A novel hypothesis based on citrullinemia type II (CTLN2) disease leads to a new approach of citrin inhibition

The citrin protein is a transporter, which leads the substrate, the amino acid, aspartate. It is vital in the urea cycle. In addition, it contributes to the proliferation of cancer cells in cancer patients. Citrullinemia type II is a metabolic disease, that is caused from a genetic mutation in the amino acid Gly-105 in citrin, and in which the citrin is dysfunctional.

In order to mimic in cancer patients the structural effect caused in citrullinemia type II to the citrin protein, and therefore cause the citrin to dysfunction, we used In-Silico techniques. A new binding site was identified based on literature knowledge about citrullinemia type II genetic disease, and then a virtual library of 12,430 compounds was designed based on known active compounds and LigPrep. Three rounds of virtual docking were performed including IFD to 1,500 compounds.

We discovered a significant difference between the XP and IFD score for the same ligand. This may be due to higher accuracy of IFD comparing with Rigid Docking, and that can provide a new perspective about the use of each docking stage. The results reveal the importance of using IFD in a more extensive way. The final compound library contains 148 molecules, which have a very high potential of inhibiting cancer proliferation, and may be used as a lead in the process of developing a drug for cancer indication. Currently, the ligands are under investigation.