34
Modeling of Biomolecular Systems Interactions, Dynamics, and Allostery Session VI Abstracts
In Silico Studies on K-RAS-PDEδ Interaction Inhibition to Design Novel Anti-Cancer Drugs
Serdar Durdagi
1
, Ramin E. Salmas
2
, Mine Yursever
2
, Sergei Y. Noskov
3
.
1
Bahcesehir University, Istanbul, Turkey,
2
Istanbul Technical University, Istanbul, Turkey,
3
Calgary University, Calgary, AB, Canada.
The family of RAS (rat sarcoma viral oncogene homolog) proteins works as a signal transduction
pathway network that transfer information from the extra-cellular environment to the nucleus. RAS
proteins are cytoplasmic proteins that translocate to the plasma membrane where they transmit
growth factor signals and drive cell proliferation. However, it’s well-known that direct inhibition
of Kirsten RAS (K-RAS) is not enough for clinically useful drugs.[1,2] Recently, Zimmermann
et
al.
[1] reported binding of mammalian phosphodiesterase D subunit (PDEδ) to K-RAS by means
of small molecule inhibitors which are suppress oncogenic RAS signalling by altering its
localization to endomembranes. These available inhibitor-bound high-resolution X-ray structures
from Zimmermann are used to better understand and compare the molecular mechanisms of
different inhibitors. We used 6 ligands from Zimmerman
et al.
[1] and performed long molecular
dynamics (MD) simulations (~0.1 μs) for the complex systems at physiological conditions to
understand their molecular mechanism at atomistic level and design novel inhibitors based on MD
simulations results. These results are used to design novel small molecule inhibitors for imparing
the K-RAS-PDEδ interaction.
In silico
cardiotoxicity of novel designed compounds are also tested
using hERG potassium channel models.
References:
et al
Nature 497, 638 (2013)
[2] J. Downward Nature Rev. Cancer 3, 11 (2003)
