Despite the current hype around so called “advanced therapies”, which range from gene editing to cell therapies, and the inexorable advance of biologic therapeutics such as monoclonal antibodies, even in 2022 the majority of drugs in development and reaching patients are still small organic molecules.
From enzyme inhibitors to receptor antagonists, allosteric modulators to suicide substrates, small molecules can modulate protein function in uniquely diverse ways. But finding the right molecule has never been easy.
For centuries medicines were found using phenotypic screens: chewing willow bark had analgesic properties and fractionation of the willow yield the active ingredient, salicylic acid, which became aspirin. Its an effective search strategy because you are using a direct measure of the outcome you want to achieve to guide the search. But its throughput is very limited, since most phenotypic assays are highly burdensome.
Low throughput is an acceptable characteristic of search when you already have a good starting point (which is why it was able to guide the isolation of an active ingredient from a mixture, for example). What happens, though, if you don’t have any kind of starting point to hand?
Starting in the middle of the 20th Century, molecular science began to provide the answer. Looking for molecules that bind to a particular molecular target is much quicker and easier than assessing function on a whole organism or even cultured cell type. And through to the end of the 20th Century our industry got progressively quicker and quicker as high-throughput screening (HTS) became the go-to technology for finding “hits” (the first molecule with a particular target binding profile).
HTS yielded the chemical starting points for many of today’s established medicines, from antacids to blood pressure controlling drugs. But it has its limitations too. While the throughput might be a million-times higher than a phenotypic screen, it is still limited to testing a tiny fraction of all available compounds (its practicable to screen millions of compounds through a typical HTS assay but not billions or more) – and of course you are limited to compounds that you have a physical supply of. Constructing larger and more diverse screening libraries was, for a while, the competitive advantage of the largest pharma companies.
Around the turn of the century, increases in computing capabilities opened up an opportunity to expand the search space by several more orders of magnitude, with the arrival of in silico screening. Rather than physically test a library of compounds for binding to a target, you could now model the …
Ask star antibody developer and Medicxi partner Kevin …More
The Cambridge Partnership is the only professional services company in the UK exclusively dedicated to supporting companies in the biotechnology industry. We specialize in providing a “one-stop shop” for accountancy, company secretarial, IP management and admin services. The Cambridge Partnership was founded in 2012 to fill a gap. Running a biotechnology company has little …