Zoltán Orgován, György M. Keserű
RCNS-HAS, Medicinal Chemistry Research Group
KRAS is one of the most interesting oncogenic targets, as its mutations play a role in high percentage of oncological indications such as lung cancer and colorectal cancer. Despite of the 30 years of research, selective inhibitors against KRAS mutants are rare. The extreme affinity of its native GTP/GDP ligand and the limited structural differences between the apo and mutated protein suggest covalent inhibitors as a promising approach. The design of covalent inhibitors for KRAS is challenging, because the active site of the protein is accommodated near to a highly flexible loop. Since all of the known covalent docking programs treat the protein rigid, the predictive power of these tools is limited. We used induced fit docking simulations combined with covalent docking in order to render the binding pocket suitable for the ligand and to form the covalent bound. With this methodology most of the experimental ligand binding conformations were reproducible, therefore this method could be useful in designing new covalent KRAS inhibitors. This work is supported by NVKP-16-1-2016-0020.