Novel therapeutic molecules targeting the h-ras isoform with g12d mutation involved in cancer formation
AssigneeIstanbul Medipol Universitesi
InventorsRamazan KASMER, Metehan ILTER, Özge SENSOY, Nihal KARAKAS, Ozan TOPÇU
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Abstract
Disclosed are therapeutic molecules that can be used as an alternative to SHP2 phosphatase inhibitors, as a novel approach to targeting RAS isoforms with the G12D mutation that is involved in cancer formation.
Claims10
H-RAS (H-RAS G12D) with G12D mutation, cerubidine (Formula I) or tranilast (Formula II) or Nilotinib (Formula III) or Imidafenacin (Formula IV) or Epirubicin (Formula V) or CHEMBL3490356 (Formula VI), ZINC16956714 (Formula VII) or ZINC16382913 (Formula VIII) or ZINC08648721 (Formula IX) molecules for use as inhibitor agent, wherein they are shown as follows;
A method used for detecting inhibitor molecules that can inhibit the interaction of mutant H-RAS with RAF by imitating phosphorylated H-RAS proteins, comprising the steps of;
- i. Comparing the H-RAS G12D mutant, wild type H-RAS and phosphorylated H-RAS protein systems with molecular dynamics simulation, Clustering the trajectories of the H-RAS G12D mutant, wild type H-RAS and phosphorylated H-RAS protein systems after comparison,
- ii. Modeling of pharmacophore groups for the binding pocket detected after clustering,
- iii. Coupling of the candidate molecules to the binding pocket detected on the H-RAS G12D mutant protein,
- iv. Determining the stability of ligands with the appropriate binding pose and their effect on protein dynamics by molecular dynamics simulations,
- v. Detecting molecules that have the potential to disrupt the interaction surface of RAF and the mutant H-RAS G12D as inhibitor molecules.
Dependencies are inferred from the claim text.