Retropharmacology: From Drug to lead

Drug discovery is a lengthy, high-risk, and costly endeavor; many strategies are available to accelerate the development process to provide high-quality drug candidates. The diminished interest in Natural products drug discovery as the industry embraced promising and exciting new technologies, particularly combinatorial chemistry. However, these new technologies promise to fill the drug development pipeline with small-molecule candidates is unfulfilled. Learning from the past with the appropriate strategy for the future is essential to make a significant difference.

Valerian has been used as a medicinal herb science at least the time of ancient Greece and Rome as a sedative, migraine treatment, pain reliever, insomnia, and other disorders as an alternative to benzodiazepine drugs.

Valerenic acid, a significant constituent of common valerian, is a potent modulator of  GABA-A receptors. In order to develop a broader understanding of structural requirements for GABA-A modulatory activity of valerenic acid. Kopp et al. (chem med chem) synthesized several analogs and found that some of the derivatives such as tetrazole (pic) are proved to be the most potent allosteric potentiators of GABA-induced ion currents, and its activity exceeds the activity of valerenic acid and Diazepam.

This reverse pharmacology approach, relates to reversing the routine ‘laboratory-to-clinic’ progress to ‘clinics-to-laboratories’ (inspired by traditional medicine), can offer a smart strategy for new drug candidates.

The rise biopharmaceuticals

The movement of big pharma into biologics  (biopharmaceuticals) understandably has a direct effect on the pharmaceutical landscape. Companies show a diminishing portfolio revenue from small molecule drugs, primarily because of patent expiration on blockbuster drugs (small molecules) and the reallocation of industry resources towards biologics.

Biologics represent one of the most promising frontiers in pharmacotherapy; USFDA approved more biologics in 2009, the figure includes 19 new molecular entities (NMEs) and six novel biologics. In 2008 FDA approved 21 NMEs and three novel biologics. A substantial improvement in biologics approvals in 2009. (fig.1, Nature Medicine, 139, 16, 2010). Moreover, it is expected to take over from small molecule field in the coming years (fig 2, Nature reviews / drug discovery). However, their cost can be substantial, reaching $200,000 or more annually for treatment (Cerezyme), and the large molecules drugs are administered via injection – a less popular option with patients.

Biologics are gradually going to replace the traditional approach to drug design. Students need to understand industries changing needs if they plan on carriers in this area.