Theoretical Research On The Interaction Between CBP Bromodomain And Different Inhibitors

Acting as the only protein that can recognize and bind the acetyl-lysine of histone,bromodomain(BRD)plays an important role in post-translation modification progress relating to the human health.The conformation of bromodomain is a simple left-handed bundle consisting of four ?-helices.Key residues in the binding site are highly conserved.At present,there are 56 known BRD from human sources,which could be divided into eight categories.In this paper,we focus on the discussion about CBP(cAMP responsive element binding protein binding protein),one of the most widely studied acetyltransferases.It has been found that the gene of tumor suppressor p53 mutated in patients with acute leukemia,lymphoma and autoimmune diseases.And the binding between acytl-K382 of p53 and CBP-BRD is over-expressed.Therefore,the CBP-BRD is regarded as a promising drug target.With the fast development of technology,inhibitors with better inhibiting effects and higher selectivity are available.In this study,we choose five selective inhibitors to detect the effects of different inhibitor structures and different substituents on the binding capacity of inhibitors.SGC-CBP30 is the first generation of highly selective inhibitors and helpful to guide the work to a new inhibitor.The remaining four inhibitors CPI-098,CPI-703,CPI-637,GNE-272 were born in 2016,basing on different synthesis ideas.Each of them has its own characteristics and could make a reference for development of highly efficient and selective inhibitors and further research.Molecular dynamics simulations(MD simulations)method could help us get more information about protein conformation changes at atomic level and the energy variety in the changing progress.Nowadays,MD simulations method has been highly valued by researchers.In this study,five complexes were performed MD simulations and MM-GB/SA respectively.Basing on the calculation results,we find that Asn1168 and Pro1110 are two key residues to anchor inhibitors with forming hydrogen bonds.And there are several other key residues helping to stabilize the binding through hydrophobic interactions.From the point of geometric structure,the compound with better inhibiting effect is to occupy the binding pocket in the maximum extent and make full use of the surrounding residues to form more stable interaction.Besides,there are several theoretical discoveries that could help modifying and designing new inhibitors,such as adding charged substituent to form stable hydrogen bond with Gln1113,changing large hydrophobic substituents to enhance the hydrophobic interaction with Val1174 and Phe1177 and adding highly negative charged substituents to stable Arg1173.Basing on above results,we performed rational drug design,tested oral bioavailability and drug promiscuity.As result,we got a new compound with higher binding capacity and lower drug toxicity.