Structural Biochemistry/Medicine & Drug Design

Structural biochemistry has become vital in the development of new medicine. Medicines are now being studied with the tools of biochemistry such as X-Ray Crystallography. Modern methods of biochemistry are usually used to understand the enzyme structure by understanding the folding and bending of the structure. Enzymes are biological catalysts that increase the rate of reactions by lowering the energy required to form the transition state of the reaction. Enzymes are typically made of a protein or of a group of proteins. Understanding protein tertiary and quaternary structure can tell scientists how a medicine does its job. Medicinal scientists have made use of the structure of enzymes to develop new drugs from old drugs. Drugs cross the cell membrane by first letting a message or drug encounter the outside of a cell and make it contact the receptor. Then, a connecting transducer passes the message inward, which finally gets signal amplified, prompting the cell to complete its function. Many scientists believe that in 10 to 20 years the field of medicine will be drastically different especially in the manner in which doctors prescribe drugs to their patients. Currently, drugs are administered based on average dosages that have been determined based on the size of an individual and their age. The effectiveness of a drug is depicted on a graph called "dose-response curves". These graphs are created to show a relationship between the desired effect of the drug and the amount of the drug administered. Typically there is another curve displaying the amount of drug that causes maximal side effects. Pharmacologist uses this data to first prove that the drug is effective and then use it to provide doctors with a safe dosage range to the drug to their prescribe patients.

Good medicine design relies on many variables which include its absorbency into the body, its activity of working correctly, how long it will be active, and its toxicity. Knowledge of the structures of target molecules allows for a more direct path of finding a molecule that will fit the shape of the target perfectly, creating the most useful drug. Therefore, molecules that obviously don’t fit the target will automatically be known to not work in its present state and should be disregarded or reconfigured.

In the future the goal is to provide tailor-made drugs for each individual. The idea is that a drug will be designed based on the individuals DNA sequence which describes the individual’s personal biochemistry. The desire behind this is for a drug that is more effective and that causes fewer side effects. The desire for tailor-made drugs was not even a realistic venture less than a decade ago, but with the extreme advances in DNA sequencing this dream could become a reality in a couple of decades.

Nanomedicine

The number of people diagnosed with cancer every year continues to be extremely high. Scientists have been diving into the relatively new field of nanoparticle based drug design in hopes of making more effective anti-cancer drugs. Current chemotherapy techniques are effective at destroying cancer cells, but also are toxic to healthy cells that are essential to the body.

Nanomedicines can be chemically engineered to specifically target cancer cells without obtaining the harsh effects of chemotherapy. Different parts of nanoparticles can be modified in order for the medicine to be able to enter into the bloodstream of a person and target the cancer cells without being broken down by the liver. Some nanoparticles are packaged in lipsomes, while many new compounds are delivered through biodegradable polymers. For example, polyethylene glycol (PEG) is a biodegradable polymer that protects the nanoparticles from being visible to immune cells, which helps the medicine to reach its target destination. Some of the nanoparticle shells are made with sugars such as “cyclodextrins,” but are covered in PEG. The hydroxyl groups on the sugars make the compounds soluble in water, yet easy to disintegrate in acidic environments in order to release the drug. Approximately twelve nanoparticle based anti-cancer drugs are in clinical trials and are waiting to be approved to be distributed to the world.

Nanoparticles are also being used to carry RNA molecules to target cancer cells through antisense therapy. If the RNA molecules are able to reach the cancer cells with the help of nanoparticles, then they can have the ability to bind to the cancer cells’ own RNA and inactivate certain genes. For example, antisense therapy can halt the production of proteins in cancerous cells, which helps stop the overall growth of the cancer.

Natural substances used for medicine

Natural products have assisted medicine in many different ways. It is found that natural products contain many disease and cancer fighting properties. They can be synthesized into a compound to used in medicine. For example, small plant like organisms such as cyanobacteria that reside in wet environments have these powerful cancer and bacteria killing sources. A professor named Dick Moore from the University of Hawaii at Mano was able to devise a way to find compounds that was especially good against slowly developing and difficult to treat tumors. An example of this was a compound called cryptophycin-8, which could rip apart the cellular scaffolding in a wide variety of solid tumors used in mice.

Also there has been a huge variety of substances and chemicals in the sea that have immensely powerful cancer and disease fighting capabilities. This has propelled scientists to develop new ways to synthetically create compounds that are derived from these natural products in the sea. The goal of making a good drug is the result of scientists playing around with natural compounds to extract their medicinal properties but taking away the parts that causes unwanted side effects.

Cordyceps militaris in Sphagnum near Suileag Bothy. It is an example of a natural substance that has medicinal properties - geograph.org.uk - 1132170

Medicines can potentially be made from even the most strange materials. For example, chemist Jim Gloer from the University of Iowa has been researching for ways to use a fungus that lives in animal feces to create antibiotics. These organisms are called coprophiles, which means feces loving have a lot of potential for developing useful drugs. These fungi release chemicals that kill off neighboring species, which is what biomedical researches and scientists want so that they can develop medicines that kill unwanted fungus that are hazardous to humans.

Biochemistry of disease

According to World Health Organization’s International Statistical Classification of Diseases and Related Health Problems, the current definition of disease include in 22 chapters. These are divided into over 2500 blocks which give us thousands of phenotypic descriptors of disease.

Biochemists are focused on understanding structure of molecules and process in which these molecules come together. Understanding these processes also give us a chance to “correct” them when they go wrong. But there are many different keys that come into consideration to acquire therapies. For example in the case of drug development, it is the combination of the knowledge of chemistry, biochemistry, pharmacology, toxicology, etc. This is obviously not a predictable process because the high failure rate of experimental drugs.

Biochemists look into biochemistry of disease to study important points which they can use to develop new disease therapies. These major points in the field are biosynthesis of unusual microbial metabolites, structure-based design of inhibitors, mechanisms or drug resistance, and the role of protein folding dynamics that can lead to inappropriate protein folding and aggregation.

References

Service, Robert F. "Nanoparticle Trojan Horses Gallop From the Lab Into the Clinic." Science 15 October 2010: 314-315

Davis, Alison. "The Chemistry of Health." 'NIGMS August 2006: 36-42. http://publications.nigms.nih.gov/chemhealth/coh.pdf

In the field of Biochemistry, several important themes contributing to drug design should be evaluated in order to cure diseases, including structure-based design of inhibitors, mechanisms of drug resistance, biosynthesis of unusual microbial metabolites, and the role of protein dynamics that can lead to protein-misfolding.

The Biochemistry of Disease: Desperately Seeking Syzygy Annual Review of Biochemistry Vol. 78: 55-63 (Volume publication date July 2009) DOI: 10.1146/annurev-biochem-120108-082254 John W. Kozarich http://www.annualreviews.org/doi/abs/10.1146/annurev-biochem-120108-082254?journalCode=biochem