This question is fascinating because it challenges chemists to reconsider the fundamental properties of small molecules that allow them to achieve the extraordinary outcome of selective perturbation of protein function. The question is important because if the answer is "no," then it suggests that the potential impact of small-molecule-mediated perturbation of protein function has been only minimally realized to date. The significance of such a finding would be broad and significant, both in the pharmaceutical industry where small molecule-mediated protein perturbation is used to promote and restore human health, and in the field of chemical genetics where small molecule perturbations are used to selectively modulate and thereby understand complex living systems.

"To the left is a photo (click image for a larger view) that we took during the last step (the 'folding process') of the diversity-oriented synthesis summarized in Scheme 10 of the Angewandte Chemie-International Edition article," says Burke. "In this synthesis, skeletal diversity was achieved combinatorially by transforming a collection of substrates having different appendages that pre-encode skeletal information into a collection of products having distinct molecular skeletons using common reaction conditions." For more detailed accounts of this synthesis see: M.D. Burke, E.M. Berger, and S.L. Schreiber.  “A Synthesis Strategy Yielding Skeletally Diverse Small Molecules Combinatorially.” J. Am. Chem. Soc. 2004, 126, 14095-14014; M.D. Burke., E.M. Berger, and S.L. Schreiber. “Generating Diverse Skeletons of Small Molecules Combinatorially.”  Science 2003, 302, 613-618).

A key challenge facing diversity-oriented synthetic chemists is to prepare collections of unnatural/unprecedented small molecules having maximized structural complexity and diversity, and the potential to attach an array of appendages site- and stereoselectivity during a post-screening, maturation stage. I believe that this article builds a foundation for a systematic planning algorithm that aims to assist organic chemists in the development of efficient synthesis pathways (3-5 steps) that generate such collections as products.

For a long time, the field of organic synthesis has focused on the challenge of synthesizing, one at a time, the complex molecules found in nature. Many of these natural molecules are useful as medicines and tools for science because they cause changes in living organisms at the molecular level that promote health and understanding. Recently, chemists have started to question whether or not the molecules found in nature are really the best ones for these important applications, that is, might there be unnatural molecules yet to be discovered that would be more ideally suited for the job? In order to answer this important question, chemists are beginning to think about how to make diverse collections of unnatural molecules in the laboratory, and then screen them to find new molecules with optimized properties for medicine and science. Unfortunately, progress in this area has been limited to date, because preparing diverse collections of unnatural molecules is very challenging. This article contributes a general and systematic planning strategy that should assist organic chemists in achieving this important goal.

I had the privilege of working on this problem during my time as a graduate student in Professor Stuart Schreiber’s group at Harvard. Key to the development of this planning strategy for diversity-oriented synthesis was the recognition that the challenge of planning the synthesis of a collection of compounds that are maximally complex and diverse is very different than the challenge of designing a synthesis pathway to yield a single complex molecular target. Great progress has been achieved regarding the latter, including the development of a systematic approach for synthesis planning, known as "retrosynthetic analysis," in which the target structure is transformed into a sequence of progressively simpler structures by formally performing chemical reactions in the reverse-synthetic direction. The impact of this approach on the field of target-oriented synthesis has been broad and profound. We became very excited about the prospect of similarly promoting the advancement of diversity-oriented synthesis by developing a complementary planning algorithm customized for the unique challenges of maximizing structural complexity and diversity.