...The Long Road to Direct Factor Xa Inhibitors: A History of Anticoagulation Marjorie Burnsworth Tacoma Community College July 24, 2014 Abstract This paper explores the history of the chemical research and development of anticoagulant medications over the years and how this has lead to the development of direct factor Xa inhibitors (fXa inhibitors). Since ancient doctors first used leeches to treat their patients, people have been aware of the properties of anticoagulants and anti-thrombolytics, but the development of Heparin almost 100 years ago signified the start of a century of chemical discovery and development in the field of anticoagulation that has peaked in the last 25 years. Following the development of Heparin, scientists next developed Vitamin K Antagonists (VKA's), such as Coumadin, which gave an oral option for anticoagulation but they were not without side effects. Nearly 30 years passed before chemists came up with the next step forward in anticoagulation, low-molecular-weight-heparin (LMWH). It was LMWH that first opened scientists eyes to factor Xa and the possibility of considering it as a possible target for future anticoagulation. In order to proceed with development, however, they had to look back to the past. Back to leeches and heparin, as these would prove hold the keys to the future development of direct factor Xa inhibitors. The Long Road to Direct Factor Xa Inhibitors: A History of Anticoagulation ...
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...insight commentary Virtual screening of chemical libraries Brian K. Shoichet Department of Pharmaceutical Chemistry, University of California, 600 16th Street, San Francisco, California 94143-2240, USA (e-mail: shoichet@cgl.ucsf.edu) Virtual screening uses computer-based methods to discover new ligands on the basis of biological structures. Although widely heralded in the 1970s and 1980s, the technique has since struggled to meet its initial promise, and drug discovery remains dominated by empirical screening. Recent successes in predicting new ligands and their receptor-bound structures, and better rates of ligand discovery compared to empirical screening, have re-ignited interest in virtual screening, which is now widely used in drug discovery, albeit on a more limited scale than empirical screening. T he dominant technique for the identification of new lead compounds in drug discovery is the physical screening of large libraries of chemicals against a biological target (high-throughput screening). An alternative approach, known as virtual screening, is to computationally screen large libraries of chemicals for compounds that complement targets of known structure, and experimentally test those that are predicted to bind well. Such receptor-based virtual screening faces several fundamental challenges, including sampling the various conformations of flexible molecules and calculating absolute binding energies in an aqueous environment. Nevertheless, the field has...
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...Unit II: Genetics Brief Overview Reading: Chapters 3, 4, 9-12, 14 (Note: you have reviewed much of this already) The earth is teeming with living things. We can easily see some of the larger organisms—trees, grass, flowers, weeds, cats, fish, squirrels, dogs, insects, spiders, snails, mushrooms, lichens. Other organisms are everywhere, in the air, in water, soil and on our skin, but are too small to see with the naked eye—bacteria, viruses, protists (single celled eukaryotes such as amoebae), and tiny plants and animals. Life is remarkable in its complexity and diversity, and yet it all boils down to a very simple idea—the instructions for making all this life are written in nucleic acids, usually DNA. Most organisms have a set of DNA that contains the instructions for making that creature. This DNA contains four “letters” in which these instructions are written—A, T, G, and C. The only difference between the code for a dog and the code for a geranium is in the order of those letters in the code. If you took the DNA from a human and rearranged the letters in the right way, you could produce an oak tree—arrange them slightly differently and you would have a bumble bee—arrange them again and you would have the instructions for making a bacterium. Acting through more than two billion years, the process of evolution has taken one basic idea—a molecular code that uses four letters—and used it over and over, in millions of combinations to produce a dazzling array of life forms...
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