Quantum Chemistry Studies On Halogen Bonds And The Reaction Mechanism In The Synthesis Of C-nucleosides And Virtual Screening For Antiviral Drugs

With the development of computer technologies,applying theoretical calculations to interpret or predict experimental results has become a widely used strategy in various areas.Quantum chemistry approaches could properly describe molecular electronic structures,and thus have been utilized in calculating systems involving non-covalent interactions and reaction transition states.Meanwhile,as one of the important strategies of lead compound discovery in modern pharmaceutical industry,computer-aided drug design has shown advantages in both cost and efficiency.This dissertation is mainly constituted by two parts.The first section focuses on using quantum chemistry approaches to explore the non-covalent interactions in drug discovery and synthesis reactions,involving the interaction nature of halogen bonds(chapter 2)and the reaction mechanism behind the anomeric selectivity of C-nucleosides(chapter 3).The second section is virtual screening and bioactive compounds discovery against proteins of epidemic viruses,including coxsackievirus A10(chapter 4)and Zika virus(chapter 5).As a common type of non-covalent interactions,halogen bonds(XB)formed between organohalogens and protein residues may influence both bioactivity and druggability properties of a ligand.Recent studies and survey of the crystal structure databases suggested that,XBs could form in all 9 differently charged complexes,even involved with the negatively charged XB donor or/and the positively charged XB acceptor.This makes it difficult to understand the concept of electrophilicity for a XB donor and nucleophilicity for a XB acceptor in the IUPAC recommended definition.In chapter 2,9 XB systems with highly comparable structures were designed to mimic all possible charge states of XBs.Quantum chemistry and wave function analysis approaches were used in the theoretical exploration of interaction nature.The calculation results showed that,all 9 differently charged halogen bonds could be stable in highly dielectric solvents.The net binding energies obtained by removing the contribution of background interactions could be as strong as-1.2,-3.4 and-8.3 kcal/mol in solvents for XBs involving Cl,Br and I,respectively.Orbital and dispersion interactions were found to be always attractive,and thus should be regarded as the essential interaction terms of a XB;while electrons transferred uni directionally from a XB acceptor to a XB donor in all studied systems,and thus should be regarded as the basic profile.These observations demonstrated that,the intrinsic electrophilicity or nucleophilicity of a XB donor or a XB acceptor would not be affected by the charge state of the complexes.Intramolecular charge redistribution inside both the XB donor and XB acceptor was found to be system dependent,but always led the interaction to be more attractive and less repulsive,and form a more stable halogen bond.Accordingly,we suggested that the orbital-based origin of XB could successfully describe the complicated behavior of differently charged XB complexes,while electrostatic contribution may still cause dramatical influence to the overall interaction strength.These results should help us better understand the IUPAC recommended XB definition,and promote the application and development of halogens in all corresponding areas.Non-covalent interactions may also affect the product selectivity in medicinal chemistry reactions.In chapter 3,we explored the origin and mechanism of the anomeric selectivity in the synthesis of the C-nucleosides with quantum chemistry calculations.C-nucleosides have been widely used in developing antivirals against RNA viruses.Our collaborators reported a new strategy to synthesis C-nucleosides with butyloxycarbonyl(Boc)to protect the amino group in the aglycone.This strategy was proved to be highly efficient and anomeric selective.However,the anomeric selectivity was found to be determined by the protecting groups of the sugar lactones.Density functional theory calculations were conducted to explore the structures and free energies of the transition states in the reactions.The reaction mechanism behind the anomeric selectivity were then deduced based on the optimized structures and calculated free energy barriers.The results showed that,in the reduction reaction of the hemiketal intermediates,the reductive triethyl silane(Et3SiH)could form intermolecular non-covalent interactions,including cation-? or weak hydrogen bonds,with the aromatic rings or methoxy groups of the protecting groups on the sugar moiety,respectively.These non-covalent interactions may be the main factors that stabilize the transition states and determine the product anomeric selectivity.These findings may provide new insights for mechanism exploration and method development in the silane-mediated synthesis of C-nucleosides.As one of the most important pathogens of hand,food,and mouth disease(HFMD),coxsackievirus A10(CV-A10)still lacks antivirals showing both in vitro and in vivo activities.In chapter 4,we performed virtual screening against the capsid protein VP 1 of CV-A10 based on the cryo-EM structure solved by our collaborators.Among the 258 compounds sent for bioassay,4 were proved to have good bioactivity.The binding residues for these 4 compounds in the protein pocket were demonstrated to be similar with that for the pocket factor of the VP 1 protein.Amongthe 4 compounds,ICA135 showed the best performance,with an in vitro IC50 value of 1.45 ?M.In the in vivo assessment,ICA135 was proved to be efficient in improving the therapeutic signs and survival rate of infected mice.Further molecular docking analysis and bioassay demonstrated that,ICA13 5 exhibited broad-spectrum inhibitory activity against various human enteroviruses besides CV-A10,including enterovirus A71,coxsackievirus A16,enterovirus D68,coxsackievirus B3 and poliovirus 1,with tested IC50 values ranging from 0.566 to 9.68 ?M.The Zika epidemic broke out worldwide in 2015.The genetic teratogenicity of the virus and its effects on the nervous and immune systems may cause great social harms.In particular,at the time of the Zika virus outbreak,basic researches were in a great lack,especially in terms of protein structures and active molecules.In chapter 5,we constructed the model of the Zika virus NS5 protein based on its amino acid sequence using homology modeling,followed by virtual screening of in-house database.5 of the 120 molecules sent for bioassay were found to have good dose-related activity.Among them,NSF104 is a nature product termed procyanidin.By molecular similarity searching of NSF104,we found a series of compounds sharing the same basic structure of catechin.Among the 15 procyanidin analogues sent for bioassay,4 compounds exhibited good dose-related activity,with NSF245 showing the best performance with an IC50 value of 1.493 ?M,twice more active than that of the newly reported efficient compound Epigallocatechin Gallate(EGCG,viz.,NSF244)at that time(4.371 ?M).