Pharmacophore property

Lee, M.L. Schneider, G. (2001) Scaffold Architecture and Pharmacophoric Properties of Natural Products and Trade Drugs Application in the Design of Natural Product-Based Combinatorial Libraries. Journal of Combinatorial Chemistry, 3, 284-289. 

Lee ML, Schneider G, Scaffold architecture and pharmacophoric properties of natural products and trade drugs Application in the design of natural product-based combinatorial libraries,/ Comb Chem 3 284-289, 2001. 

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. 

Fig. 8.3 Concept of PhDOCK. Conformers of similar molecules are aligned on the largest common pharmacophore. The pharmacophore of each cluster is consequently matched on spheres in the binding pocket labeled with pharmacophoric properties.

D pharmacophoric properties calculation to bias combinatorial libraries ... 

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... 

Fig. 3. CLM (common ligand mimic) with linker to SL (substrate ligand) is prepared by computationally matching the pharmacophore properties of the nicotinamide ring of NADH bound to dihydrodipicolinate reductase (DHPR) (11).

The R-group descriptor from Holliday et al. [20] is a further example of a topological pharmacophore fingerprint. However, this approach characterizes a distribution of pharmacophoric properties at topological distances from an attachment point. 

Lee, M.-L. and Schneider, G. (2001) Scaffold architecture and pharmacophoric properties of trade drugs and natnral prodncts. J. Comb. Chem. 3,284-289. 

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