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. Source Target Protein Approach Reference(s) HIV gp41 Structure led to strategies that target viral entry. [43]–[45] HIV Protease Protease–inhibitor complexes allowed lead optimization. [46]–[52] HIV Reverse transcriptase Non-nucleoside inhibitor complexes led to drug design that targets pockets outside the enzyme's active site. [53]–[55] Influenza virus Neuraminidase Complex with a transition state analog led to inhalable and orally active neuraminidase inhibitors. [56]–[59] Rhinovirus Coat protein Small fatty acid molecules bound in hydrophobic pocket led to new strategies of antiviral drug design. [60] Vibrio Cholera toxin Five receptor-binding sites provided inspiration for design of novel multivalent inhibitors. [61] Bacteria Peptide deformylase Protein–inhibitor complexes led to macrocyclic compounds with improved potency, selectivity and metabolic stability. [62] Trypanosoma GAPDH Novel adenosine analogs showed enhanced selectivity towards the parasite target versus human protein. [63],[64] Human Cyclophilin and calcineurin A ternary complex with cyclosporine A led to insights into its immunosuppressive activity. [65] Human Renin The ligand-bound structure allowed design and improvement of orally active non-peptide inhibitors to regulate blood pressure. [66] Human Coagulation factor Xa Structure-based design led to improved pharmacological anticoagulant properties in a primate model. [67] Human Adenosine deaminase Optimization of a non-nucleoside inhibitor led to an orally active anti-inflammatory compound in a rat model. [68] Human Kinases Structures of kinases provided a basis to improve and design new therapeutics for various human diseases including cancer. [69] Open in a separate window 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. Name URL Target Focus Berkeley Structural Genomics Center (BSGC) http://www.strgen.org/ Near complete coverage of Mycoplasma genome Center for Eukaryotic Structural Genomics (CESG) http://www.uwstructuralgenomics.org/ PSI Center—Eukaryotic bottlenecks, specifically solubility Center for Structural Genomics of Infectious Disease (CSGID) http://csgid.org/csgid/ Medically relevant infectious disease targets Center for Structure of Membrane Proteins (CSMP) http://csmp.ucsf.edu/index.htm PSI Center—Bacterial and human membrane proteins Integrated Center for Structure and Function Innovation (ISFI) htp://techcenter.mbi.ucla.edu/ PSI Center—Protein solubility and crystallization improvement Israel Structural Proteomics Center http://www.weizmann.ac.il/ISPC/ Member of Structural Proteomics in Europe (see below) Joint Center for Structural Genomics (JCSG) http://www.jcsg.org/ PSI Center—High-throughput pipeline development and operation Marseilles Structural Genomics Program http://www.afmb.univ-mrs.fr/rubrique93.html Human health Medical Structural Genomics of Pathogenic Protozoa (MSGPP) http://www.msgpp.org/ Structural and functional genomics of ten species of pathogenic protozoa Montreal-Kingston Bacterial Structural Genomics Initiative (BSGI) http://euler.bri.nrc.ca/brimsg/bsgi.html ORFs from pathogenic and nonpathogenic bacterial strains Mycobacterium Tuberculosis Structural Genomics Consortium (TBsgc) http://www.doe-mbi.ucla.edu/TB/ Mycobacterium tuberculosis—To understand pathogenesis and for structure-based drug design Mycobacterium Tuberculosis Structural Proteomics Project (X-MTB) http://webclu.bio.wzw.tum.de/binfo/proj/mtb/ 35 Mycobacterium tuberculosis targets to identify five for drug development New York SGX Research Center for Structural Genomics (NYSGXRC) http://www.nysgrc.org/nysgrc/ PSI Center—High-throughput pipeline development and operation Ontario Center for Structural Proteomics (OCSP) http://www.uhnres.utoronto.ca/centres/proteomics/ Enzymatic activity characterization Oxford Protein Production Facility http://www.oppf.ox.ac.uk/OPPF/ Human and pathogen targets of biomedical relevance RIKEN Structural Genomics/Proteomics Initiative http://www.rsgi.riken.jp/rsgi_e/ Protein functional networks Seattle Structural Genomics Center for Infectious Disease (SSGCID) http://www.ssgcid.org/ Medically relevant infectious disease targets Southeast Collaboratory for Structural Genomics http://www.secsg.org/ High-throughput eukaryotic genome-scan methods development Structural Genomics of Pathogenic Protozoa http://www.sgpp.org/ PSI Center - Three-dimensional structures of proteins from four major pathogenic protozoa Structural Proteomics in Europe (SPINE) http://www.spineurope.org/ Structures of medically relevant proteins and protein complexes Structural Proteomics in Europe 2-Complexes (SPINE2 - Complexes) http://www.spine2.eu/SPINE2/ Structures of protein complexes from medically relevant signaling pathways Structural Genomics Consortium http://www.thesgc.org/ Medically relevant human and pathogen proteins Structure 2 Function Project http://s2f.umbi.umd.edu/ Poorly characterized and hypothetical protein targets The Accelerated Technologies Center for Gene to 3D Structure http://atcg3d.org/default.aspx PSI Center—Technologies development of X-ray source, synthetic gene design, and microfluidic crystallization The Midwest Center for Structural Genomics (MCSG) http://www.mcsg.anl.gov/ PSI Center—High-throughput methods development and operation The Northeast Structural Genomics Consortium (NESG) http://www.nesg.org/ PSI Center—Protein domains, network families, biomedical relevance Open in a separate window Note: Some centers with fewer than ten released structures in the PDB (www.rcsb.org/pdb/) are not shown.