Too many aromatics stink

A recent discussion centered on whether fragment libraries should be designed to include more “3-dimensional” molecules and reduce the number of flat, aromatic compounds. Two new papers suggest that doing so may improve pharmaceutical properties. What effect this would have on screening success is still unclear.

The first paper, published by Timothy Ritchie and Simon Macdonald of GlaxoSmithKline in this month’s Drug Discovery Today, correlates the number of aromatic rings with several metrics associated with success in drug development. For this analysis, each ring in a fused system is counted separately, so indole is counted as having two aromatic rings. The researchers conclude that more than three aromatic rings correlates with an increased risk of compound attrition during drug development:

The fewer the number of aromatic rings contained in an oral drug candidate, the more developable that candidate is likely to be.

This is not surprising, but with their access to a vast internal data set the researchers provide considerable supporting evidence. For example, the mean aromatic ring count declines from 3.3 to 2.3 as GSK compounds move from preclinical candidate selection to proof-of-concept in humans. Measured (kinetic) solubility decreases dramatically with increasing ring count: even two aromatic rings leads to many low solubility compounds, and with four aromatic rings the median solubility is only 0.012 mg/ml. Both c log P and log D increase with increasing ring count, as do serum albumin binding, P450 3A4 inhibition, and hERG inhibition – all factors one usually wants to decrease in drug development.

One caveat is that the authors do not control for size. As aromatic rings are added, molecular weight is likely to increase, and thus many of the properties could simply reflect the pharmaceutical liabilities of larger molecules. This is where the second paper comes in. In J. Med. Chem., Frank Lovering and colleagues at Pfizer (nee Wyeth) analyze the effect of aromaticity itself by defining a simple metric:

Fsp3 = number of sp3 hybridized carbons / total carbon count

The smaller the number, the more aromatic the compound; the larger the number, the less aromatic. Besides being a straightforward measure of saturation, the formula inherently controls for molecular size.

When the researchers examined published data sets, they found that the mean Fsp3 increases from 0.36 for 2.2 million molecules in discovery to 0.47 for 1179 approved drugs. They also investigated measured solubility and found a strong correlation: 104 molecules with a log S of -6 (quite insoluble) had an average Fsp3 of 0.31, while 194 molecules with a log S of 0 (very soluble) had an average Fsp3 of 0.56. The effect is even more striking with melting points, which negatively correlate with solubility: 1153 molecules with a melting point of 125 deg. C had an average Fsp3 of 0.31, while 375 molecules with a melting point of 275 deg. C had an average Fsp3 of 0.18.

OK, so let’s say we accept the premise that increasing aromatic character in a molecule leads to lower solubility and worse properties overall. The easiest solution might be to reduce the number of aromatics in a screening collection, but would this really be wise? Ritchie and MacDonald note that aromatics, with their rigid structures, are likely to have increased potency relative to unsaturated molecules. And particularly for fragment libraries, you want all the binding energy you can get.

An interesting study would be to correlate the hit rate for fragments with their aromatic character. Does the hit rate increase with decreasing Fsp3? These data must exist in companies that have been doing FBDD for years. Indeed, at FBLD 2009, Ijen Chen of Vernalis presented a nice analysis of hits against 12 targets, in which she noted that roughly 2/3 of the fragment library members didn’t hit any of the targets. I don’t think she mentioned aromaticity specifically, but she did note that the hits tended to be slightly more rigid and hydrophobic than the non-hits – just what you would expect for low-Fsp3 molecules.

So by all means avoid having too many aromatics, but don’t go to extremes: it’s finding the right balance of binding energy and pharmaceutical properties that makes drug discovery such a tricky business.