Pharmacophore five-point

Calculated properties were restricted to ClogP <3, the number of rotatable bonds <5, the number of hydrogen bond acceptors (HBA) <4 and the number of hydrogen bond donors (HBD) between 1 and 3. The topological polar surface area (TPSA) was set to <70 A2. In addition, a special feature count excludes structures that are too functionalised (feature rich) or dull (absence of pharmacophoric interaction points). This feature count is the sum of HBA, HBD and the number of five-and six-membered aromatic rings and selection was restricted to fragments with a feature count in the range 4-7. 

Several researchers have exploited the wealth of crystal structures of kinase inhibitor complexes to build protein-based pharmacophores for this target class (20). Aronov and Murcko (21) considered the crystal structures of four promiscuous kinase inhibitors, i.e., inhibitors with an affinity of at least 2 pM on five representative kinases. After aligning the structures of the four proteins, they assigned pharmacophoric features to the bound inhibitors, which led to the identification of five clusters of pharmacophoric features. These served to define a five point pharmacophore for kinase frequent hitters (Fig. la). This pharmacophore could discriminate frequent hitters from selective kinase inhibitors. Recently, McGregor (22) aligned 220 kinase crystal structures from the PDB and assigned one of seven possible pharmacophoric types to each atom of the bound ligands. 

To derive an ACE pharmacophore, four points were defined for each molecule. The derivation of these four points for captopril is shown in Figure 12.8. Five distances (also shown in Figure 12.8) were defined between these four points. Note that one of the points corresponds to the presumed location of the enzyme s zinc atom. The number of rotatable bonds in each inhibitor varied between 3 and 9 and the molecules were considered in order of increasing number of rotatable bonds. The entire conformational space was explored for the first (most... 

Tinti and Noffe observed that the combination of the cyano analogue of suosan with the elements of asparatame yields superaspartame which has a potency 14 (KX) times that of sucrose (aspartame has a potency of about 180 times that of sucrose. Fig. 39.19). Subsequently, these authors discovered sweet guanidines such as the compound SC-45647 which has a potency 28000 times that of sucrose. More recently, they reported iV-alkyl-substi-tuted aspartame derivatives such as neotame which has a potency 10 000 times that of sucrose. For these three high-potency sweeteners, Walters et al. were able to identify a five-point pharmacophore model in which the carboxylate, the two hydrophobic groups and two NH groups match well... 

The receptor relevance of BCUT descriptors has inspired several groups to apply them in conjunction with other methods. Beno and Mason reported the use of simulated annealing to optimize library design using BCUT chemistry space and four-point pharmacophores concurrently (33) and the use of chemistry spaces in conjunction with property profiles (52). The application of such composite methods to target class library design is readily apparent. Pirard and Pickett reported the application of the chemometric method, partial least squares discriminant analysis, with BCUT descriptors to successfully classify ATP-site-directed kinase inhibitors active against five different protein kinases... 

Fig. 3a,b Common seven-point pharmacophore for CSI. a Pharmacophoric points within the colchicine binding site together with the most important residues involved in interactions with them, b Colchicine is able to map five features, while podophyllotoxin (c) matches six points. The figure has been generated from the IS AO and 1SA1 structures of PDB, using the information provided by the paper of Nguyen and co-workers [38]... 

Three-point pharmacophores have traditionally been used for many applications but have recently been more and more replaced by four-point pharmacophores (Mason et al. 1999), which increases the complexity of the search but also the resolution of the pharmacophore analysis. This is the case because the additional point increases the total number of inter-point distances from three for a three-point pharmacophore to six for a four-point pharmacophore. Pharmacophore searching is further refined by assigning alternative features to each point (e.g., hydrogen bond acceptors, donors, or charged groups) and ranges to inter-point distances (rather than an exact distance). For example, five different features (e.g., atom types or groups) may be permitted for each point... 

Moreover, geometric atom pairs and geometric binding property pairs were proposed, substituting the topological distance between two atom types with the - geometric distance [Sheridan et a/., 1996]. PPP-pairs are a particular case of geometric atom pairs where only pairs of the five potential pharmacophore points are considered [Brown and Martin, 1996]. 

Five pharmacophore point types are used to generate PDT fingerprints hydrogen-bond acceptor atom, hydrogen-bond donor atom, acceptor site, donor site, and hydrophobic center. While donor and acceptor atoms are part of the molecule, site points refer to interaction points located on a virtual receptor defined by geometrical criteria [Martin, Bures et al., 1993]. Interfeature distances from 2.5 to 15.0 A are divided into 27 distance bins of equal width (i.e.,... 

Fig. 4.3 The PHACIR algorithm comprises of five steps. The first two steps are needed to generate conformers of a given query molecule with the program CORINA. Then, based on these conformations, each atom is assigned a distinct atom type as hydrogen donor, hydrogen acceptor, positive, negative, or lipophilic. All possible three-point-pharmacophores are then calculated, and...

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