Modelling the molecular world we live in, one system at a time

 Imagine being able to see our world at a molecular level. Wouldn't that be amazing? But if we could, would it be useful?

Most of traditional science is built on experiments and the results are explained using theoretical knowledge. Traditionally, drugs were discovered when people tried out new herbs or combinations of herbs and found that it made them feel better. As technology and science has progressed, traditional herbs have been purified to isolate and characterize the active substance. Sometimes, as in the case of Aspirin, the active substance has then been synthetically enhanced to increase the effect of the drug. Although drugs have been used for centuries, it doesn't mean that scientists know how they work. Knowing that a drug works is not the same as knowing how it works. However, by using new technology, such as modern high-performance computers and physics-based theoretical models, we can make computer simulations that can be visualized to improve our understanding of the drugs - at the molecular level.

Although computer simulations look nice, how can we be sure that what we see is what is actually happening in a real biological system?

The accuracy of computer simulations can be assessed by comparing the computational results with experimental data. When experimental and computational data correlate, the validated model can be used to make new predictions. Computational chemistry simulations can give us many different outputs, such as UV and NMR data. Computational biology simulations, such as molecular dynamics and Monte Carlo simulations, can give us potential energies and structural information of larger systems, such as proteins and nucleic acids.

There are plenty of interesting systems to study. How do you choose the most interesting one?

Choosing an experimental system can be very easy, but it can also be very difficult. Many factors should be considered before settling on one. One important factor to know before starting is how much previous research has been made. If everything is already known about a system it might not be very interesting to study. On the other hand, if very little is known about a system, it might be difficult to validate your results. Furthermore, will the study of your choice of system bring you one step closer to answering your research question? What do you want to know, and is the system you chose a suitable system for finding that out?

A day when you learn something new is not a wasted day

Cyclooxygenase (COX) 1 and 2

Non-steroidal anti-inflammatory drugs (NSAIDs) are the second most prescribed class of drugs in Sweden today, after antibiotics. While antibiotics are only sold in pharmacies as prescription drugs, NSAIDs can be bought either with a prescription or over-the-counter (OTC) in pharmacies and retail shops. In 2016 NSAIDs were prescribed to more than 1 million patients in Sweden and more than 300 million defined daily doses (DDD) were dispensed in a population of 10 million.

NSAIDs inhibit the physiological responses of pain, inflammation and fever by inhibiting the enzymes cyclooxygenase (COX) 1 and 2. These are isoforms of each other. The first-generation, or traditional, NSAIDs bind to the two isoforms non-selectively. They have side-effects including gastroin-testinal bleeding and renal problems. Nonetheless, they are indicated in medical conditions including arthritic conditions, acute musculoskeletal dis-orders, and other painful conditions resulting from trauma, including fractures and minor surgery.

The second-generation NSAIDs, the coxibs, are selective only for COX-2. These have fewer of the side-effects associated with traditional NSAIDs, but increase the risk of myocardial infarctions due to thrombosis. However, apart from the anti-inflammatory and analgetic properties, these drugs also have an inhibitory effect on angiogenesis, a useful property in cancers therapies.

To counteract the side-effects of first and second generation NSAIDs, third generation NSAIDs could be developed. Minimization of side-effects and efficient targeting of the desired symptoms could be achieved by improving the NSAID affinities and tailoring their ratio of binding to COX-1 and COX-2. However, to design drugs with these properties it is important to understand the binding modes and mechanisms of existing NSAIDs.