Design, Synthesis, and Evaluation of Novel COX-2 Inhibitors
Cyclooxygenase-2 (COX-2) is the molecular target of non-steroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors. Our laboratory has combined structural analysis with functional studies to define the molecular determinants of the interaction of ligands (substrates and inhibitors) with COX-2. For example, we recently reported the identification of a critical H-bonding interaction that leads to the selectivity of aspirin for acetylation of Ser-530 in COX-2. Many NSAIDs are aralkyl carboxylic acids. Comparative analysis of the effect of site-directed mutation of active site residues on the binding of substrates and inhibitors to COX-1 and COX-2 led us to hypothesize that neutral derivatives of esters and amides would bind selectively to COX-2. We tested this hypothesis by synthesizing a series of neutral derivatives of NSAIDs and demonstrating increases in selectivity for COX-2 of several orders of magnitude. We are exploiting this discovery to prepare novel COX-2 inhibitors as anti-inflammatory drugs and cancer preventive agents.
CORRECTION: Perhaps because the Scientific Method presents a linear and rigid representation of the process of science, many people think that doing science involves closely following a series of steps, with no room for creativity and inspiration. In fact, many scientists recognize that creative thinking is one of the most important skills they have whether that creativity is used to come up with an alternative hypothesis, to devise a new way of testing an idea, or to look at old data in a new light. Creativity is critical to science!
CORRECTION: Especially when it comes to scientific findings about health and medicine, it can sometimes seem as though scientists are always changing their minds. One month the newspaper warns you away from chocolate's saturated fat and sugar; the next month, chocolate companies are bragging about chocolate's antioxidants and lack of trans-fats. There are several reasons for such apparent reversals. First, press coverage tends to draw particular attention to disagreements or ideas that conflict with past views. Second, ideas at the cutting edge of research (e.g., regarding new medical studies) may change rapidly as scientists test out many different possible explanations trying to figure out which are the most accurate. This is a normal and healthy part of the process of science. While it's true that all scientific ideas are subject to change if warranted by the evidence, many scientific ideas (e.g., evolutionary theory, foundational ideas in chemistry) are supported by many lines of evidence, are extremely reliable, and are unlikely to change. To learn more about provisionality in science and its portrayal by the media, visit a section from our .
The ancient Greeks first proposed that matter consisted of fundamental particles called atoms. Chemistry took its present scientific form in the 18th century, when careful quantitative experiments by Lavoisier, Proust, and Dalton resulted in the law of definite proportions, the law of conservation of mass, and the law of multiple proportions, which laid the groundwork for Dalton’s atomic theory of matter. In particular, Avogadro’s hypothesis provided the first link between the macroscopic properties of a substance (in this case, the volume of a gas) and the number of atoms or molecules present.
CORRECTION: This misconception likely stems from introductory science labs, with their emphasis on getting the "right" answer and with congratulations handed out for having the "correct" hypothesis all along. In fact, science gains as much from figuring out which hypotheses are likely to be wrong as it does from figuring out which are supported by the evidence. Scientists may have personal favorite hypotheses, but they strive to consider multiple hypotheses and be unbiased when evaluating them against the evidence. A scientist who finds evidence contradicting a favorite hypothesis may be surprised and probably disappointed, but can rest easy knowing that he or she has made a valuable contribution to science.
: When we, in everyday language, say that we believe in something, we may mean many things that we support a cause, that we have faith in an idea, or that we think something is accurate. The word is often associated with ideas about which we have strong convictions, regardless of the evidence for or against them. This can generate confusion when a scientist claims to "believe in" a scientific hypothesis or theory. In fact, the scientist probably means that he or she "" the idea in other words, that he or she thinks the scientific idea is the most accurate available based on a critical evaluation of the evidence. Scientific ideas should always be accepted or rejected based on the evidence for or against them not based on faith, dogma, or personal conviction.
CORRECTION: Some scientists and philosophers have tried to draw a line between "hard" sciences (e.g., chemistry and physics) and "soft" ones (e.g., psychology and sociology). The thinking was that hard science used more rigorous, quantitative methods than soft science did and so were more trustworthy. In fact, the rigor of a scientific study has much more to do with the investigator's approach than with the discipline. Many psychology studies, for example, are carefully controlled, rely on large sample sizes, and are highly quantitative. To learn more about how rigorous and fair tests are designed, regardless of discipline, check out our side trip .
This last hypothesis suggested that the alchemists’ goal of transmuting other elements to gold was impossible, at least through chemical reactions. We now know that Dalton’s atomic theory is essentially correct, with four minor modifications:
: In everyday language, the word usually refers to an educated guess or an idea that we are quite uncertain about. Scientific hypotheses, however, are much more informed than any guess and are usually based on prior experience, scientific background knowledge, preliminary observations, and logic. In addition, hypotheses are often supported by many different lines of evidence in which case, scientists are more confident in them than they would be in any mere "guess." To further complicate matters, science textbooks frequently misuse the term in a slightly different way. They may ask students to make a about the outcome of an experiment (e.g., table salt will dissolve in water more quickly than rock salt will). This is simply a prediction or a guess (even if a well-informed one) about the outcome of an experiment. Scientific hypotheses, on the other hand, have explanatory power they are explanations for phenomena. The idea that table salt dissolves faster than rock salt is not very hypothesis-like because it is not very explanatory. A more scientific (i.e., more explanatory) hypothesis might be "The amount of surface area a substance has affects how quickly it can dissolve. More surface area means a faster rate of dissolution." This hypothesis has some explanatory power it gives us an idea of a particular phenomenon occurs and it is testable because it generates expectations about what we should observe in different situations. If the hypothesis is accurate, then we'd expect that, for example, sugar processed to a powder should dissolve more quickly than granular sugar. Students could examine rates of dissolution of many different substances in powdered, granular, and pellet form to further test the idea. The statement "Table salt will dissolve in water more quickly than rock salt" is not a hypothesis, but an expectation generated by a hypothesis. Textbooks and science labs can lead to confusions about the difference between a hypothesis and an expectation regarding the outcome of a scientific test. To learn more about scientific hypotheses, visit in our section on how science works.