Inhibition of mutant RAS-RAF interaction by mimicking structural and dynamic properties of phosphorylated RAS

Author:

Ilter Metehan1,Kasmer Ramazan23,Jalalypour Farzaneh4,Atilgan Canan4ORCID,Topcu Ozan2,Karakas Nihal25,Sensoy Ozge67ORCID

Affiliation:

1. Graduate School of Engineering and Natural Sciences, Istanbul Medipol University

2. Medical Biology and Genetics Program, Graduate School for Health Sciences, Istanbul Medipol University

3. Cancer Research Center, Institute for Health Sciences and Technologies (SABITA), Istanbul Medipol University

4. Faculty of Engineering and Natural Sciences, Sabanci University

5. Department of Medical Biology, International School of Medicine, Istanbul Medipol University

6. Department of Computer Engineering, School of Engineering and Natural Sciences, Istanbul Medipol University

7. Regenerative and Restorative Medicine Research Center (REMER), Institute for Health Sciences and Technologies (SABITA), Istanbul Medipol University

Abstract

Undruggability of RAS proteins has necessitated alternative strategies for the development of effective inhibitors. In this respect, phosphorylation has recently come into prominence as this reversible post-translational modification attenuates sensitivity of RAS towards RAF. As such, in this study, we set out to unveil the impact of phosphorylation on dynamics of HRASWT and aim to invoke similar behavior in HRASG12D mutant by means of small therapeutic molecules. To this end, we performed molecular dynamics (MD) simulations using phosphorylated HRAS and showed that phosphorylation of Y32 distorted Switch I, hence the RAS/RAF interface. Consequently, we targeted Switch I in HRASG12D by means of approved therapeutic molecules and showed that the ligands enabled detachment of Switch I from the nucleotide-binding pocket. Moreover, we demonstrated that displacement of Switch I from the nucleotide-binding pocket was energetically more favorable in the presence of the ligand. Importantly, we verified computational findings in vitro where HRASG12D/RAF interaction was prevented by the ligand in HEK293T cells that expressed HRASG12D mutant protein. Therefore, these findings suggest that targeting Switch I, hence making Y32 accessible might open up new avenues in future drug discovery strategies that target mutant RAS proteins.

Funder

Health Institute of Turkey

The Scientific and Technological Research Council of Turkey

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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