Furthermore it was recently reported that loss of PTPs facilitates nerve regeneration following spinal cord injury, owing to the interaction of its ectodomain with chondroitin sulfate proteoglycans. In addition to its neural function, PTPs has been implicated in chemoresistance of cancer cells. First, we discovered that RNAi-mediated knockdown of PTPs in cultured cancer cells confers resistance to several chemotherapeutics. Additionally, we have discovered that loss of PTPs hyperactivates autophagy, a cellular recycling program that may contribute to chemoresistance of cancer cells. Taken together, it is apparent that modulation of PTPs may have therapeutic potential in a range of contexts. Notably, inhibition of PTPs could potentially provide benefit following SCI through enhanced neural regeneration. In addition, it is possible that PTPs inhibition may yield therapeutic value in diseases in which increasing autophagy represents a promising treatment strategy. Furthermore, a small molecule would provide value as a molecular probe or tool compound to interrogate the cellular functions and disease implications of PTPs. Several approaches exist for the identification of small molecule inhibitors of phosphatases. While high-throughput screening of compounds in vitro has been successfully utilized to discover inhibitors of LAR, PTP1B, SHP2, CD45, and others, the technical and physical investment is considerable as is the potential for experimental artifacts leading to false negatives and positives. Alternatively, a primary screen for inhibitor scaffolds can be guided by in silico virtual screening. This method involves high-throughput computational docking of small molecules into the crystal structure of a phosphatase active site and selecting the molecules which bind favorably, akin to a natural substrate. Following the selection of the best-scoring scaffolds, each scaffold can then be tested and validated for phosphatase inhibition in vitro. This 1801747-11-4 approach has gained popularity as the PD1-PDL1 inhibitor 2 number of enzymes with solved crystal structures has increased and it is advantageous in many ways. First, utilization of the phosphatase structure allows for the exclusion of molecules which have little chance of interacting with the active site, greatly reducing the number of scaffolds to be biochemically screened and improving the screen results. Second, an understanding of the unique structural features and residues comprising the active site as well as proximal folds or binding pockets can guide the selection and refinement of an inhibitor. Furthermore, an in silico approach is incredibly efficient in that it allows tens of thousands to millions of compounds to be screened virtually in a matter of weeks.
