Substructural modification pattern

Numerous structural "evolution" processes observed in a number of agrochemical and medicinal series of compounds were collected and arranged so that the substructural modification patterns involved in each process could be used as possible "rules" for bioisosteric transformations to be attempted in drug design studies. EMIL is a system that incorporates a database for these structural evolution examples and a data-processing engine constructed to release "higher-ordered" candidate structures from a "lower-ordered" input structure "automatically" with the aid of the database. 

In each data sheet, the core of information is the identification of substructural modification patterns which could be utilized as possible "rules" for the bioisosteric transformation in the lead evolution phase of the dnig design research not only within a single series, but also extended into other categories of bioactive compounds. There are numerous examples in which the structural evolution has occurred from agrochemicals to medicines (an example is the azole-type antimycotics shown in Fig. 1), from herbicides to fungicides as well as to insecticides and vice versa (Fujita, T. In Trends in QSAR and... 

Fig. 5. Substructural Modification Pattern in the Azole-Type Fungicides Y is any substituent which can be deleted and/or replaced with others, and A and A2 are the "unchanged substructures through the structural transformation (the preparation was assisted by Masanori Yoshida).

Operation of the System Each of the substructural modification patterns in the database is utilized as the "rule in the system. The structure of a primary lead compound represented by Ri-(ai) is first introduced in the system. Then, the search of the database is initiated. If an example, in which a structure Si-(ai) is successfully transformed to an elaborated structure Si-(bi), is hit by the search, then, the system "automatically" constructs a candidate structure Ri-(bi) for the higher-ordered lead compound. The substructural modification pattern from ai to bi originally identified in the structural evolution example from Structure A, [Si-(ai)], to Structure B, [Si-(bi)], is... 

Paquette s early attempts to arrive at a suitably functionalized pyranfocused on gaining access to the dithiane 53 whose role it was to provide a nucleophilic site at C9. The substructure of 53 was recognized to correspond well from the functionality and stereochemistry standpoints to the pattern resident in Fukui s lactone (49), which is readily available from L-malic acid. To enable proper structural modification, the hydroxyl group in 49 was first masked as the PMB ether by implementation of the trichoroacetimidate process (Scheme 15.5). 

Both natural substrates of a ribonucleotide reductase, ribonucleoside 5 -phosphates and dithiols (Scheme I) are complex molecules composed of several substructures. The enzymes share an interesting specificity pattern in tolerating manifold (although not unlimited) modifications at all but one substructure which must not be altered (Fig. 8). 

Set reduction involves the successive elimination of candidate structure atoms from sets corresponding to each pattern atom on the basis of an analysis of neighbourhood and connectivity information. The technique has been widely used as a component of 2-D substructure searching systems and we have developed a modification of the technique which can be used for geometric searching. The first stage of the algorithm involves the creation of a distance table. The NQ pattern atoms are labelled from 1 to NQ and for each of the NQ(NQ-l)/2 distinct interatomic distances in the pattern (or less if not all of the query distances are specified for the search), a list of pairs of atoms from the structure is produced. The distance between the atoms in these pairs is equal to that between the pattern atoms (to within any specified tolerances), and the atom type of the first atom corresponds with the type of the first query atom (and similarly for the second atom). 

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