Lead generation enumeration

Figure 17.2 An example of a lead generation design and testing cascade including diversity schemes, library enumeration, predicdve models, panels of in vitro assays, and ultimately in vivo pharmacokinetic and efficacy tests in animal models.

One element of database generation that is a key consideration is whether to expand the representative compounds to include alternative tautomers, protonated and deprotonated forms of the molecule, and also to enumerate stereochemistry fully if not specified in the input. Depending on the molecules in question and the options considered, these can lead to a 10-fold increase in the size of the database to be explored. However, such an expansion is necessary if methods are used that are sensitive to such chemical precision (e.g., docking). For 3D similarity searching, it is sometimes more efficient to consider various modifications to the query, leading to multiple searches against a smaller database. 

The transformation used above to enumerate tautomers would lead to identical products when applied to symmetrically substituted pyrazoles. The set of structures generated in the enumeration process is converted to a sorted list of canonical SMILES [23] from which duplicates are easily eliminated. Structures registered in alternative tautomeric forms are converted to identical lists of SMILES that can each be represented by their common first member. This effectively extends the definition of canonical SMILES to cover an ensemble of tautomeric forms and makes it possible to check for duplicate structures without having to register multiple forms [16, 26]. 

In most of the enumerations of benzenoid systems the number of hexagons, h, has been used as a leading parameter. This is to say that the numbers of non-isomorphic benzenoids with a given h have been determined, and this set has occasionally been subdivided into different classes see e.g. a consolidated report [30] with supplements [31]. Also when special classes of benzenoids have been generated specifically the numbers of benzenoids were produced as a function of h. 

Physicochemical Reactions with MIC MIC can interact with a large number of molecules as well as with itself Indeed, 21 identified (Varadarajan et al., 1985) and almost ten unidentified chemicals (Sriramachari, 2004) were detected in the culprit MIC Tank E-610. An MIC trimer as well as other metabolites of MIC such as dimethyl isocyanurate and 2,4-dione of methyl isocyanate were identified in autopsy samples from Bhopal victims (Chandra et al, 1991, 1994 Saraf et al, 1995). Reaction of MIC with water is important because this will occur whenever MIC comes into contact with a body or environment, as happened in Bhopal. It is important to note that while excess water can neutralize MIC, a small quantity of water is sufficient to generate heat during the reaction, which would lead to vaporization of MIC, as actually happened in Bhopal. Some important interactions of MIC are enumerated below ... 

A Fragmentation Enumeration Approach to Generating Novel Drug Leads... 

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