It’s a Question of Balance – Broadening Concepts of Drug Discovery

Professor Colin Suckling discusses drug discovery and how a linear approach is no longer relevant…

Since the 1960s it’s been accepted that the way to discover new drugs is to take a well-characterised disease with a good understanding of the biological cause of the disease. This would require the identification of a functional biological unit such as a protein that was critical to the process underlying the disease. The candidate drug was then designed and tested to engage with this single functional biological unit, essentially switching it off or on as required thereby treating the disease. We usually refer to the functional biological unit as the drug target. The single target, single drug, single effect paradigm has been remarkably successful and with refinement and elaboration became the conventional approach to small molecule drug discovery in the pharmaceutical industry. For example, penicillins and cephalosporins are effective antibacterial drugs because they block the assembly of bacterial cell wall without which the bacteria cannot survive. Statins reduce cholesterol levels because they prevent the biosynthesis of cholesterol by blocking its biosynthesis at a specific step. There are dozens of other examples. It’s a logical, linear sequence but it promotes a rigid sequential process for drug discovery.

When in the 1990s it began to emerge that most of the easy single targets for new drugs had been hit a great deal of effort went into the discovery of new, more arcane targets, often with the assistance of sophisticated genetic approaches. Many reports were highlighted in the popular media when a scientific team discovered that a particular gene was connected in one way or another with a disease. This would lead to a cure in 10 years (or so) the popular science piece would run. It hasn’t happened. One reason is that complex diseases in which the balanced function of the body is disturbed cannot be associated with linear processes. This is particularly the case with diseases of the central nervous system and the immune system in which interacting networks of biological systems play key roles, now reasonably well but still imperfectly understood. Let me illustrate this with two projects to which I’ve contributed some chemistry and in doing so note some points of relevance to drug discovery today that these studies raise in my mind.


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