Probing The P4Pocket Structure Of Mcl-1and Bcl-2Protein By Small Molecules

Currently, the study of antitumor drugs has been changed from traditional antitumor drugs to targeted antitumor drugs, Bcl-2protein became the center spot. Compared with traditional anticancer drugs, It possessed targeted, low-toxic and high potency advantages. Therefore, it is important for the design and synthesis of new small molecule Bcl-2-like inhibitors to research the structure features of Bcl-2-like proteins and the interaction model with small molecule inhibitors.Small molecule S1is a Bcl-2/Mcl-1protein inhibitors, which was found by our lab. The carbonyl of S1simulate the D67residues of Bim to binding with the R146remnants of Bcl-2protein and the R263residues of Mcl-1protein within BH3groove by forming hydrogen bonds; Sulfur morpholine substituent replace the L62residues of Bim to occupying the p2pockets.In order to simulate the Bim petitide more profectly and improve the drugbilty of S1, we designed and sysiniese A and B series compounds based on the binding model between S1and Bcl-2protein.Furthermore, we took the structure-activity study. The results indicated that both of A and B series compounds could occupy the p4pocket; Normal propyl amine and n-butyl amine can partially occupied to p4pocket, hexyl amine and amphetamine can occupy p4pocket perfectly; Moreover, the p4pocket of Mcl-1protein is more width than that of Bcl-2. The regions beween arginine residues and p4pocket prefer to using flexible strong carbon chain rather than big or rigid strong groups. occupying the p2and p4pocket in the same time could significantly enhance the affinity of small molecules for protein, which illustrated S13or9-derivatives can still keep the original combination patterns of S1. In addition, on the molecular optimization process, we carried out the retrospective analysis by plotting the FQ relative to the molecular weight growth curve.FQ curve upward trend which proved that the optimal route is reasonable. This could provide reference and guidance for design and synthesis of Bcl-2-like inhibitors in the future.Finally, we got two mall molecule inhibitors——1:9and E10with high binding affinity and well druggability. For Bcl-2protein, the Ki value was30nm and73nm, respectively, which is four times and10times as large as S1, respectively. For Mcl-1protein, the Ki value was14nm and8nm, respectively, which is five times and8times as large as S1. Moreover, they were proved to be "pure" BH3mimetic by cell experiments.