Discovery program productivity

Strohl, W.R. (2000) The role of natural products in a modern drug discovery program. Drug Discovery Today, 5, 39-41. 

A successful natural products drug discovery program requires several key components ... 

Synthesized libraries of compounds such as Optiverse are not the only source of new leads. Natural products also play an important role in lead discovery. There are numerous examples where natural products have led to the discovery of new drugs. It is also clear that they represent an inexpensive source of nature s molecular diversity in a lead discovery program. However, a key limitation that must be overcome if leads are to be developed into drugs is they are usually difficult to synthesize, thereby making it more resource-intensive to generate related compounds with better properties. 

As there was no ethnomedicinal history to guide the selection of organisms to probe for bioactive natural products, two basic approaches were taken. Early discovery programs sought to establish... 

To make the DERA-catalyzed process commercially attractive, improvements were required in catalyst load, reaction time, and volumetric productivity. We undertook an enzyme discovery program, using a combination of activity- and sequence-based screening, and discovered 15 DERAs that are active in the previously mentioned process. Several of these enzymes had improved catalyst load relative to the benchmark DERA from E. coli. In the first step of our process, our new DERA enzymes catalyze the enantioselective tandem aldol reaction of two equivalents of acetaldehyde with one equivalent of chloroacetaldehyde (Scheme 20.6). Thus, in 1 step a 6-carbon lactol with two stereogenic centers is formed from achiral 2-carbon starting materials. In the second step, the lactol is oxidized to the corresponding lactone 7 with sodium hypochlorite in acetic acid, which is crystallized to an exceptionally high level of purity (99.9% ee, 99.8% de). 

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