Lead-like compound

Combining molecular properties with potency provides a simple yet powerful overview of a screening dataset and can be used to quickly identify ligand-efficient lead-like compounds. In Fig. 17.5, a set of 429 compounds active against 5-hydroxytryptamine lA receptor are displayed in a PSA-ClogP plot with the size of the circle related to ligand efficiency. One can easily spot the efficient binders in area of favorable properties. 

The PSSC concept may open up new opportimities for research in the developing field of chemical genomics. Central to this field is the identification of small molecule lead-like compounds that bind to a gene family product (i.e. a protein). Such small molecules can subsequently be used to elucidate the function of other gene products/proteins of the same gene family. The PSSC concept may broaden this approach by considering more distantly related genes and proteins. 

Horio, K., Muta, H., Goto, J. and Noriaki, H. (2007) A simple method to improve the odds in finding Lead-Like compounds from chemical libraries. Chemical e[ Pharmaceutical Bulletin, 55, 980-984. 

Various examples of 2-fold sequential nucleophilic substitutions on insoluble supports have been reported in the literature. Suitable polyelectro-philes are polyhalo triazines, pyrimidines, and purines, and the most common nucleophiles are amines, thiols, and phenols. The use of 2,3-dichloropropionic acid18 and 4,5-difluoro-2-nitrobenzoic acid19 is discussed below to illustrate the scope and limitations of this strategy for the preparation of lead-like compound arrays. 

Table 3.1 Comparison of rule of three (R03)l7] with criteria for compounds of reduced complexity and for lead-like compounds.l27]...

Applications to Lead-like Compounds Bound to Small Proteins... 

The ability of NOE matching to identify the correct pose from a collection of decoy poses was demonstrated on three test cases involving lead-like compounds bound to small proteins. One of these test cases involves muscle fatty acid-binding protein (mFABP) and the other two involve the leukocyte function-associated antigen 11-domain (LFA-1). As these results have been presented in detail elsewhere,1151 here we only summarize the results obtained when the BMRB average chemical shifts (diamagnetic protein statistics) were used for chemical shift predictions. The compounds used for these test cases are shown in Scheme 5.1 (compound 3 contains a proprietary core, which is represented by an ellipse). 

TABLE 1.5. Drug-like versus lead like compound characteristics... 

In parallel, hits are nominated from the group of actives, and chemical optimization is begun, to generate optimized leads. Ideally, the biased library consists of lead-like compounds and allows an efficient, short optimization program. We can anticipate that this parallel approach in chemical biology will lead to time reduction by 3.5 years as compared to the classical linear approach. 

Property filters are a particular implementation of partitioning methods they are used to select drug-like or lead-like compounds from large chemical libraries. Like the cell-based methods, these filters are based on a partition of the chemical space but each selected molecular descriptor is divided into only two or three subranges of values. While property filters mainly aim at optimizing drug-likeness, cell-based methods at optimizing diversity of chemical libraries. 

MetaSite has repeatedly proven useful in the optimization of metabolic properties of lead-like compounds [95, 96] (see earlier) and it was used to study potentially labile sites of compound 4 in detail. 

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