Identification of binding sites in nicastrin and binding modes of its inhibitors

Background: Nicastrin is a confirmed breast cancer target, but the lack of knowledge about its binding sites and structural basis interactions with known small molecules makes development against it challenging. Methods: Molecular docking molecular dynamics simulations were used in this work to identify nicastrin, gamma-secretase component that has been implicated potential drug target chemotherapy. Results: Docking calculations identified three sites, however site analysis using druggability assessment region encompasses DYIGS motif, as most favorable site. This was validated by 50 ns dynamic simulation inhibitor CID44433923 free energy found be -11.4 kcal/mol mainly driven hydrophobic interactions. Per residue decomposition showed Gln139, Val138 Arg105 had relatively high contribution towards binding. These results suggest these residues might critical nicastrin inhibition. Binding mode previously reported inhibitors Asp143 key interactions. Conclusions: affords an insight into mechanism direct design efforts nicastrin.