A study that identified 12 novel
compounds that may prove valuable against new drug targets for leishmaniasis
and Chagas disease was not without complication. Here, we discuss the findings
but also the challenges the researchers reported in their hit-to-lead study.
With the recent news that
University of Bath researchers have identified promising cancer drug candidates
using high-throughput screening methods, it is clear that hit-to-lead processes
are successful in the drug discovery field.1
Hit-to-lead is a method used by
researchers to identify compounds that can eventually be used against
therapeutic targets. Using a high-throughput screening process, scientists can
identify promising lead compounds before developing them further into drug
candidates.2
Although researchers utilise this
method often, it is not without limitations. Here, we discuss how hit-to-lead
methods can be used in drug discovery and their associated challenges.
Identifying leads
Researchers can narrow down their
search for drug candidates using hit-to-lead techniques that reveal which
compounds are most active against a target. Our ability to generate biological
data libraries far exceeds our ability to test them,3 meaning that there is an
abundance of available data with no use, as of yet.
Scientists at Scripps Research
conducted a study that utilised the hit-to-lead process. They screened
approximately 150,000 compounds to discover which were most active against
leishmaniasis and Chagas disease targets. Whole-cell phenotypic assays were
used to test the molecules for leads against Leishmania donovani (the causative
agent of visceral leishmaniasis) and Trypanosoma cruzi (the causative agent
of Chagas disease).
Of note, it is important that researchers conducting high-throughput screens choose the most relevant in vitro assay to improve translation to in vivo and clinic results because significant differences may exist in drug sensitivity between different life-cycle stages of the parasite. In the present study, the researchers used high-throughput primary screens and then counter screened against the reduced set of screen hits to further down-select to higher priority compound hits. For L. donovani an additional assay to assess trypomastigote cidality was employed to further characterise the value of the compound hits
The outcome
The results of a drug discovery programme often rest upon the selection of appropriate lead generation strategies. The use of high-throughput screening in this study leant itself to the identification of eventual drug candidates, as it usually has a 50 percent success rate in delivering hits that can be clinically applicable.
The researchers reported that, of
the 21 compounds that were hits, nine were found to have known kinetoplastid
activity.
Overall, the researchers
successfully identified 12 novel chemotypes with low- to sub-molecular activity
against the targets. Of these, seven were active against both T. cruzi and L. donovani, The researchers say that these compounds may be
valuable tools to identify new drug targets.
Challenges of the research
Despite the successes of
hit-to-lead methodology in drug discovery, there are challenges to overcome.
One of the issues the authors
report is ensuring that the most relevant in vitro assay was selected to
improve translation to in vivo effectiveness. This is important to ensure the
effectiveness of the compound. However, the researchers also had to use assays
with sufficient throughput and cost-effectiveness. During hit-to-lead
optimisation, scientists look to improve target-binding qualities and maximise
their potency. However, this often leads to compounds with high molecular
weights, which may.
The researchers also commented on
their use of an axenic assay. Although an axenic assay has the advantage of
being a high-throughput assay, it also has drawbacks as axenic amastigotes are
different from intracellular amastigotes regarding protein expression and drug
susceptibility, permeability barriers and pH gradients. For example, compounds
affecting parasite-host infection cannot be identified with this assay and
permeability barriers and pH gradients introduced by the phagolysosome are not
recapitulated in the assay media.
A further challenge was ensuring
that the in vitro assays were staged within the conditions of the disease,
including parasite lifecycle stage and relevant host cells. Otherwise, the
molecules would not replicate their effectiveness when applied to the disease
in clinical trials.
Of note, for the L. donovani
screening, compound availability restrictions limited profiling of all
chemotypes.
Therefore, despite facing several
challenges during this study, the researchers were still able to identify
leads.
Conclusion
This study successfully
identified and characterised 12 novel chemical series, seven of which were
active against both T. cruzi and L. donovani and may prove valuable for
identifying new drug targets. However, it was not without its challenges;
correct assay selection, assay handling, recreating disease conditions and
having enough compounds to screen were all complications and limitations the
researchers faced.
The authors say that they have
disclosed these hit structures and associated activity with the goal to
“contribute to the drug discovery community by providing unique chemical tools
to probe kinetoplastid biology and as hit-to-lead candidates for drug discovery.
From source:
https://www.drugtargetreview.com/article/50524/the-challenges-of-hit-to-lead-in-drug-discovery/
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