The chemist as astronaut: searching for biologically useful space in the chemical universe.
Chemical space whether defined by small molecules or large proteins is larger than can be usefully explored. One of the challenges of drug discovery is thus the definition of the overlap between chemical space, biologically useful space and pharmacological space and how this may be employed in the discovery of new small molecule drugs. Despite the decrease in drug discovery productivity in recent years there is no shortage of targets for small molecule intervention, including stroke, pain, neurodegenerative diseases, inflammation and bacterial and viral infections. Only an extremely small fraction of available chemical space has thus far been explored and it is likely that prior synthetic constraints and bias to existing frameworks and scaffolds have contributed to this. Several approaches are being employed to explore more fruitful paths to discovery. These include recognition that existing therapeutic entities already occupy validated pharmacological space and thus are good leads, the use of molecular fragments that permits a broader exploration of chemical space, and the role of templates that permit fragments to combine to generate active species. Finally, a new focus on natural product-like scaffolds from both synthetic methodologies and the genetic reengineering of biosynthetic pathways is likely to prove valuable. However the exploration of chemical space will alone not solve the current deficit in drug discovery productivity. It is necessary to recognize that cellular environments are not the dilute homogeneous solutions of many screening systems and that a more integrated systems approach will serve to maximize any success of chemical space exploration.
Triggle
David J
DJ
School of Pharmacy and Pharmaceutical Sciences, State University of New York, 126 Cooke, SUNY at Buffalo, Buffalo, NY 14260-1608, USA. triggle@buffalo.edu
D002626:Chemistry, Pharmaceutical; D055808:Drug Discovery; D000078329:Workforce