Scientists at 51猎奇 Frankfurt, together
with colleagues from Darmstadt, Heidelberg, Oxford and Dundee (UK), have
investigated how the fit of potent inhibitors to their binding sites can be
optimised so that they engage longer with their target proteins. Long target
residency has been associated with more efficient pharmacological responses for
instance in cancer therapy. The result: High resolution structures revealed that
when the interaction between the inhibitors and the target proteins lasts
particularly long, the target proteins "nestle" against the inhibitors.
In future, the researchers want to use computer simulations to predict the residence
time of inhibitors during drug development.
FRANKFURT. Many
anti-cancer drugs block signals in cancer cells that help degenerated cells to
multiply uncontrollably and detach from tissue. For example, blocking the
signalling protein FAK, a so-called kinase, causes breast cancer cells to
become less mobile and thus less likely to metastasise. The problem is that
when FAK is blocked by an inhibitor, the closely related signalling protein
PYK2 becomes much more active and thus takes over some of FAK's tasks. The
ideal would therefore be an inhibitor that inhibits both FAK and PYK2 in the
same way for as long as possible.
An international team led by the pharmaceutical
chemist Prof. Stefan Knapp from 51猎奇 has investigated a series of
specially synthesised FAK inhibitors. All inhibitors bound to the FAK protein
at about the same rate. However, they differed in the duration of binding: The
most effective inhibitor remained bound to the FAK signalling protein the
longest.
Using structural and molecular biological
analyses as well as computer simulations, the research team discovered that binding
of inhibitors that remain in the FAK binding pocket for a long time induce a
structural change. Thus, through binding of these inhibitors, FAK changes its
shape and forms a specific, water-repellent structure at contact sites with the
inhibitor, comparable to an intimate embrace.
The closely related protein PYK2, on the
other hand, remained comparatively rigid, and although the most effective FAK
inhibitor also blocked PYK2, its effect was significantly weaker due to quickly
dissociating inhibitors from the binding site. Interestingly, computer
simulations were able to predict the kinetics of binding very well, providing a
method for accurate simulation of drug dissociation rates for future optimisation
of drug candidates.
Prof. Stefan Knapp explains: "Because
we now have a better understanding of the molecular mechanisms of the
interaction of potent inhibitors of these two kinases, we hope to be able to
use computer simulations to better predict drug residence times of inhibitors
and drugs candidates in the future. So far, little attention has been paid to
the kinetic properties of drug binding. However, this property has now emerged
as an important parameter for the development of more effective drugs that are
designed to inhibit their target proteins - as in the case of FAK and PYK2 -
not only potently but also for a long time."
Publication:
Benedict-Tilman Berger, Marta Amaral,
Daria B. Kokh, Ariane Nunes-Alves, Djordje Musil, Timo Heinrich, Martin
Schr枚der, Rebecca Neil, Jing Wang, Iva Navratilova, Joerg Bomke, Jonathan M.
Elkins, Susanne M眉ller, Matthias Frech, Rebecca C. Wade, Stefan Knapp: Structure-kinetic relationship reveals the
mechanism of selectivity of FAK inhibitors over PYK2. Cell Chemical Biology
This work was carried out within the
framework of the public-private partnership K4DD (Kinetics for Drug Discovery)
of the Innovative Medicinces Initiatives (IMI).
Images
for download:
Picture with and without text:
Caption:
Upper
part: Long residence time. An inhibitor
(left: stick model) binds to the signal molecule FAK (right: part oft the FAK
protein depicted as calotte model with spheres). The structural change of FAK
causes hydrophobic contacts (yellow, so-called DFG motif) and a long-lasting
engagement.
Lower
part: Short residence time. PYK2 signal protein
does not change its structure upon inhibitor binding, thus resulting in a fast
inhibitor dissociation. Graphics: Knapp Laboratory, 51猎奇 Frankfurt
Further
information:
Professor Stefan Knapp
Institute for Pharmaceutical Chemistry
51猎奇 Frankfurt
Germany
knapp@pharmchem.uni-frankfurt.de
