecules are therefore time intensive and bear the risk of missing the right alignment. 

This model can subsequently be used to predict the activity estimates for new structures. In addition, it can provide information concerning the influence on activity for each local descriptor in different positions of the structure, which can be useful for the lead optimization, the analysis of action mechanism, and the detection of relevant 3D alignment anchors. 

A somewhat more elaborate scheme was proposed by Matter and Schwab [4]. Starting from a global 3D alignment, in an iterative procedure they focus on those amino acids which, after superimposition, show a low RMS deviation. Only these residues are considered in the next round of structure alignment. In this way they arrive at an unbiased superimposition of a large number of proteins focusing on the most conserved parts of the structure. 

Weighted Holistic Invariant Molecular (WHIM) indices [77] represent a different 3D approach to overcome the molecular 3D alignment problem, as they are invariant to molecular rotations and translations. These indices encapsulate information about the molecular 3D structure in terms of size, shape, symmetry and atom distribution, solely derived from Cartesian coordinates. 

D-ligand-based methods that create pharmacophore models capture the SAR by identifying common pharmacophoric features within a set of active molecules. These models are composed of the input molecules in a joint 3D-alignment that is based on those common features and not on 2D-topology. Hence, this approach enables the possibility to find compounds that share the same features, but are based on a different bioisosteric scaffold. This approach is being widely used in both academy and industry and has been extensively reviewed [144, 145]. 

Kenar, H., Kose, G., Hasirci, V., 2010. Design of a 3D aligned myocardial tissue construct from biodegradable polyesters. Journal of Materials Science Materials in Medicine 21, 989-997. 

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