Ligands Screening For Autoinducer-2(AI-2) Secrete Proteins MTAN And LuxS Targeting

5′-methylthioadenosine/S-adenosylhomocysteine nucleosidase （MTAN） catalyzes5′-methylthioadenosine （MTA） to adenine and5′-methylthio-D-ribose （MTR） related topolyamine biosynthesis. MTAN is important for methionine salvage and methylation, and itis also involved in generation of S-ribosylhomocysteine （SRH） fromS-adenosylhomocysteine （SAH） in bacterial quorum sensing. MTA analogues had beendesigned as inhibitors both for Streptococcus pneumoniae and Escherichia coli MTANs, andtheir binding ability contact with MTAN had been tested based on the values of Ki [Singh, etal., J. Biochemistry,45（2006）12929]. In this study, we calculated up to200topologicalindices of33MTA analogue structures, including electrotopological state indices， kappashape indices and the molecular connectivity indices. Multi-Linear Regression （MLR） modelwas explored to analyze the relationship between these indices and their Ki values. The bestmodels trained by the stepwise method were constructed by three indices, SssS、ka3andSHsssNHp with R and R_adj²0.862，0.711, respectively. Based on this knowledge, we filtratedthe lead-like subset of the ZINC database, and373molecules were selected as potentialinhibitors, then DOCK method with anchor_and_grow algorithm was employed to study onthese molecules. As a result,53of the molecules successfully docked into the active site ofMTAN with lower gird score （GS） and energy score （ES）. We also found A114、E424、S306and D438, which are near to the active site of MTAN, as new bonding site of potentialinhibitors. Therefore, the structure–activity relationship （QSAR） models should be useful toelucidate the relationship between compound structures and biological activities, and thedocked molecules may facilitate design of more potent MTAN inhibitors.