Chapter 3
Design and Application of Fragment Libraries for Protein Crystallography Downloaded by UNIV OF GUELPH LIBRARY on June 2, 2012 | http://pubs.acs.org Publication Date (Web): September 30, 2011 | doi: 10.1021/bk-2011-1076.ch003
Computational Approaches to Compound Selection John Badger* DeltaG Technologies, 4360 Benhurst Ave., San Diego, CA 92122, USA *E-mail:
[email protected] The x-ray diffraction analysis of protein crystals soaked in libraries of fragment compounds is able to identify those small compounds that specifically bind to critical sites on the protein. This crystal structure data may be used in the subsequent design of focused scaffold libraries for early lead discovery. By applying simple computational tools to search through the several million off-the-shelf screening compounds currently available it is possible to implement fragment screening methodologies in academic and small biotechnology laboratory environments.
Background Fragment-based screening for lead discovery (FBLD) is now an established methodology with a proven record of success. Hajduk and Greer have reviewed a decade of positive results from early leads to the clinic, listing 47 compounds at significant development stages, including four compounds in clinical trials and two compounds that were developed within two years of project inception (1). Influential theoretical work that has encouraged protein screening with low molecular weight compounds emphasizes the ligand efficiency, the binding energy per non-hydrogen atom, rather than the total binding affinity for deciding which compound hits from the initial screen are most likely to evolve into clinical candidates (2). Specifically, relatively low affinity compounds may be considered useful for lead development if the ligand efficiency exceeds 0.3 and this factor favors lower molecular weight compounds for a given binding affinity. © 2011 American Chemical Society In Library Design, Search Methods, and Applications of Fragment-Based Drug Design; Bienstock, R.; ACS Symposium Series; American Chemical Society: Washington, DC, 2011.
Downloaded by UNIV OF GUELPH LIBRARY on June 2, 2012 | http://pubs.acs.org Publication Date (Web): September 30, 2011 | doi: 10.1021/bk-2011-1076.ch003
In a separate development, feature analysis modeling of the probability of a compound binding to a specific site on a protein indicates an exponentially falling probability with increasing compound complexity (3). This result suggests that screening libraries containing relatively small and simple compounds will yield higher hit rates than libraries containing larger, more complex molecules although the reduced number of interaction points will mean that the binding affinities will often be relatively weak. As a practical matter, it is considered simpler to manage a compound’s chemical properties through the lead development process by growing it from a small starting compound than by attempting to modify a compound which is already approaching its maximum tolerable size for use as an orally deliverable drug. The development of FBLD may have a greater practical impact than just a re-interpretation of existing conventional high throughput screening technologies (HTS) towards the inclusion of lower molecular weight compounds in screening libraries. Screening with small fragment libraries that contain 100-1000’s of compounds rather than the traditionally large HTS libraries containing ~1,000,000 compounds drastically reduces the cost and data management complexity of the initial screen; fragment screening is a practical methodology that can be applied in small pilot programs within academic and small biotechnology environments. Some specific therapeutic areas may be particularly well suited to the application of FBLD. Fragment screening appears to be an appropriate methodology for CNS drug discovery and development because the chemical properties that typify fragment compounds are comparable to the compound properties required for passive transport across the blood-brain barrier (BBB). CNS compounds capable of passive BBB transport are small molecules with low molecular weights (
