How to find anti-cancer agents

Date:
April 12, 2022
Source:
Paul Scherrer Institute
Summary:
Researchers have developed a novel substance that disables a
protein in the cell skeleton, leading to cell death. In this way,
substances of this type can prevent, for example, the growth of
tumors. To accomplish this, the researchers combined a structural
biological method with the computational design of active agents.



FULL STORY ========================================================================== Researchers at the Paul Scherrer Institute PSI and the Italian Institute
of Technology IIT have developed a novel substance that disables a protein
in the cell skeleton, leading to cell death. In this way, substances of
this type can prevent, for example, the growth of tumours. To accomplish
this, the researchers combined a structural biological method with the computational design of active agents. The study appeared in the journal Angewandte Chemie International Edition.


==========================================================================
The cell skeleton, also called the cytoskeleton, pervades all of our cells
as a dynamic network of thread-like protein structures. It gives cells
their form, aids in the transport of proteins and larger cell components,
and plays a crucial role in cell division. The central building block
is the protein tubulin. It arranges itself into tube-shaped structures,
the microtubule filaments.

Active agents that attach to the cell skeleton are among the most
effective drugs against cancer. They block tubulin, and thus prevent
cell division in tumours. PSI researchers, in collaboration with the
Italian Institute of Technology in Genoa, have now developed another
potent substance that disables tubulin. The have dubbed it 'Todalam'.

"Todalam prevents tubulin from arranging itself in the form of
microtubule filaments," explains first author Tobias Mu"hlethaler, who co-designed and studied the substance as part of his doctoral research
at PSI. "The protein remains as if frozen in a structure that doesn't
fit into microtubules." Rationally designed There are typically two
different approaches for developing new drugs: Researchers can test an
enormous number of molecules to fish out the ones that appear promising,
or they can specifically design chemical molecules that achieve the
desired effect. The PSI and IIT researchers chose the second path,
which is often more difficult.

In doing this, they were able to build on their own groundwork, research
in which they had already located places in tubulin where molecules can
dock especially well. These are the so-called binding pockets, of which
they found 27. In addition, the researchers identified 56 fragments
that bind to these sites. This work, too, had been published earlier in Angewandte Chemie International Edition.

In the current study based on this prior work, the researchers
initially selected a newly discovered binding pocket on tubulin. They
used computational design to combine the structures of three molecular fragments, which preferentially dock at this point, into a single chemical compound, and then they synthesised it in the laboratory. "By combining
the three fragments into one molecule, we hoped to enhance the effect,
since the new molecule fills the binding pocket better," says Michel
Steinmetz, head of the Laboratory of Biomolecular Research at PSI.

Using measurements at the Swiss Light Source SLS, the researchers checked
to see how well the molecule actually fits into the binding pocket. In
two further cycles, they improved the substance until they arrived at
Todalam. "With relatively simple chemistry, we managed to get to a potent compound," proudly says Andrea Prota, a scientist in the Steinmetz group
who collaborated closely with Mu"hlethaler.

Simple chemical structure In cell cultures, the researchers demonstrated
that Todalam kills cells. No wonder, since tubulin is essential for
life. "The better a substance binds to a critical site in tubulin, the
more toxic it is for the cells," Steinmetz explains. That makes Todalam
a promising starting point for developing a drug.

The cytoskeletal inhibitors currently in clinical use are natural
substances with large, complex structures and are therefore difficult to synthesise. The newly developed compound Todalam, on the other hand, can
be produced in a simple chemical synthesis in the laboratory. "That also
means that the compound could be produced in large quantities relatively easily," Steinmetz stresses.


========================================================================== Story Source: Materials provided by Paul_Scherrer_Institute. Original
written by Brigitte Osterath. Note: Content may be edited for style
and length.


========================================================================== Journal Reference:
1. Tobias Mu"hlethaler, Lampros Milanos, Jose Antonio Marti'nez,
Thorsten
Blum, Dario Gioia, Bibhas Roy, Andrea Prota, Andrea Cavalli,
Michel O.

Steinmetz. Rational Design of a Novel Tubulin Inhibitor with a
Unique Mechanism of Action. Angewandte Chemie International Edition,
2022; DOI: 10.1002/anie.202204052 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/04/220412141020.htm

--- up 6 weeks, 1 day, 10 hours, 50 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1:317/3)