Study of Pyridoxal 5' Phosphate (PLP) Analogs as Potential Inhibitors to the Enzyme Low Molecular Weight Protien Tyrosine Phosphatase (LMW-PTP)
Edward McIntee, Chemistry
It has been shown that Low Molecular Weight Protein Tyrosine Phosphatase (LMW-PTP) human isoform II has increased expression in certain types of cancerous cells. Moreover, it has also been shown that increased expression of LMW-PTP can be predictive of more aggressive or invasive cancers. Our project has been centered on discovering a specific inhibitor for LMW-PTP using analogs of Pyridoxal 5' Phosphate (PLP), a known inhibitor. While PLP is a successful inhibitor, it is not specific to LMW-PTP human isoform II. A combinatorial library of PLP analogs was created using Maestro (Schrodinger, LLC) at the Minnesota Supercomputing Institute. This library was created by linking all the primary amines sold by Sigma-Aldrich to the aldehyde on PLP creating an amide linker. The modeling was done at a pH 5.5 +/- 2 (the pH at which in-vitro biochemical testing is done), and the entire library was docked using High Throughput Visual Screening (HTVS). The 19 compounds which displayed the highest glide scores were then docked to PTP using Standard Precision Docking in both LMW-PTP human isoform I and II, and compared to PLP. Some of these compounds displayed some specificity and good binding affinity. These results were analyzed to determine which intermolecular forces were involved in docking, and which compounds appear to specifically inhibit the Human Isoform II. The predicted compounds will be synthesized and tested using an in-vitro screening assay.
Louwagie, Nathan, "Study of Pyridoxal 5' Phosphate (PLP) Analogs as Potential Inhibitors to the Enzyme Low Molecular Weight Protien Tyrosine Phosphatase (LMW-PTP)" (2011). Honors Theses. 127.