Biophysics and fragment-based
drug discovery go together like Nutella and strawberries. Indeed, SAR by NMR
ushered in the dawn of fragment-based methods two decades ago, and most
fragment-based programs today make use of NMR, SPR, and/or ITC – not to mention
X-ray crystallography. Interestingly, the same is not necessarily true for
high-throughput screening (HTS) programs. In a recent paper in Drug Discovery Today, Rutger Folmer
makes a strong case for engaging biophysics early and often in HTS. He bolsters
his argument with more than 20 examples from internal programs at AstraZeneca.
The first descriptions of using
NMR to profile HTS hits were not published until several years after SAR by NMR,
but they were rather shocking, with up to 98% of hits failing to confirm. Nor
is this merely a historical problem, as discussed here. Aggregators, redox cyclers, generically reactive covalent modifiers – all of these are problems
not just in fragment screening but in HTS as well. Sometimes the most potent
hits are artifacts, particularly for more difficult targets. The key to
triaging out pathological actors is to assess binding and not rely solely on
inhibition.
That means bringing biophysics into
hit profiling at the earliest stages, before trying to optimize fruitless hits.
As Rutger points out, it is often difficult to rally colleagues to look at less
active molecules after they have wasted months pursuing more potent dead ends.
And biophysics can make an impact
even before running screens.
Profiling published tool compounds or in-licensing opportunities with biophysical
techniques can reveal unwelcome surprises. Testing the output of early HTS pre-screens
(7000-10,000 compounds) before a full HTS (2 million compounds at AstraZeneca)
can reveal whether an assay is particularly susceptible to false positives. In
some cases this can result in reconfiguring the assay, for example by choosing
a different detection technology or modifying the protein construct.
Posts
1 comment:
I never cease to be amazed that pharma has created and uses massive sets of screening compounds containing aggregators, redox cyclers, generically reactive covalent modifiers – & then after screening goes through the process of weeding these out. Am I the only one that finds this bizzare? And yet like it or not HTS is the first port of call for a great proportion of drug discovery efforts. There are alternatives. Even more cost effective ones but it seems they are underused because often times limited resources drive conservatism. As someone one said to me nobody ever got fired for following the industry norm. Gaps in the knowledge of how to pursue hits from alternative approaches do not help the case for alternatives.
Post a Comment