Similarity search approach mapping

The standard screening approach when several active molecules have been identified is pharmacophore mapping followed by 3D database searching. This approach assumes that the active molecules have a common mode of action and that features that are common to all of the molecules describe the pharmacophoric pattern responsible for the observed bioactivity. This is a powerful technique but one that may not be applicable to the structurally heterogeneous hits that characterize typical HTS experiments or sets of competitor compounds drawn from the public literature. In such cases, it is appropriate to consider approaches based on 2D similarity searching and we present here a comparison of approaches for combining the structural information that can be gleaned from a small set of reference structures. 

One more way to conduct a similarity-based virtual screening is to retrieve the structures containing a user-defined set of pharmacophoric features. In the Dynamic Mapping of Consensus positions (DMC) algorithm those features are selected by finding common positions in bit strings for all active compounds. The potency-scaled DMC algorithm (POT-DMC) " is a modification of DMC in which compounds activities are taken into account. The latter two methods may be considered as intermediate between conventional similarity search and probabilistic SAR approaches. 

If the model and the new protein are indeed similar, and if they are oriented in the same way in unit cells of the same dimensions and symmetry, they should give very similar Patterson maps. We might imagine a trial-and-error method in which we compute Patterson maps for various model orientations and compare them with the Patterson map of the desired protein. In this manner, we could find the best orientation of the model, and then use that single orientation in our search for the best position of the model, using the structure-factor approach outlined earlier. 

It is possible, as shown by Rossmann and Blow (1962), to search for redundancies in Patterson space that correspond to the multiple copies of molecular transforms. Rossmann and Blow show, however, that the Patterson map does not need to be computed and used in any graphical sense, but that an equivalent search process can be carried out directly in diffraction or reciprocal space. Using such a search procedure, called a rotation function, they showed that noncrystallographic relationships, both proper and improper rotations, could be deduced in many cases directly from the X-ray intensity data alone, and in the complete absence of phase information. Translational relationships (only after rotations have been established) can also be deduced by a similar approach. Rotation functions and translation functions constitute what we call molecular replacement procedures. Ultimately the spatial relationships among multiple molecules in an asymmetric unit can be defined by their application. 

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