Computer software is ubiquitously present in our everyday life and has all sorts of practical applications from self-driving cars to Go-playing programmes, like AlphaGo, which is able to defeat the human masters of the game. It is, therefore, of little surprise that computers play an increasingly critical role in the discovery of new pharmaceutical drugs.

Drugs work in many different modes of action. A drug binds to a biological receptor, mostly proteins, to either produce a biological response (agonist) or to inhibit the biological function of the receptor (antagonist). For example, Oseltamivir (you may be more familiar with its trade name, Tamiflu) is an antagonist drug which blocks the function of a viral protein called neuraminidase, which is involved in the escape of the influenza virus from the host cell after replication.

Most traditional drugs are (relatively) small molecules with low molecular weight which result in some biological effect or response. The computational search of a library of these ‘small-molecules’ to find the biological active one (not all of the molecules in the library may have an effect) is called Virtual Screening.

These libraries typically range in the millions of different molecules, and since most molecules are flexible, each molecule may also have many different 3D shapes making this a big data problem. The idea is to shift expensive and time-consuming in vitro (in a test tube) and in vivo (in a living organism) experiments, to in silico (in a computer).

Virtual screening is divided in two main approaches: ligand-based or structure-based. In ligand-based virtual screening a known molecule that is biologically active is used to guide the search for other molecules with ‘similar’ properties. The reasoning here is that ‘similar’ molecules should exhibit similar biological behaviour, including activity. The problem with this approach is that similarity is a loosely defined concept. In structure-based virtual screening a small molecule is docked to a protein using the complementary features between the small molecule and the protein (e.g. a negative charge on the protein found in close proximity to a positive charge on the small molecule).

Computational techniques allow us to study many different aspects of pharmacological importance – e.g. how strongly does the small-molecule bind to the biological target of interest, or what is the safety profile of the molecule. The output of a virtual screening experiment is a ranked list of library molecules. The ranking reflects the probability of the small molecule having biological activity. Depending on the availability of resources, a number of top-ranking molecules are synthesised (produced) in a chemical laboratory. These are then passed on to wet-lab molecular biologists who can test activity of these molecules to confirm the results of the computational studies.

Virtual screening allows us to increase pharmaceutical productivity, a much needed improvement given the concerning growing resistance to many current medicinals. Computational drug discovery is an area of active research under study at the newly-inaugurated Centre for Molecular Medicine and Biobanking at the University of Malta.

Did you know…

• “Sphenopalatine ganglioneuralgia” is the scientific term for brain freeze

• Summer is their season, but house flies have a lifespan of only two weeks

• The average person accidentally eats 430 bugs each year of their life. Time to become vegetarian...

• Starfish have no brains

• The average growth of hair is just half an inch per month, which makes us wonder why we need a monthly visit to the hairdresser

For more trivia: www.um.edu.mt/think

Sound bites

• Sharks have a sixth sense that helps them locate prey in murky ocean waters. They rely on special pores on their heads and snouts, called ampullae of Lorenzini, that can sense electric fields generated when nearby prey move. The pores were first described in 1678, but scientists have not been sure how they work. Now, the answer is a bit closer. The pores, which connect to electrosensing cells, are filled with a mysterious clear jelly. This jelly is a highly efficient proton conductor. In the jelly, positively charged particles move and transmit current. This jelly is the best biological proton conductor discovered so far.

• Sharks can also see in murky water because of a special feature that makes their eyes more sensitive to light. A membrane in the back of the eye called the tapetum lucidum reflects sunlight back into the eye so the shark can make more use of what little light there is. Because of the tapetum lucidum, a shark can see about 10 times better than a human can in dim light.

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