Pharmacophores oriented-substituent

The Oriented Substituent Pharmacophore PRopErtY Space (OSPPREYS) approach, introduced by Martin and Hoeffel [6], is in software terms an extension of CCG s MOE package, written using SVL. The 3D oriented substituent pharmacophores are aimed towards better representation of diversity and similarity in combinatorial libraries in the 3D pharmacophore space. Combinatorial library design often operates only on substituents rather than on the final products as the complications related to the conformational coverage in the 3D space and the scaffold dependency limit the product-based approaches to smaller libraries. The 3D oriented substituent pharmacophores add two more points and the corresponding distances to each substituent pharmacophore which represent the relationship of the substituents in the product with only little additional information. The fingerprints permit the creation of property space by multidimensional scaling (MDS) and, since scaffold independent, can be stored separately and applied to different libraries [6],... 

Martin, E.J., Hoeffel, T. J. Oriented substituent pharmacophore PRopErtY space (OSPPREYS) a substituent-based calculation that describes combinatorial library products better than the corresponding product-based calculation. Journal of Molecular Graphics and Modelling 2000, 18, 383-403. 

Multi-pharmacophore descriptors can be slow to calculate for large sets of compounds. When specifically applied to library design, it is possible to calculate descriptors for reagents where the attachment bond to the scaffold can give a frame of reference. Several variants on this approach have been developed. In the OSPREY (Orientated Substituent Pharmacophore PRopErtY space) approach [135], two additional points are added to a substituent to represent the relationship with the scaffold. One-, two-, and three-point pharmacophore descriptors are then calculated for fhe substituents, including the distances to the two orienting points. The inclusion of the orienting points means that the descriptors are equivalent to... 

Orientated substituent pharmacophore PRopErtY space One window free energy grid Orexin receptor... 

A unique feature of the experimental system is that in addition to the typical 3D sub.structure query type for pharmacophore pattern matching, a framework type of query is also supported. This latter type of query is typically u.sed in locating a synthetic precursor that will lead to a desired geometric orientation of substituents. 

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