Compositions and methods of targeting mutant K-Ras
The invention relates to a method of modeling K-Ras proteins with one or more mutations that result in constitutive activity, and identifying compounds that inhibit interactions among activated K-Ras proteins and their upstream and downstream effectors.
1. An improved method of screening for compounds that bind to a mutant K-ras protein, the method comprising:
performing a molecular dynamics simulation on the K-ras protein to obtain a simulated K-ras G12V structure;
identifying in the simulated K-ras G12V structure a first and a second mutant conformation;
wherein the first mutant conformation has a first mutant groove defined by Glu91, Asp92, Tyr96, Ala11, Gly60, Ala59, Thr35, Pro34, and Ile36;
wherein the second mutant conformation has a second mutant groove outlined by Asp92, Ala11, Gln61, Glu62, Gly60, Ala59, Thr35, Arg68, Thr58, and Tyr71;
identifying a compound that binds to the first or second mutant groove; and
testing the compound for binding to the mutant K-ras protein by contacting a K-ras protein having the G12V substitution with the compound, and screening for compounds that bind to the mutant K-ras protein.
2. The method of claim 1 wherein the molecular dynamics simulation uses a molecular mechanical force field.
3. The method of claim 1 wherein the molecular dynamics simulation uses explicit water.
4. The method of claim 1 wherein the molecular dynamics simulation is performed for a period of at least 500 ns.
5. The method of claim 1 wherein the step of identifying the set of candidate compounds is performed by molecular docking simulations using a library of candidate compounds.
6. The method of claim 1 wherein the set of candidate compounds is ranked by estimated affinity.
7. The method of claim 6 further comprising a step of molecular mechanics-Poisson-Boltzmann surface area simulation.
8. The method of claim 1 wherein the candidate compounds are capable of blocking an interaction of Asp33 and Ile36 with PI3K.