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Yearly Archives: 2022

July 19, 2022 no comments

How to find a drug: the past, present and future of small molecule drug discovery

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 …

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February 7, 2022 no comments

Re-Imagining Med Chem Strategies: the Tyranny of the n+1 Compound

Finding small molecule drugs is much harder than …

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May 24, 2021 no comments

Why Small Beats Big: the Hidden Cost of Too Many Voices

The coronavirus pandemic has taught us a lot …

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February 16, 2021 no comments

The history – and the future – of antibody discovery technologies

Monoclonal antibodies are now well-established as a mainstay …

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January 8, 2021 no comments

Why Sarepta’s most recent failure in DMD was entirely predictable

Yesterday, Sarpeta (NASDAQ: $SRPT) announced that its gene …

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January 2, 2021 no comments

One dose or two? What the debate about COVID vaccination teaches us about science – and its limitations

Over the past week a furious debate has …

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November 9, 2020 no comments

The Hidden Superpower of Strategic Focus

The first death unequivocally caused by COVID was reported to …

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April 14, 2020 no comments

COVID19: Serology is harder than it looks

More than a month after the World Health …

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January 24, 2018 no comments

The Cult Of DNA-centricity

  Understanding the role of DNA in biology is …

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October 21, 2014 no comments

D&D On R&D – Lessons For Pharma From The Dungeon Master

The discovery and early development phases of pharmaceutical …

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