Drug Discovery


Chemical space, high throughput screening and the world of blockbuster drugs


We are constantly told that if a high throughput screen does not identify hit(s) then blame it on the compounds in your library. The community has accepted this notion and unleashed a chemical space exploration through the use of novel or pre-existing synthetic chemistries to supposedly generate better ones. Its efforts, unfortunately, did not result in a giant step for mankind to combat disease, rather this article would argue that we are still at the same start-up line as we were 30 years ago and should perhaps listen to the call of nature to revive natural product research as it has amassed the most diverse libraries over the past millions of years.


T


he most memorable and thought-provok- ing editorial was by Roger Lahana in 1999 on combinatorial chemistry (CC) and high throughput screening (HTS)1; and appropriately entitled ‘How many leads from HTS?’ It was dur- ing the phase of heavy investments by large Pharma and biotech companies alike in CC, automation, novel assay technologies and HTS as the only way forward to discover drugs and reduce overall cost and time. This revolutionary phase became obsessed with numbers and turned HTS into a numbers generator; where companies were viewed as successful if they had assembled multi- million compound libraries and generated several million data points per year. Not surprising at all that when some of the attendees of the CHI High- throughput technologies meeting, back in May of


Drug Discovery World Spring 2013


1999 in Washington DC (USA), were asked the question of how many leads have we got from CC and HTS so far? Their overwhelming response was none!1. A few months later, a response to Lahana’s editorial was published2. Its author claimed that the purpose of screening is not to identify the mol- ecule, rather to identify good leads from which clinical candidates could be synthesised using rational/classical chemistry approaches; they fur- ther added that if screening fails to identify good leads, then either the assays were no good or the quality of the library was poor2. Surprisingly, Fox and colleagues in 2001 reported what was thought to be the earliest signs of success of HTS as evident with up to 46 drug candidates apparently obtained from HTS over an eight-year period (1990 to 1997), as recorded through their worldwide survey


By Dr Hakim Djaballah


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