Discovery of novel inhibition site centered on 114-bit tryptophan of Thioredoxin reductase 1 through computer-aided drug design

Abstract

Thioredoxin reductase 1 (TrxR1) is an oxidoreductase playing the important role in the tumor cells. It is a new type of drug therapy target. Most of the existing TrxR1 inhibitors act directly covalently on the active sites. Herein, molecular docking-based virtual screening approach was used to screen inhibitors with new binding site of TrxR1 from the SPECS database. After experimental test, compound 22 was identified as the reversibility inhibitor of TrxR1 U498C mutant (It has similar structure and function to replace the wild-type TrxR1 which is difficult to express) with IC50 value of 15.31 ± 0.57 μM. The molecular docking results showed that the interaction between compound 22 and TrxR1 was centered on inactive site Trp114. Furthermore, phenazine compounds 24–30 with similar structures as 22 were also screened out from our phenazine database. Compounds 24–27 had longer chain structures and better inhibitory activity than compound 22, while compounds 28–30 were the opposite. Compounds 24–27 can be more stably bound in the protein cavity on Trp114 than compounds 28–30. Then we verified amino acids centered on Trp114 can regulate TrxR1 activity by amino acids mutation. Taken together, A new inhibition site are found that can regulate TrxR1 U498C mutant activity by acting on amino acids sequence at inactive sites centered on Trp114 and can provide ideas for the discovery and research of new TrxR1 inhibitors.