Matched molecular pairs

Tab. n.5 Matched molecular pair analysis of the effect of substituent on aqueous solubility... 

Leach, A.G., Jones, H.D., Cosgrove, D.A., Kenny, P.W., Ruston, L., Macfaul, P., Wood, J.M., Colclough, N. and Law, B. (2006) Matched molecular pairs as a guide in the optimization of pharmaceutical properties a study of aqueous solubility, plasma protein binding and oral exposure. Journal of Medicinal Chemistry, 49 (23), 6672-6682. 

Of the recently developed formalisms reminiscent to Bioster analogue pairs, the sodefined compound pairs that differ only by just one atom or small atomic group. Applying MMP methodology to sets of analogue series retrieved by systematic searching from publicly available bioactivity databases, several common and uncommon bioisosteric replacement pairs could be identified [29]. 

Wassermann, A.M.and Bajorath, J. (2011) Large-scale exploration of bioisosteric replacements on the basis of matched molecular pairs. Future Medicinal Chemistry, 3, 425-436. 

In what follows, the working definitions of MMPs, transformations, and contexts will be given. A brief review of the related literature on the subject of matched molecular pair analysis vfill follow. Finally, the last section ofthis chapter will focus on a large-scale experimental study that was carried out. Therein, a detailed account of the experiments will be given and the findings will be discussed. 

Figure 6.1 A matched molecular pair and itscontext. The transformation is H 2> CF3 (single-point change), highlighted in light gray. The asterisk on the context denotes the attachment point.

Table 6.1 Recent studies on matched molecular pair analysis.

More recently, Hajduk and Sauer analyzed the molecular transformations in Abbott Laboratories in-house data (84 000 structures) and their effect on the potency against 30 proteins [23]. They generated the matched molecular pairs using an algorithm based on the MCS function provided by the Daylight Toolkit Their analysis was limited to chemically sensible transformations, such as group additions (i.e., H 3> Y) and multiple region-specific phenyl substitutions. The results illustrated that no transformation seemed to consistently favor potency increase. 

After the MMPs and their respective contexts and transformations had been generated and stored in the database, several descriptors were employed in order to represent the context of matched molecular pairs. The approach included the consideration of both the local environment around the attachment point and whole molecule/context representations. This division allowed for a hierarchical view of the context representation, starting from the whole molecule and focusing progressively on the well-defined local area where the transformation took place. For the whole molecule representation approach, Murcko frameworks [30] were employed. For the localized approach, atom environments [31] were used. 

After the generation of the matched molecular pairs for each end point, according to the three criteria mentioned earlier (see Section 6.4), the matched molecular pairs were stored in a database, along with their corresponding context, transformation, and AP value. 

Richmond, N.J., Pickett, S.D., Hussain, J., Pritchard, J.M., Cooper, A.W.J., and Macdonald, S.J.F. (2010) Lead optimization using matched molecular pairs inclusion of contextual information for enhanced prediction of hERG inhibition, solubility, and lipophihcity. Journal of Chemical Information and Modeling, 50 (10), 1872-1886. 

Warner, D.J., Griffen, E.J., and St-Gallay, S.A. (2010) WizePairZ a novel algorithm to identify, encode, and exploit matched molecular pairs with unspecified cores in medicinal chemistry. Journal of Chemical Information and Modeling, 50, 1350-1357. 

Figure 10.8 Histograms showing distribution of change in iog(potency) for isosteric replacement of 3-phenoi, as derived from a matched molecular pair analysis of the Pfizer IC50 data set. In addition, the ratio of replacements that are as good (at ieast within...

Figure 11.4 Assessment of Drug Guru performance of the Remove -Cl transformation for reducing hERG affinity (dofetilide displacement assay) using a matched molecular pair analysis of 151 compound pairs.

FIGURE 10.2 Matched molecular pair of oxadiazoles differing only by oxygen to nitrogen exchange 1,3,4-oxadiazole (left) and 1,2,4-oxadiazole (right) with experimental data on... 

Leach AG, Jones HD, Cosgrove DA, et al. Matched molecular pairs as a guide in the optimization of pharmaceutical properties a study of aqueous solubility, plasma protein binding and oral exposure. J Med Chem 2006 49 6672-6682. 

Birch AM, Kenny PW, Simpson I, et al. Matched molecular pair analysis of activity and properties of glycogen phosphorylase inhibitors. Bioorg Med Chem Lett 2009 19 850-853. 

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