Target structure definition

At this point we have mainly considered recognition in terms of rules that apply across any target with defined geometry. Next, we consider how they can be derived within target families and how under these conditions it is possible to use the consistency within families to derive rules for the binding of fragments from experimental data even where structural definition is imprecise. 

Many authors use the term pharmacophores to define functional or structural elements possessing biological activity. This does not correspond to the official definition elaborated by an IUPAC working party and published in 1998 [1] A pharmacophore is the ensemble of steric and electronic features that is necessary to ensure the optimal supramolecular interactions with a specific biological target structure and to trigger (or to block) its biological response. As a consequence ... 

Here, it is appropriate to add certain proviso. The above recommendations by no means should be considered a set of rigid instructions. They are generally applicable to molecules of medium complexity and may be useless if applied to a target structure that contains an intricate set of interfering, polyfunctional groups at multiple chiral centers. A rather different approach should be used in such cases and its consideration definitely lies outside the limits and aims of our book. 

A pharmacophore does not represent a real molecule or a real association of functional groups but is a purely abstract concept that accounts for the common molecular interaction capacities of a group of compounds toward their target structure. The pharmacophore can be considered to be the largest common denominator shared by a set of active molecules. This definition discards a misuse often found in the MEDICINAL CHEMISTRY literature, which consists of naming as pharmacophores simple chemical functionalities such as guanidines, sulfonamides, or dihydroimidazoles (formerly imidazolines), or typical structural skeletons such as flavones, phenothiazines, prostaglandins, or steroids. 

There is an intimate relationship between the conopeptide type, its structure, and its selectivity different types of conopeptides target different neuronal receptor types. However, with the same conopeptide type (or subtypes), selectivity varies tremendously, as different sites within the same receptor can be targeted by the conopeptides whose difference is only one amino acid. This is illustrated by the selectivity of a-conotoxins (Table 3) toward the nAChR. This is further augmented by a new level of conotoxin diversity, as a nonnative disulfide bond connectivity in a-conotoxin AuIB reduces structural definition but increases biological activity. ... 

Target selection. 3D structure (experimertal or theoretical) Hot Spot predicTiorts Druggeble pocket definition Aiiosteric site detection Fiexibiiity prediction Target structures ready... 

By definition, any target structure that is a substructure (or superstructure) of the database molecule will have a subsimilarity (or supersimilarity) of 1.0, and hence a subsimilarity (supersimilarity) search can be viewed as a form of fuzzy substructure (superstructure) search. A further difference from the systems described thus far is in the nature of the output. The description of similarity searching that has been given previously assumes that a user browses down a ranked output until sufficient database structures have been identified. Here, conversely, the user specifies a threshold similarity value, and the output consists of an unordered list of all database structures (or database reactions) that have a similarity to the target that exceeds the chosen threshold value. 

Retrosynthetic analysis of antheridic acid produced a totally different plan of synthesis from that which had been employed for the structurally related target gibberellic acid. The synthesis of antheridic acid, which included a number of novel steps, allowed definitive assignment of structure and revised stereochemistry at C(3). 

Definition of potential paths for chemical structure changes to improve the targeted properties... 

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