Mechanism Study Of Some Small Inhibitor Molecules On HBV And BRD

The rapid development of computational chemical biology and computer-aided design technology provides guidance and ideas for the development of drug molecules for the treatment of various clinical diseases.In this paper,the inhibition mechanism of HBV capsid assembly inhibitors,the inhibition mechanism of several BRD9 inhibitors and the selective mechanism of BET inhibitors were explored by means of computational simulation methods.It provides important reference information for the design and modification of high efficiency inhibitors.Chapter 1: The computational simulation methods,HBV and BRDs were briefly described.Finally,the main research work of this paper were given.Chapter 2: As effective lead compounds for chronic hepatitis B virus(HBV),HBV capsid assembly inhibitors have got increased attention,which induce aberrant capsid assembly and thereby affect viral replication.In this work,molecular docking,molecular dynamics simulations,binding free energy calculations and per-residue energy decomposition were implemented to investigate the binding mechanism between tetrahydropyrrolopyrimidines scaffold inhibitors and HBV capsid protein.The models established by three-dimensional quantitative structure-activity relationship could be used to predict the anti-HBV activities of the tetrahydropyrrolopyrimidines molecules.The obtained results displayed that the non-polar interaction,hydrogen bond interaction,polar interaction and ?-? stacking interaction together help to stabilize the conformation of inhibitors in the interface of HBV core proteins,and residues Pro25,Thr33,Trp102,Ile105,Tyr118,Ile139,Leu140(chain B),and Val124,Trp125,Thr128,Arg133(chain C)were important participants during binding process.The replacement of the electronegative groups F,Cl and sulphonamide in inhibitor 28 a would alter the major inhibitory effects of binding and activation.This study will help understanding the molecular mechanisms and novel designed small molecules could act as better inhibitors.Chapter 3: Bromodomain-containing protein 9(BRD9)has been employed as a potential target for anticancer drugs in recent years.In this work,molecular simulation approaches were performed to elucidate the different binding modes between four pyridinone-like scaffold inhibitors and BRD9 bromodomain.Analysis results indicate that non-polar contribution mainly deriving from van der Waals energy is a critical impact on binding affinity of inhibitors against BRD9.Some key residues Phe44,Phe47,Val49 and Ile53(at ZA loop)enhance the binding energy of inhibitors in BRD9 by means of providing hydrophobic interactions.Moreover,it is observed that BRD9 is anchored by the formation of a stable hydrogen bond between the carbonyl of the inhibitors and the residue Asn100(at BC loop),and a strong ?-? stacking interaction formed between the residue Tyr106(at BC loop)and the inhibitors.The existence of dimethoxyphenyl structure and the aromatic ring merged to pyridinone scaffold are useful to enhance the BRD9 binding affinity.These findings will provide theoretical guidance for the rational design of effective inhibitors targeting BRD9?Chapter 4: The bromodomain and extra-terminal domain(BET)family of proteins are prospective therapy drug targets for numerous human diseases,but there are few reports of highly selective inhibitors.To clarify the selectivity of nitroxoline to BET family proteins over non-BET family protein,we employed computational simulation methods in this study.Based on the calculation of cavity volume,it was found that the BRD4BD1 active pocket was the smallest and the selectivity of nitroxoline was the highest.On the contrary,nitroxoline had the lowest selectivity to BRD9.That is,the size of active pocket has a certain impact on the selectivity difference.In addition,the interaction of nitroxoline with the BET family and BRD9 shows that varying degrees of critical residues around the binding pocket are also factors of significant selectivity.The effect of conserved residues Phe53/59/83/52,Val57/63/87/56,Cys106/117/136/105,Ile116/132/146/115 in BD1 and Phe372/334/376,Val376/338/380,Tyr386/348/390,Tyr428/390/432 in BD2 is a factor in the selective inhibition of the BET family by nitroxoline.Among them,the key factors for the high selectivity of nitroxoline to BRD4BD1 are that the large favorable contribution of van der Waals and non-polar interactions from the residues Phe83,Val87,and Ile146.Respecting to BRD9,the residues are mainly Phe44,Ile53,Tyr99 and Tyr106.In summary,this work has detailed the mechanism of action between the nitroxoline and BET family,and also provides a reference for further design of more promising BET inhibitors.