In search of (un)desired side effects
Morphological fingerprinting could help identify side effects and new bioactive compounds in drug discovery

Date:
January 27, 2022
Source:
Max Planck Institute of Molecular Physiology
Summary:
Pharmaceutical researchers speak of a hit when they come across
a promising substance with a desired effect in early drug discovery.

Unfortunately, hits are rarely bull's-eyes, often showing
undesirable side effects that not only complicate the search for
new hits, but also the subsequent development into a drug. A new
study could now help to better identify one of the most frequently
observed side effects already in early drug discovery, but also
to find new bioactivities.



FULL STORY ========================================================================== Pharmaceutical researchers speak of a hit when they come
across a promising substance with a desired effect in early drug
discovery. Unfortunately, hits are rarely bull's-eyes, often showing undesirable side effects that not only complicate the search for new hits,
but also the subsequent development into a drug. A new study by Slava
Ziegler and Herbert Waldmann from the Max Planck Institute of Molecular Physiology in Dortmund could now help to better identify one of the
most frequently observed side effects already in early drug discovery,
but also to find new bioactivities.


==========================================================================
The most commonly used cancer drugs contain active substances that
manipulate the cell's cytoskeleton by binding to microtubules. This
can disrupt cell division as well as impair other essential processes,
and leads to cell death.

Such an effect is of course not desirable for other therapies. However, microtubules' surface has many deep binding pockets that makes them particularly susceptible to modulation by a wide variety of chemical
substances with diverse chemical scaffolds.

Drug discovery is biased In the search for and development of new active substances, the study of known side effects plays a crucial role,
especially when one considers that about 13 years and more than one
billion US dollars are needed to develop a new drug.

Although there are already standardized test procedures (screens)
for identifying undesirable side effects, they by far do not cover all
targets in cells, often do not correctly reflect the cellular context or targets could be overlooked, e.g. binding to tubulin. Thus, drug search
is always biased to a certain extent.

Painting in cells A team led by Slava Ziegler and Herbert Waldmann
used a new strategy to reliably detect side effects, such as the
disruption of microtubules, at an early stage of the search for
bioactive compounds. To do this, the researchers employed the so-called
"Cell painting" approach. Here, several functional areas of the cell
are stained and then examined microscopically for changes after the
addition of chemical substances. This enables recording hundreds of
cellular parameters in a single morphological fingerprint. If one detects similarity of this fingerprint to those of known reference substances, conclusions about the effect of the unknown substance can be drawn. The
value of this approach lies in the possibility of creating fingerprints
for thousands of substances in a high-throughput process. This way,
the researchers revealed that more than 1% of about 15,000 studied
substances had a tubulin-modulating effect. Among them was also a large
number of known reference substances for which an influence on tubulin
was previously unknown.

Useful add-on for drug development "Reference substances play an
essential role in the interpretation of a screen, so they should be
carefully evaluated and tested. The compounds identified by the Cell
painting show a wide variety of chemical scaffolds and even small chemical modifications can have a dramatic impact on the tubulin-binding properties
of a compound. This risk is ubiquitous, especially during the compound optimization phase, where existing atoms are exchanged or removed and
new atoms are added in order to improve the pharmacological properties.

Additional morphological profiling during the search for hits and their optimisation could not only help unmask side effects such as tubulin
modulation early on, but also identify desired and new bioactivities,"
says Slava Ziegler.

"Moreover, this approach could save time and money as
it helps to early assess whether a promising substance
has what it takes to become a useful compound or not." ========================================================================== Story Source: Materials provided by Max_Planck_Institute_of_Molecular_Physiology. Note: Content may be edited
for style and length.


========================================================================== Journal Reference:
1. Mohammad Akbarzadeh, Ilka Deipenwisch, Beate Schoelermann,
Axel Pahl,
Sonja Sievers, Slava Ziegler, Herbert Waldmann. Morphological
profiling by means of the Cell Painting assay enables identification
of tubulin- targeting compounds. Cell Chemical Biology, 2021; DOI:
10.1016/ j.chembiol.2021.12.009 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220127104249.htm

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