BioAcyl Corp

It is widely recognized that the pharmaceutical industry has been central to the success of the biomedical enterprise in reducing morbidity and mortality of many diseases. Drug discovery has followed a well-choreographed strategy derived from the early work of Ehrlich1: A specific protein target is identified, and small-molecule or biological therapeutics are developed that modify that target's function to prevent or attenuate manifestations of the underlying disease mechanism. While this approach has been successful for over a century, the drug development process has witnessed declining success over the last several decades with some analysts declaring that the industry is in the midst of an innovation crisis.2 That crisis is reflected in a decrease in the overall success rate of pharmaceutical agents, with an increase in the attrition rate for drugs in development, as well as an increase in the mean development time and the cost per new drug ultimately approved for use. Importantly, this crisis has occurred in the setting of increasing investment in research and development and, in particular, in new, cutting-edge methods and technologies that would logically be expected to enhance the yield of approved drugs.

Adverse off-target effects, only some of which are routinely assessed during the drug screening process, are undoubtedly a consequence of the fallacy of the ‘magic bullet’ hypothesis of Ehrlich. While pharmacologists have long-recognized that drugs are promiscuous in their interactions with protein targets, the magnitude of that promiscuity has only recently been assessed by Chartier and colleagues.4 These investigators analyzed the extent to which the binding sites for 400 drugs are recapitulated in 14 082 binding pockets contained within 7895 different proteins with known tertiary structures. On average, they found 25 targets per drug, with 24 drugs having between 100–800 targets. This value represents a minimum, given that the set of tertiary structures of all human proteins is incomplete, and that other post-translational (covalent) modifications of amino acid side chains are not considered.