To address the problem of attrition during lead compound discovery and early development, some large drug firms - Pfizer perhaps both the most vocal and committed -- are banking on file enrichment and selection. Better-informed compound library construction and more efficient lead selection could double the useful hit rate, they say, in effect doubling the number of successful new drug introductions downstream. There's room for combining empirical and rational approaches; for example, combining novel fragments to extend diversity with privileged fragments (or scaffolds) that reflect rational assumptions about drug motifs. For now, however, the proposition of file enrichment is much more theory than reality, until it is shown to actually reduce attrition both before and during clinical development, and so improve productivity.

Given the large number of targets pharma companies must now screen and for which they must find small-molecule ligands, are venture funds currently looking to invest in new chemistry technologies that could help? Yes--but one big problem is the business model.

At a time when high-cash discovery deals, and particularly platform deals, are increasingly difficult to find, a number of companies have pursued alternative strategies for creating important transactions. In the first place, many biotechs have changed their attitude to technology transfer, willingly selling technology, and sacrificing any product-related upside from their clients' programs, in return for more significant upfront funding to pay for creating a more integrated in-house discovery effort. Several companies have also, by focusing efforts on just a few partners, expanded the relationships into a series of deeper and more valuable collaborations. Other biotechs have recognized the value of barter, trading off cash compensation for assets, like combinatorial chemistry expertise, assays, cell lines or even product candidates, which allows them to build internal value faster.