Computational Design and Experimental Discovery of an Anti-estrogenic Peptide Derived from Alpha-Fetoprotein

Breast cancer is the most common cancer among women, and tamoxifen is the preferred drug for estrogen receptor-positive breast cancer treatment. Many of these cancers are intrinsically resistant to tamoxifen or acquire resistance during treatment. Consequently, there is an ongoing need for breast cancer drugs that have different molecular targets. Previous work has shown that 8-mer and cyclic 9-mer peptides inhibit breast cancer in mouse and rat models, interacting with an unsolved receptor, while peptides smaller than eight amino acids did not. We show that the use of replica exchange molecular dynamics predicts the structure and dynamics of active peptides, leading to the discovery of smaller peptides with full biological activity. Simulations identified smaller peptide analogues with the same conserved reverse turn demonstrated in the larger peptides. These analogues were synthesized and shown to inhibit estrogen-dependent cell growth in a mouse uterine growth assay, a test showing reliable correlation with human breast cancer inhibition.

Computational approaches for the design of peptides with anti-breast cancer properties

Background: Breast cancer is the most common cancer among women. Tamoxifen is the preferred drug for estrogen receptor-positive breast cancer treatment, yet many of these cancers are intrinsically resistant to tamoxifen or acquire resistance during treatment. Therefore, scientists are searching for breast cancer drugs that have different molecular targets. Methodology: Recently, a computational approach was used to successfully design peptides that are new lead compounds against breast cancer. We used replica exchange molecular dynamics to predict the structure and dynamics of active peptides, leading to the discovery of smaller bioactive peptides. Conclusions: These analogs inhibit estrogen-dependent cell growth in a mouse uterine growth assay, a test showing reliable correlation with human breast cancer inhibition. We outline the computational methods that were tried and used along with the experimental information that led to the successful completion of this research.

A Method for Assessing the Sustainability of Design in Developing World Projects

Projects for the developing world usually find themselves at the bottom of an engineer’s priority list. There is often very little engineering effort placed on creating new products for the poorest people in the world. This trend is beginning to change now as people begin to recognize the potential for these projects. Engineers are beginning to try and solve some of the direst issues in the developing world and many are having positive impacts. However, the conditions needed to support these projects can only be maintained in the short term. There is now a need for greater sustainability. Sustainability has a wide variety of definitions in both business and engineering. These concepts are analyzed and synthesized to develop a broad meaning of sustainability in the developing world. This primarily stems from the “triple bottom line” concept of economic, social, and environmental sustainability. Using this model and several international standards, this thesis develops a metric for guiding and evaluating the sustainability of engineering projects. The metric contains qualitative questions that investigate the sustainability of a project. It is used to assess several existing projects in order to determine flaws. Specifically, three projects seeking to deliver eyeglasses are analyzed for weaknesses to help define a new design approach for achieving better results. Using the metric as a guiding tool, teams designed two pieces of optometry equipment: one to cut lenses for eyeglasses and the other to diagnose refractive error, or prescription. These designs are created and prototyped in the developed and developing worlds in order to determine general feasibility. Although there is a recognized need for eventual design iterations, the whole project is evaluated using the developed metric and compared to the existing projects. Overall, the success demonstrates the improvements made to the long-term sustainability of the project resulting from the use of the sustainability metric.