Biosynthonics: Charting the Future Role of Biocatalysis and Metabolic Engineering in Drug Discovery

Abstract

Ironic as it sounds, the pharmaceutical industry is ailing. Despite doubling their R&D expenditures over the past decade, innovator drug companies have struggled to increase their annual drug approval rates. Worse still, candidate attrition rates and development times actually rose during this period. It now costs well in excess of a billion dollars and takes over a decade to discover and develop a new drug. A variety of prognostications have been made regarding the future course that the pharmaceutical industry might take, but none has been as controversial as the suggestion that small-molecule drugs could disappear by 2030. Rest assured that these claims could not be further from the truth. Herein, I outline how biocatalysis and metabolic engineering could drive the next wave of innovation in small-molecule drug discovery. The recent past has witnessed staggering developments in analytical chemistry, genome sequencing and assembly, flow chemistry, chemi- and bioinformatics, metabolic engineering and synthetic chemistry, as well as exponential improvements in the raw computing power that is available for drug research; integrating these parallel innovations into a single platform could translate a vastly higher number of small-molecule drugs to the bedside. I term this integrated approach as “biosynthonics”. Many of its individual elements are already in use drug discovery and development, albeit in a scattered manner, and despite the substantial progress that has occurred in each individual domain, a lot still remains to be achieved if biosynthonics is to become a broad platform for generating focused libraries of natural product-like molecules. It is hoped that this article spurs debate and future collaborations toward achieving these goals, which, if successful, would undoubtedly improve small-molecule R&D productivity.