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Structural Biology and Drug DesignBY: Geetanjali Murari | Category: Bioinformatics | Submitted: 2013-03-18 23:07:50
Article Summary: "The field of bioinformatics has made the tiring task of drug designing quite easy and time saving. The example of designing drug for HIV protease target is also mentioned in the given article. Through this article I have illustrated the drug-receptor interactions, modelling of 3D molecular structure of proteins..."
Traditional drug design is a serendipitous procedure where scientists identify new drugs either by fiddling with the existing drug or by testing thousands of compounds in a laboratory. The modern technological developments led to the emergence of techniques like high throughput screening, combinatorial chemistry, micro-array, etc which have accelerated the identification of new potential leads. These techniques by themselves suffer from the lacunae that there is very little understanding of the specific drug-receptor interactions.
The structure based drug design involves the integrated applications of traditional biology and medicinal chemistry along with an array of advanced technologies like X-ray crystallography, computer modelling of molecular structures and protein biophysical chemistry to focus on the 3D molecular structure and active site characterization of the proteins that control the cellular biology.
In order to bring the drug into the market a typical time frame of 12 to 15 years and a financial investment of about 5-7 billion dollars is required. Various logical steps and approaches are involved in the structure based drug design to cut down the cost and turnover time.
Each one of us has several different types of proteins in our body. Proteins are made of amino acids hooked end-to end like beads on a necklace. Even spider webs and silk fibres are made up of the strong, pliable protein fibroin which is stronger than a steel rod and yet most elastic and flexible. The light of fireflies is due to the protein called luciferase. To become active, proteins must twist and fold into their final or native conformation. The final shape enables proteins to accomplish their function in our body. Some proteins are synthesised at a constant rate, while others are made only in response to the requirement of organisms. Some of them perform unique vital functions and some are specific to a certain class of organisms.
The initial targets for structure based drug design are selected on the basis of their involvement in the biological pathways integral to the course of a disease. The target produces the protein in sufficient amount to study cloning, expression and purification. The precise knowledge of the 3D structure of the protein, NMR or X-Ray Crystallography serves as a blueprint for the drug design of a lead compound. Around 80% of the known protein structures are determined using X-ray crystallography. Over 50% of the proteins encoded or predicted by the genomic sequencing have unknown functions. The determination of 3D structure along with other experimental approaches like gene knockout, etc helps in the identification of the functions of the novel drug targets.
In the human body, proteins are present in different shapes and sizes as they have diverse functions in our body. The studies of these different shapes of proteins help us in understanding the disease caused by abnormal proteins. For example, Troponin C triggers muscle contraction by changing shape. The protein grabs calcium in each of its fists then punches other proteins to initiate the contraction. Antibodies are the immune system proteins that rid the body of foreign material, including bacteria and viruses. The two arms of the Y-shaped antibody bind to a foreign molecule. The stem of the antibody sends signals to hire other members of the immune system. Collagen in the cartilage and tendons gain its strength from its three stranded rope like structure.
The 3D structure of a protein i.e. the target is like a lock. With the molecular modelling software, the researchers can make a mold of the lock and of the natural molecule, called a substrate that fits into the lock. An array of small molecules are scanned or docked against the protein structure. Once the shape and chemical properties of the target molecule are identified, structure based drug design strategies help us approach the job more rationally. The drug molecules with distorted shapes or properties can be discarded. The rest identified molecules which are predicted to have a good affinity are assayed after synthesis. X-ray crystallography reveals the exact nature of the 3D interaction. This information can be used to rapidly identify the inhibitors possessing better efficacy using both in-silico approaches and synthetic approaches. Thus, the structure based approaches help the design of new modified compounds to overcome its deficiencies without interfering with the compound's ability to interact with the active site of the target protein.
Although, researchers have yet not found a cure for AIDS, structural biology has greatly enhanced the study of HIV-AIDS and has played a key role in the development of drugs in the treatment of the deadly disease. Human Immunodeficiency Virus belongs to the retrovirus family that carries RNA as their genetic material which is transcribed into DNA with the help of reverse transcriptase. When HIV was identified as a retrovirus prior work gave the researchers an immediate start. The viral proteins that had already been identified became the initial drug target. In 1989, the X-ray crystallographic structure of HIV protease was determined. The scientists hoped that by blocking this enzyme (HIV protease), they could prevent the virus from spreading in the human body. The structure was a reference to determine the types of molecules that might block the enzyme. These molecules can be retrieved from chemical libraries or can be designed virtually on a computer screen and then synthesized in a laboratory. Many dimeric proteins have two active sites. HIV protease has one site made up of both subunits. If this single active site is blocked with the small molecule, the whole enzyme could be shut down and theoretically the virus could be hindered from spreading inside the human body. Several pharmaceutical and biotech companies started designing the target drug that had the same two-fold symmetry as HIV protease by using the shape of the enzyme as a guide. In Abott laboratories they conceptually took the enzyme's natural substrate chopped these molecules in half, rotated them 180 degrees and glued the two identical halves together. The first such molecules fit perfectly into the active site of the enzyme and were also an excellent inhibitor; it prevented the HIV protease from functioning normally. But it wasn't water soluble so couldn't be absorbed by the body and would never be effective as a drug. Abott laboratories continued to modify the structure of the molecule to improve its properties. They eventually ended up with a molecule called as Norvir. Between Dec, 1995 and March, 1996, FDA approved the first three HIV protease inhibitors, i.e., Hoffman-La Roches' Invirase TM, Abott's Norvir TM and Merck and co., Inc.'s Crixivan.
The structure based drug design has an important role in the target identification and characterization. It reduces time and money in the drug development. The development of HIV protease inhibitor is the biggest challenge met with the help of structure based drug design. India has a rich knowledge of traditional remedies of varied efficacy for several ailments which can be exploited. We have to identify the target acted upon by the identified molecules and apply the structure based rational optimization techniques to refine and improve the traditional remedies. Biological molecules are much more complex than just lock and keys and human bodies can react to theses drug molecules in numerous unpredictable ways. Thus, the journey from the drug design to the drug marketing is complex and difficult.
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