The Role of Medical Structural Genomics in Discovering New Drugs for Infectious Diseases

Whether we think of Alzheimer's disease, microbial infection, or any other modern-day disease, new medicines are urgently needed. The number of new drugs registered since the advent of genomics, however, has not lived up to expectations. One recent review revealed that over 70 high-throughput biochemical screens against genetically validated drug targets in bacteria failed to yield a single candidate that could be tested in the clinic [1]. The reasons for the failure of high-throughput biochemical screens are not completely clear, but it could reflect the limited diversity of chemical libraries used and/or the absence of structural information for many of the targets. Indeed, structure-based drug design is playing a growing role in modern drug discovery, with numerous approved drugs tracing their origins, at least in part, to the use of structural information from X-ray crystallography or nuclear magnetic resonance (NMR) analysis of protein targets and their ligand-bound complexes. Although it is beyond the scope of this brief overview to present a comprehensive list of structures that have led to useful drugs, Table 1 lists some examples in which protein structure information has provided insights to the design and development of new therapeutic entities. These cases include both novel drug design based on native and ligand-bound structures and optimization of inhibitors based on the binding mode revealed by the structures of inhibitor–target complexes. These approaches have allowed increased affinity for the target and/or improvement of pharmacological properties while maintaining target affinity. Table 1 Examples of how target protein structure can assist drug discovery and development. With the increasing availability of complete human and pathogen genome sequences and the substantial progress in structure determination methods, it is no surprise that the field of “structural genomics” has emerged recently. Its aim is to solve as many useful protein structures as possible from the entire genome of a single organism or group of related organisms. Over the past ten years, over 20 structural genomics initiatives have begun around the world (Table 2). The impact of these efforts on structural biology has been substantial, both in the sheer number of new structures and, perhaps even more importantly, in the development of new methodologies, especially the use of robotics and informatics to generate and capture data in a systematic way [2]. Over the next five years, thousands of new protein structures, many bound to their ligands, will be elucidated; laying the groundwork for structure-based design and development of new and improved chemotherapeutic agents against pathogen proteins. Here, we will focus on the intersection of structural biology with chemistry and biology—a field called “medical structural genomics”—particularly on how the structures of medically relevant drug targets in pathogens can serve as a starting point for inhibitor design and drug development. We argue that the pharmaceutical industry should be persuaded to complement the publicly funded structural genomics initiatives by making public the structural coordinates of their drug targets for important infectious disease organisms in a timely fashion and by developing public–private partnerships to provide the maximal synergy between target validation, structure determination, and hit-to-lead development. Table 2 Structural genomics projects worldwide submitting to the Protein Data Bank. Target Selection A prerequisite of medical structural genomics is that the proteins whose structures are determined must be well-validated as good drug targets. The term “drugability” is often used to loosely describe how tractable any given target is for the development of a drug candidate. For infectious organisms, one key factor in defining drugability is that the target protein be essential for survival of the microbe. While essentiality has traditionally been defined using techniques such as “gene knockout” and RNA interference, these are not always feasible and should be complemented by chemical biology approaches (see below). Furthermore, the meaningfulness of these experiments can often be difficult to assess, since the interplay of host and pathogen is complex and full of surprises. For example, tremendous effort has been devoted recently to the development of antagonists for targets in the fatty acid biosynthesis pathway of bacteria [3]. Potent drug-like molecules with high bioavailability have been developed that can effectively shut down bacterial replication in vitro. These compounds were found to be ineffective in subsequent animal testing, however, because fatty acids are quite abundant in vertebrates, so bacteria can secure these host molecules for their survival and growth even if their own fatty acid biosynthesis pathways are blocked [4]. Thus, to improve target selection for medical structural genomics, it will be important to collaborate with chemical biology groups to undertake screening campaigns to identify compounds that cause the death of a pathogen under the appropriate assay conditions [5]. If the target protein of a drug is known, medical structural genomics offers a rapid and efficient way to obtain ligand-bound structures by using high-throughput X-ray crystallography and/or NMR. Conversely, when the target of a cell-active compound is unknown, medical structural genomics efforts provide purified protein for many potential drug targets that can be screened for interaction with the active compound by a number of biophysical methods (such as thermal stability [6]). The Medicinal Structural Genomics of Protozoan Pathogens (MSGPP, http://www.msgpp.org/) initiative has already begun such an effort by screening thousands of anti-malaria compounds against 67 potential Plasmodium falciparum targets expressed in bacteria (WC Van Voorhis, unpublished data). These approaches aim to generate knowledge about the biological effect of a small molecule on a target protein. Follow-up experiments are then needed to test the activity of this compound in live organisms in order to validate the target; this valuable “chemical validation” makes the target much more likely to be drugable, and thus worthy of more intensive effort. The future will likely see more medical structural genomics centers working with chemical biology groups that have collections of “phenotype-defined” compounds (i.e., those with known anti-pathogen activity). The result will be synergistic target validation and hit-to-lead development using structure-based drug design.