Is There a Trend for High Activity Molecules

In an effort to understand if HAMs are, in any way, different from LAMs (low activity molecules), we extended this survey to compounds published between 1991 and 2002, as indexed in WOMBAT [26]. This database [27] contains 4927 unique structures with at least one measured activity better than 1 nM (HAMs), and 34028 unique structures with at least one activity less than 1 XM (LAMs). Between HAMs and LAMs, 1080 molecules are common, that is, they have at least one activity above 1 nM and at least one activity below 1 XM. This is not uncommon for, for example, highly selective molecules. We did not exclude these from either set since we monitor trends, not exact figures. We studied these trends using 2-D-(two-dimensional) descriptors, that is, descriptors that do not use information related to the three-dimensional characteristics of model compounds. These descriptors can be classified as follows  

To further investigate the qualities of small, but active compounds, we performed a query in WOMBAT [26] for molecules with activity better than 10 nM and MW 200. 

While not convincing from a statishcal perspective, the results in this section are consistent with a trend high-activity molecules published in the past decade of medicinal chemistry literature are more likely to be found in the large, hydrophobic and poor solubility corner of chemical property space. These results are not consistent with, for example, cell-based [41] and median-based [42] partihoning of biologically active compounds however, such analyses were performed in the presence of inactive compounds selected from MDDR[41] or ACD [42], with quite probably unrelated chemotypes. ACD, the Available Chemicals Directory [43], and MDDR, the MDL Drug Data Report [43], are databases commonly used by the pharmaceuhcal industry. 

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