Structural Biology in Pharmaceutical Research

Structural Biology in Pharmaceutical Research INTRODUCTION Molecular biology plays a key role and contributes a lot in determining the 3D structure of a molecule be it proteins, nucleotides or any other biological macromolecule. It also helps in finding the target sites when it comes to drug designing. Many structural biology techniques are used in the field of pharmaceutical research. These mainly include X-ray crystallography and NMR Spectroscopy. However, structural biology also includes the help of bioinformatics. Structure based drug design plays a major role when it comes to pharmaceutical research and also it has advanced a lot over the years. The remarkable discovery of peptidomimetics and nonpeptides proves this. This was done using techniques like X ray crystallography and NMR spectroscopy as well as other computer based methods. One of the widely used tools in structural biology is X-ray crystallography. This is used to determine the atomic as well as the molecular structure of a crystal where the crystalline atoms cause diffraction of X-rays in many specific directions. It is a form of high resolution microscopy. Using this technique, visualizing protein structures at the atomic level becomes easier and helps in understanding its functions. It also gives information about how proteins react with other molecules and undergo changes in their conformation. As well as the process of catalysis with respect to enzymes. All this knowledge is necessary for designing drugs which are meant to ta rget specific sites or are used for industrial processes. Crystallography, being the most widely used technique may not be successful at all times. With this, NMR comes to the rescue. It helps in elucidating 3D structures of target ligand complexes. With advances in genome sequencing, protein expressions, crystallography and NMR; these have helped in using protein 3D structure for fast discovery of drugs. The role of structural biology and bioinformatics in this is that they help in the manufacturing of drugs that are target specific and well optimized. Also, due to the determination of structure, fragment binding becomes possible. For a drug to work efficiently, it needs to bind to the specific site or the target proteins. Using computer for this is a very good technique which finds and optimizes target proteins that are required. For a substance to bind a target it has be extremely specific like a lock and a key. Structural biology methods and molecular modeling are tools that are used in the developments of such molecules. In the process of drug discovery, computational chemistry proves to be a tool of great help. After the molecule has binded to the desired molecule and the binding properties are known, the suitability of the compound can be improved using the computer. The drug’s binding affinity can be calculated digitally using the computer. Also, using these methods it is also possible to calculate if the changes in the structure would lead to any undesirable or toxic properties. These methods save a lot of time as compared to lab work especially in the early stages of drug designing. Due to this, an increase in the success rates can be observed. Fig 1: Drug Discovery Process Courtesy: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1609333/figure/fig1/ X-RAY CRYSTALLOGRAPHY In order to determine the precise molecular structure of the target protein, X-ray structure analysis is used. In this, the crystal lattice structure of the protein diffracts the X-ray beam in a typical way. The diffraction pattern can be analyzed and due to this, the density of electrons can be read which are present in the parts of the target protein. This in turn, helps in determination of the position of the atoms. Several repetition of this process and refining the image is done till the researchers obtain a 3D structure of the target molecule. Usage on X-ray crystallography in drug discovery has been present since a long time where 30 years ago the 1st three dimensional structure of proteins were determined. However, not all the pharmaceutical companies resort to this technique as it is considered time consuming and too expensive. A total change in drug design has occurred in the past years, thus using 3D structures in the designing processes. For structure that were not available with X-ray crystallography, other methods were used which included comparative models based on homologues. Crystal structures of key drug targets are now available like AIDS drugs such as Agenerase and Viracept were developed using the crystal structure of HIV protease and the influenza drug Relenza was designed using the crystal structure of neuraminidase.Drugs originating from structure based design have entered clinic trials and some of them have even been marketed as drugs now. Knowing the protein structure is a key component in the process of drug design. It is used in lead optimization which is a process that revolves around the usage of structure for guiding chemical modification of the molecule of lead for giving the perfect fit with respect to shape, bonds and other interactions. Protein structure is also used in target selection; this involves homology recognition but with the recent advances in structural genomics this has become easier. X-ray crystallography is also used in the direct screening of chemical fragments. Astex Technology has developed â€Å"Pyramid†, where fragment libraries are screened in cocktails using X-ray crystallography. Fragment hits that are derived from Pyramid are optimized in order to maintain good ligand efficiency. NMR NMR spectroscopy was the first structural technique to be made full use in fragment screening. Target Immobilized NMR Screening (TINS) Usage of NMR spectroscopy on targets that are immobilized helps in binding of small molecules. A process called as Target Immobilized NMR Screening (TINS) has ennumerable advantages; one of them being that a minimum quantity of the non isotopically labeled protein is needed. This method helps in binding in the range of KD values of 100nM to 20mM. If the reference protein is selected carefully, the number of false positive hits that one may get can be avoided. Due to this, maximum valid hits are ensured. These hits can be treated with biological assays. A variety of soluble proteins as well as membrane proteins have been screened. The combination of target immobilization and small screening of fragments using NMR proves to be of immense help in Early Drug discovery. STEPS IN DRUG DISCOVERY PROCESS TARGET IDENTIFICATION FROM SEQUENCE STRUCTURE HOMOLOGY RECOGNITON Structural bioinformatics is a backbone for the identification of new members of supefamilies. Protein structures impart a major information about the families and super families. The proteins that have evolved would be having some common structures or features that they would be exhibiting thus leading to the importance of â€Å"homology recognition†. An example of this was the recognition of HIV proteinase which belonged to be a member of the pepsin/renin superfamily. Recognition of distant homologues can be done using methods like sequence-structure matching that are classified as profile methods or threading. Profile methods involve the sequence comparison algorithms using traditional methods. Computer programs like FUGUE aid in this and helps in the recognition of homologues. Another method used is Threading which fits a probe sequence and evaluates compatibility between the sequenced and the structure that is proposed. This method is powerful for fold recognition. Example of a computer based program is GenTHREADER. After the homologue of the structure is known and identifies, it can be modeled using a variety of procedures. Although structural bioinformatics is helpful, it is necessary to have an accurate experimental structure. Target validation and the identification of ligand binding regions Structures defined by structural genomics programs are mainly of proteins that do not have a known function but they have been identified as proteins only on the basis of their gene sequences. Hence, the need for the development of computerized based methods arises which would identify sites which are involved in the interactions. PROSITE, a sequence motif database identifies the specific residues that have functions. Several attempts have been made to predict the interaction sites using computerized based methods either by identifying high-energy conformations or identifying clefts that can accommodate ligands. LEAD DISCOVERY The trait of a target is based on the number of drug like ligands for a target class. Classification of the targets into families has helped in designing compound libraries for particular families. Screening of a small fragments or molecule is needed and this can be done using biophysical assays. Ligand docking is a method that helps to find the best binding position and orientation. The best docking programmes are successful in dockin 70-80% of ligands in the ligand-protein complexes. A major drawback of this method is that there are difficulties in predicting affinities of different compounds. CONCLUSION Knowledge of the three-dimensional structures of protein targets plays a major role in all stages of drug discovery. Its place in lead optimization is well established with large teams of structural biologists recruited into all major pharmaceutical companies. The success of the method is evident from drugs in use and new ones reaching the market. But structural biology and bioinformatics show that many key targets for drug discovery are multidomain and multiprotein complexes. Such systems pose significant challenges not only for characterization using structural techniques but also because the inter-protein surfaces are usually poor in distinguishing features. BIBLIOGRAPHY RESEARCH PAPERS: Blundell, T., Sibanda, B., Montalvao, R.W., Brewerton, S., Chelliah, V., Worth, C., Harmer, N., Davies, O.,1 and Burke D(2006) Structural biology and bioinformatics in drug design: opportunities and challenges for target identification and lead discovery. Philos Trans R Soc Lond B Biol Sci. 361(1467): 413–423. Congreve, M., Murray CW., and Blundell T(2005) Structural biology and drug discovery. Drug Discov Today. 2005 Jul 1;10(13):895-907. BOOK: Structural Genomics and High Throughput Structural Biology(2006)edited by Michael Sundstrom, Martin Norin, Aled Edwards. WEBSITE: http://www.pharmaceutical-business-review.com/suppliers/zobio/products/nmr-based-structural-biology http://www.bayerpharma.com/en/research-and-development/technologies/research-technologies/computational-chemistry-structural-biology/index.php

Geographical Layout of an Area on Its Politics Essay

What is the effect of the geographical layout of an area on its politics, society, and economy? Physical characteristics of a specific area can have a substantial impact on its history. Regardless of how close one area is to another the outcome of the civilization could be completely different because of how the people have had to adapt to live in their respective areas. This issue would explain how intertwined history is with geography. Europe’s geography provided many disadvantages and advantages which have been the factors for its many successes and failures. Since the majority of Europe is surrounded by water it was a peninsula. This made it so they could trade with ease. The many rivers and mountain ranges of Europe most certainly aided in protecting certain civilizations from invasion or being involved in wars. The wildly vast and diverse geographic features in Europe set the tone for trading routes to prosper, long-lasting cultures to develop, and battles to occur that would change the identity of the region indefinitely. A region’s geographic shape is instrumental in determining what a region will become. Due to Europe’s geographical shape it became a hotspot for any and all trade. With natural resources plentiful Europe was constantly bustling with business. The Iberian Peninsula gave Spain and Portugal easy access to trade with foreign countries. The Balkan Peninsula gave many countries along the Aegean Sea the effortless option to trade. The many Peninsulas provided great advantages for Europeans due to the plentiful food the oceans supplied. These advantages molded many European civilizations into what they are today whether they isolate themselves from others or interact. The specific geographical features within a region provided protection, but also could have provided isolation. The many rivers and mountain ranges of Europe provided many people with fertile soil and a feeling of safety. However, the mountain ranges could stop trade between countries and slow the advancement of technology and knowledge between these regions. The rivers on the other hand would encourage trade and it would flourish. The physical characteristics of a region affect the decisions people greatly. Europe has a wide variety of terrains. Some help the people who live there, while others force people to adapt. These features influenced the development of many areas. For example the Alps acted as a barrier throughout the Punic Wars. It was perhaps the Roman Empire’s greatest asset. Several times Hannibal was forced to attack by sea instead of being able to invade from the North. This is not the only time in history was affected by geographical features. Climate overcame Hitler’s forces in the Invasion of Russia. The cold winter air killed off many of Hitler’s forces. That event alone could have changed the entire turnout of WWII. Europe’s features both hindered and kindled its growth as a world power. People’s choices have always been affected by their surroundings. The geographic features found in Europe were a commodity and the reason Europe succeeded the way it did for so long. Europe is filled with a wide variety of natural resources and geographical features. Sometimes their surroundings were beneficial and other times it was detrimental. Geography affected the choices of everyone. These features are what caused certain trade routes to emerge, cultures to find their identities, and wars to take place where they did.

An Introduction to the Dunning-Kruger Effect

At one point or another, you’ve probably heard someone speak with confidence on a topic that they actually know almost nothing about. Psychologists have studied this topic, and they’ve suggested a somewhat surprising explanation, known as the Dunning-Kruger effect: when people don’t know much about a topic, they’re often actually unaware of the limits of their knowledge, and think they know more than they actually do. Below, we’ll review what the Dunning-Kruger effect is, discuss how it affects people’s behavior, and explore ways that people can become more knowledgeable and overcome the Dunning-Kruger effect. What is the Dunning-Kruger Effect? The Dunning-Kruger effect refers to the finding that people who are relatively unskilled or unknowledgeable in a particular subject sometimes have the tendency to overestimate their knowledge and abilities.   In a set of studies testing this effect, researchers Justin Kruger and David Dunning asked participants to complete tests of their skills in a particular domain (such as humor or logical reasoning).   Then, participants were asked to guess how well they had done on the test.   They found that participants tended to overestimate their abilities, and this effect was most pronounced among participants with the lowest scores on the test.   For example, in one study, participants were given a set of practice LSAT problems to complete. Participants who actually scored in the bottom 25% guessed that their score put them in the 62nd percentile of participants. Why Does the Dunning-Kruger Effect Happen? In an interview with Forbes, David Dunning explains that â€Å"the knowledge and intelligence that are required to be good at a task are often the same qualities needed to recognize that one is not good at that task.†Ã‚   In other words, if someone knows very little about a particular topic, they may not even know enough about the topic to realize that their knowledge is limited. Importantly, someone may be highly skilled in one area, but be susceptible to the Dunning-Kruger effect in another domain. This means that everyone can potentially be affected by the Dunning-Kruger effect: Dunning explains in an article for Pacific Standard that â€Å"it may be sorely tempting to think this doesn’t apply to you. But the problem of unrecognized ignorance is one that visits us all.†Ã‚   In other words, the Dunning-Kruger effect is something that can happen to anyone. What About People Who Actually Are Experts? If people who know quite little about a topic think they’re experts, what do experts think of themselves? When Dunning and Kruger conducted their studies, they also looked at people who were quite skilled at the tasks (those scoring in the top 25% of participants).   They found that these participants tended to have a more accurate view of their performance than participants in the bottom 25%, but they actually had a tendency  to underestimate how they did relative to other participants—although they typically guessed their performance was above average, they didn’t realize quite how well they had done. As a TED-Ed video explains, â€Å"Experts tend to be aware of just how knowledgeable they are. But they often make a different mistake: They assume that everyone else is knowledgeable too.† Overcoming the Dunning-Kruger Effect What can people do to overcome the Dunning-Kruger effect?   A TED-Ed video on the Dunning-Kruger effect offers some advice: â€Å"keep learning.†Ã‚   In fact, in one of their famous studies, Dunning and Kruger had some of the participants take a logic test and then complete a short training on logical reasoning. After the training, the participants were asked to assess how they’d done on the previous test. The researchers found that the training made a difference: afterwards, the participants who scored in the bottom 25% lowered their estimate of how well they thought they had done on the preliminary test. In other words, one way to overcome the Dunning-Kruger effect may be to learn more about a topic. However, when learning more about a topic, it’s important to make sure that we avoid confirmation bias, which is â€Å"the tendency to accept evidence that confirms our beliefs and to reject evidence that contradicts them.†Ã‚   As Dunning explains, overcoming the Dunning-Kruger effect can sometimes be a complicated process, especially if it forces us to realize that we were previously misinformed. His advice? He explains that â€Å"the trick is to be your own devil’s advocate: to think through how your favored conclusions might be misguided; to ask yourself how you might be wrong, or how things might turn out differently from what you expect.† The Dunning-Kruger effect suggests that we may not always know as much as we think we do—in some domains, we may not know enough about a topic to realize that we are unskilled. However, by challenging ourselves to learn more and by reading about opposing views, we can work to overcome the Dunning-Kruger effect. References †¢ Dunning, D. (2014).   We are all confident idiots.   Pacific Standard.   https://psmag.com/social-justice/confident-idiots-92793 †¢ Hambrick, D.Z. (2016).   The psychology of the breathtakingly stupid mistake.   Scientific American Mind.   https://www.scientificamerican.com/article/the-psychology-of-the-breathtakingly-stupid-mistake/ †¢ Kruger, J., Dunning, D. (1999).   Unskilled and unaware of it: How difficulties in recognizing ones own incompetence lead to inflated self-assessments.   Journal of Personality and Social Psychology, 77(6), 1121-1134. https://www.researchgate.net/publication/12688660_Unskilled_and_Unaware_of_It_How_Difficulties_in_Recognizing_Ones_Own_Incompetence_Lead_to_Inflated_Self-Assessments †¢ Lopez, G. (2017).   Why incompetent people often think they’re actually the best.   Vox.   https://www.vox.com/science-and-health/2017/11/18/16670576/dunning-kruger-effect-video †¢ Murphy, M. (2017).   The Dunning-Kruger effect shows why some people think theyre great even when their work is terrible.   Forbes.   https://www.forbes.com/sites/markmurphy/2017/01/24/the-dunning-kruger-effect-shows-why-some-people-think-theyre-great-even-when-their-work-is-terrible/#1ef2fc125d7c †¢ Wednesday Studio (Director) (2017).   Why incompetent people think they’re amazing.   TED-Ed.   https://www.youtube.com/watch?vpOLmD_WVY-E

International Monetary Fund Argentina Project And Its...

The International Monetary Fund Argentina Project and its problems and outcomes One project of the International Monetary Fund was a series of loans given to the country of Argentina in the 1990s through 2001. In the 1990s many investors and brokers looked to Argentina for investments as they rated its economy as one of the world s strongest (Blustein, 2003, Aug 3). It was at this time that Argentina first started to follow the International Monetary Fund formula for economic stabilization in development including reducing budget in balance of payment deficits, raising interest rates, reducing inflation, privatizing state assets, and reducing trade barriers and regulation on capital flows in and out of the country (Paddock, 2002, p. 158). These policies helped reduce the hyper-inflationary levels that Argentina had reached during the 1980s. This positive outlook may have prevented a needed change in the economic policies when the effects of the Mexican peso crisis in 1995 placed Argentina s economy in a brief recession. It wasn t until 1998 that Argentine po licymakers discussed the country s finances with a senior official of the International Monetary Fund who sounded the alarm that the country might be headed for an Asian style melt down. However despite the warning significant economic changes were not made, in part due to the confidence that money could be easily acquired from the International Monetary Fund (Blustein, 2003, Aug 3). In 1999 the financialShow MoreRelatedThe Crisis Of Bolivia As Economy1661 Words   |  7 Pageshas now an accumulated valuable amount of rainy-day fund of foreign reserves. Ana Corbacho, the International Monetary Fund’s chief of mission said of Bolivia’s growth: â€Å"Bolivia has in a way been an outlier. 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