Editorial [Hot topic: Exploring Novel Chemical Space Through the Use of Computational and Structural Biology (Guest Editor: Alan C. Rigby)]

The Human Genome Project [1] identified approximately 30,000 genes and subsequent to the completion of this project a subset of these genes, approximately 3,000-10,000, have been identified as critical in the pathogenesis of disease [2, 3]. In a comprehensive review of pharmaceutical industry portfolios Drews and colleagues suggested that there are approximately 500 drug targets currently, but they proposed that there may be as many as 5,000-10,000 therapeutic targets [4, 5]. One caveat in their estimate is that many of these therapeutic targets are currently under-exploited due to the long standing notion that they are intractable to oral, bioavailable small molecules and/or represent non-druggable targets [4, 6, 7]. While many of the currenty marketed drugs continue to be developed for G-protein coupled receptors (GPCR's), nuclear receptors, ion channels and enzymatic target space there is an emerging need to expand the druggable chemical landscape, which will include target space historically perceived as undruggable. This is a lofty goal, however many groups have recently documented their success in therapeutically targeting these historically refractory complex chemical spaces including; protein-protein interactions, protein-DNA interactions and/or macromolecular complexes through peptidomimetic and/or small molecule approaches. These seminal findings have opened up new and promising avenues for drug discovery initiatives as several groups continue to push the boundaries of what is considered a druggable target. In this issue of Combinatorial Chemistry and High Throughput Screening, we provide an overview of the utility and potential of virtual screening efforts which when partnered with structural biology methods including X-ray crystallography, nuclear magnetic resonance (NMR) spectroscopy and/or rigorous homology modeling offer a cost effective, streamlined approach for identifying hits and validating leads prior to preclinical and clinical evaluation. Although this approach still faces a number of challenges it is an alternative to traditional drug discovery and development initiatives. Virtual screening, which is commonly defined as structure based virtual screening (SBVS), or ligand based virtual screening (LBVS) approaches are often used alone or in parallel with high throughput screening (HTS) for hit identification and subsequent hit-through-lead optimization strategies. The virtual or in silico approach used is highly dependent upon the structural and/or functional information available for the target and/or benchmark therapeutics. In this issue we have provided an overview of these in silico screening approaches highlighting several success stories where these approaches were used alone or were partnered with novel combinatorial chemistry/peptidomimetic approaches that are important for translating biologically active peptides into small molecule therapeutics. Alone these virtual approaches have their own merit in discovery pipelines; however as many groups continue to study this expanded drug discovery target space it is likely that a comprehensive approach involving all of these tools will be needed to overcome the many barriers for these historically refractory targets. In support of the recent success in these approaches we have provided numerous case studies documenting the efforts of several groups to overcome these obstacles and identify small molecule modulators that selectively target protein-protein interaction interfaces (PPI2), transcription factor- DNA (TF-DNA) interfaces and protein-membrane interfaces. As noted in these examples the ability to selectively target and inhibit the interaction interfaces of PPI2 and/or TF-DNA complexes represents a novel strategy aimed at reprogramming specific gene pathways that are deregulated in many diseases of significant unmet need including; inflammatory disease, cancer and HIV. Although the number of documented success stories continues to rise, the significance of these in silico approaches to targeting novel target space has yet to be fully realized. Small molecule inhibition of these critical interaction interfaces provides a promising paradigm shift in small molecule therapy through unique mechanism of pathway specific regulation.