New atomistic level insight into drug-target residence time

Date:
January 28, 2022
Source:
University of Eastern Finland
Summary:
A new study helps to explain what defines how long a drug molecule
stays bound to its target.



FULL STORY ==========================================================================
A new study from the University of Eastern Finland and the University of Tu"bingen helps to explain what defines how long a drug molecule stays
bound to its target.


==========================================================================
When a drug molecule binds to its target protein, it stays bound for some
time before eventually unbinding the target. The actual time how long a
drug molecule resides bound to its target varies among compounds. The
lifetime of the drug-target complex may play a crucial role in drug
efficacy, as a long target residence time can, in some cases, be important
for drug efficacy.

Therefore, understanding its underlying causes enables more rational
drug design.

In the new study, researchers from the University of Eastern Finland
and the University of Tu"bingen identified the key elements driving for
a long or a short target residence time among similar small molecule
kinase inhibitors on the atomistic level. The findings were published
in Nature Communications.

Dozens of small molecule kinase inhibitors have already been approved
for clinical use, most of them for the treatment of cancer.

"Initially, we were interested in what causes the discrepancy in
the target residence time between two similar small molecule kinase inhibitors," says Senior Researcher, lead author Tatu Pantsar from the University of Eastern Finland.

Prof. Stefan Laufer's group at the University of Tu"bingen has designed, synthesized and biologically characterized numerous small molecule
kinase inhibitors for a protein kinase called p38a MAPK, which enabled
this research.



==========================================================================
"In the study, we focused on two small molecule kinase inhibitors that
are equipotent in isolated enzyme assays but show difference in their
target residence times, i.e., for how long a single small molecule kinase inhibitor is bound to the target protein. We also found that the inhibitor
with a longer target residence time was more potent when tested in cells," Pantsar says.

In the study, researchers studied and compared the small molecule kinase inhibitors together with their target protein using computer simulations
that were conducted on Finnish supercomputers.

The protein behaves differently depending on the bound inhibitor.

"The simulations suggest that when a small molecule inhibitor is bound to
the protein, the protein is more dynamic when the short residence time inhibitor is bound to it. This basically means that the protein moves
more when it is binding the short residence time inhibitor, and less
when it is binding the long residence time inhibitor," Pantsar points out.

Water molecules have a great impact on the drug target residence time.



========================================================================== "These tiny yet abundant water molecules surrounding the protein appear
to be really important. When the inhibitor unbinds the protein, water
molecules will take their place in the binding site." In the simulations,
the long residence time inhibitor was less exposed to the water molecules,
and the required energy for the water molecules to reoccupy the binding
site of the long residence time inhibitor was much higher. This results
in a higher energetical barrier for the inhibitor to dissociate from
its target and thereby in a longer lifetime of the drug-target complex.

The observations on target protein behaviour and the role of water
molecules were also confirmed with a structurally diverse small molecule
kinase inhibitor that has an extremely short residence time.

The results can be useful in the early stages of drug design.

"Now that we understand better the atomistic level reasons that define
the drug residence time, it enables more rational small molecule design
that can be applied in a drug discovery project if a long target residence
time is desired.

Obviously, one needs to remember that the target residence time is just
one aspect in the very complex and difficult drug design process, where
a multitude of different things need to be considered," Pantsar concludes.

At the University of Eastern Finland, the research was carried out at
the School of Pharmacy and within the DrugTech Research Community. The
research was made possible by the computational resources provided by
CSC -- IT Center for Science Finland.

========================================================================== Story Source: Materials provided by University_of_Eastern_Finland. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Tatu Pantsar, Philipp D. Kaiser, Mark Kudolo, Michael Forster,
Ulrich
Rothbauer, Stefan A. Laufer. Decisive role of water and protein
dynamics in residence time of p38a MAP kinase inhibitors. Nature
Communications, 2022; 13 (1) DOI: 10.1038/s41467-022-28164-4 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220128100745.htm

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