High-resolution view of compound promiscuity

The distribution styles illustrate that, despite the fact that Staurosporine there are distinctions in the Staurosporine actual physical properties of the ligands, employing a one residence to discern separate gene people is way too crude. We have witnessed a exceptional progress in the quantity of described targets and compounds disclosed in the medicinal chemistry literature, mirroring the increase in expense in pharmaceutical investigation. In recent many years, the quantity of targets screened, like selectivity counter-screens, published in the medicinal chemistry literature, has been increasing dramatically. Screening data on practically 900 proteins are at present published every single year, of which >500 molecular targets are described with strong chemical make a difference (that is, IC50 < 100 nM). Currently, potent novel chemical tools and leads are first disclosed for approx80–100 new molecular targets each year (Fig. 5a). No doubt, this is a conservative estimate as many new compounds and targets are only disclosed in patents, which are not included in this initial literature analysis. The increase in the rate of discovery of chemical tools for new targets doubled from an average of 30 new targets with leads being disclosed in the 1980s to an average of 60 new targets per year in the 1990s. In comparison, an average of four new targets, for first-in-class drugs, have reached the market each year during the 1990s13.

That said, we have yet to see the increase in new targets with leads translating into a proportionate increase in the number of approved first-in-class drugs. An analysis of the targets of published compounds reveals some significant trends in the changing character of the industry's portfolio of targets and target classes (Fig. 5b), such as a relative decline in proportion of aminergic GPCRs in the industry's target portfolio and an increase in protein kinases.

Over the past 25 years, there has been a steady, inexorable rise in the median MW of reported medicinal chemistry compounds (Fig. 5c). Comparing 5-year averages from 1986–1990 to those of 1999–2003, the median MW of all reported medicinal chemistry compounds in the literature rose 68 Da (approx20%) from 354 Da to 422 Da, respectively. Interestingly, this growth is also reflected in the increase of the median MW of disclosed ligands for several gene families. For example, compounds binding to aminergic GPCRs have increased in MW by around 56 Da, from 337 Da to 393 Da between the two 5-year periods. No significant increase in mean or median potency is observed in the data to explain the increase in MW. Even so, this rise in MW contrasts with the steady state of the mean MW of approved drugs26 and the steady decline in MW through each subsequent stage of clinical development and increase in the proportion of compounds that are rule-of-five compliant27, 28 (Fig. 5d).

Of course, these calculations combine all target classes together in contrast, the industry's target portfolio is unlikely to be in a steady state, with some target classes emerging and others declining in popularity. The relative difference in molecular properties among the gene families is also reflected in compounds in clinical development however, again we notice that, even within a gene family, the median MW of compounds surviving subsequent clinical phases is declining slightly (Fig.