Structure Modeling Of Human Ribonucleotide Reductase

Ribonucleotide Reductase (RR) is the unique enzyme responsible for the conversion of ribonucleotides to2’-deoxyribonucleotides in human. Study have shown that small subunit R2can promote the transformation of various oncogenes and enhance the invasion ability of cancer cells. Therefore, the study of R2inhibitor, to inhibit the generation and transfer oftumor cells, has become one of the target for research to cure human cancer, and got more and more attention.In this article, we mainly focus the small submit R2of RR in Homo Sapiens by computational structural bioinformatics approaches. First, we applied metaPocket to identify potential ligand binding pockets on R2submit surface. Then we used AutoDock Vina to screen a large number of compounds from ZINC、DrugBank and PDB database that might bind to those pockets. Nine small molecules were screened out, which can be further validated experimentally to inhibit R2. The new R2inhibitor(gliquidone) with the best binding affinity values of the two active sites of R2provided the basis for further experimental verification. Secondly, we applied ZDOCK to build up the complex structure of RR from R1and R2. The protein binding sites of R1and R2were prediction by metaPPI.4good models of RR complex structure were obtained in the end. Last, by comparing structure and sequence of R2in Homo sapiens and in E. coli,, and hotspot residues predicted by KFC、FlodX、HOTPOINT and HotSpot Wizard, we got a pair of hotspot residues A_PHE101-D_PHE101in the interface of R2, and they are perfectly symmetrical on theamino acid sequence and spatial structure. The computational results in this work need to be validated by experiments and might provide insights to inhibit R2functions and R2dimerization mechanism.