Molecular modeling of K-Ras-G12C inhibition mechanism by prototype compound ARS-853

Kulakova A., Khrenova M., Nemukhin A.1

Lomonosov Moscow State University, Department of chemistry, Russian Federation, 119991, Moscow, Leninskie Gory, 1/3, +7(495)939-48-40,

1Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, Russian Federation, 119334, Moscow, Kosygina, 4

Proteins of Ras family are involved in transmitting cellular signals responsible for the cell growth, differentiation and survival; disruption of their functioning is associated with 30% of human cancer cases. Among the family, the most oncogenic one is the K-Ras protein. Mutations in the protein stabilize the active form, which transmits a signal for growth and differentiation to cancer cells. Thus, search of compounds that can stabilize the inactive form of protein is an actual task in nowadays science. The most promising way is the search for compounds that are bound allosterically to the enzyme. However, proteins of Ras family are called “undruggable” because of their smooth surface, without energetically favorable binding sites. Up to now there are no therapeutic drugs that can stabilize protein in inactive form. Recent studies demonstrated that the ARS-853 compound can be selectively bound to inactive form of K-Ras with oncogenic G12C mutation.

In this research we studied the interaction mechanism of K-Ras-G12C enzyme with prototype compound ARS-853 using molecular modeling methods. The mechanism of ligand binding to the protein, followed by formation of the covalent complex, was identified. Calculation of free binding energy of ARS-853 was carried out with classical molecular dynamics method using replica-exchange umbrella sampling, realized in the NAMD software package. Potential energy profile of the Cys12 addition reaction to the activated ARS-853 double bond was calculated using a combined quantum mechanics / molecular mechanics approach (QM/MM). The quantum-mechanic subsystem was described at the density functional theory (PBE0-D3/cc-pvdz) level, molecular-mechanic subsystem was described with Amber force field. All QM/MM calculations were performed with the NWChem software package.

The work was carried out using the resources of Lomonosov Moscow State University Supercomputer Center with the financial support from the Russian Science Foundation (project No. 14-13-00124).

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