Exploring Novel Target Space: A Need to Partner High Throughput Docking and Ligand-Based Similarity Searches?

Recent advances in combinatorial chemistry (CC) and High throughput screening (HTS) approaches for use in drug discovery have made it possible to synthesize and/or screen large repositories of chemically diverse scaffolds in search of small molecules that disrupt or regulate macromolecular function. Although successful in the discovery of novel therapeutics this approach is both costly and time consuming. In silico computer aided drug discovery (CADD) approaches including; structure based virtual screening (SBVS) or high throughput docking (HTD) and/or ligand based virtual screening (LBVS) are areas experiencing renewed interest both in the pharmaceutical industry and academia. The emerging success of these approaches alone or partnered with HTS platforms in search of, and/or optimization of, novel therapeutic compounds represents a potential approach for the identification of therapies that target novel space. Here we will discuss how LBVS has been and continues to be partnered with HTS in early stage compound identification and/or triage. We will also provide a significant overview of how SBVS when partnered with LBVS can overcome the limitations inherent to each approach when used alone. We will discuss this partnered approach in the context of both traditional drug discovery targets and provide thoughts on its applicability to study novel chemical space including protein-protein and/or other historical intractable interfaces.