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In mammalian cells, DNA polymerase ζ (Pol ζ) catalyzes the TLS step of ICLR. By acting simultaneously with Y-family DNA polymerase, Pol ζ completes replication of damaged DNA without removing the damage by inserting a nucleotide opposite the lesion. It has been demonstrated that Pol ζ represents a promising target for the treatment of chemotherapy-resistant tumors. The first series of small-molecule inhibitors targeting REV7/REV3L interaction have been identified recently, however, their corresponding binding mechanism is not known. Herein, we performed docking, molecular dynamics and MM/PBSA free energy calculations to study the binding mechanism of REV7 and its inhibitors. It was demonstrated that inhibitors bind to the two pockets divided by the ‘safety-belt’ structure of REV7, which was supported by the MD simulation. In addition, 2-methylfuran is an important group with an appropriate size to form the stable complex, and hydrophobic contacts were mainly responsible for stable complex formation as revealed by free energy calculation.

Structural insight into inhibition of REV7 protein interaction revealed by docking, molecular dynamics and MM/PBSA studies