Modeling of Biomolecular Systems Interactions, Dynamics, and Allostery: Bridging Experiments and Computations - September 10-14, 2014, Istanbul, Turkey

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)

34