Three-dimensional Quantitative Structure-activity Relationship Models of HIV-1 Integrase Inhibitors of DKAs

As one of the three viral encoded enzymes of HIV-1 infection, HIV-1 integrase has become an attractive drug target for the treatment. Diketoacid compounds (DKAs) are one kind of potent and selective inhibitors of HIV-1 IN. In the present work, two three-dimensional QSAR techniques (CoMFA and CoMSIA) were employed to correlate the molecular structure with the activity of inhibiting the strand transfer for 147 DKAs. The all-oritation search (AOS) and all-placement search (APS) were used to optimize the CoMFA model. The diketo and keto-enol tautomers of DKAs were also used to establish the CoMFA models. The results indicated that the enol was the dominant conformation in the HIV-1 IN and DKAs complexes. It can provide a new method and reference to identify the bioactive conformation of drugs by using QSAR analysis. The best CoMSIA model, with five fields combined, implied that the hydrophobic field is very important as well as the steric and electrostatic fields. All models indicated favorable internal validation. A comparative analysis with the three models demonstrated that the CoMFA model seems to be more predictive. The contour maps could afford steric, electrostatic, hydrophobic and H-bond information about the interaction of ligand-receptor complex visually. The models would give some useful guidelines for designing novel and potent HIV-1 integrase inhibitors.     

Design and Synthesis of p/m-[p-（un）Substituted Phenylsulfonamido]phenyl β-Diketo Acids and Quinoxalone Derivatives

Diketo acid derivatives are potent and selective HIV-1 integrase inhibitors. To investigate the detailed synthesis of those derivatives, a series of p/m-[p-（un）substituted phenylsulfonamido]phenyl β-diketo acid derivatives have been designed and synthesized. The quinoxalone derivatives as the potential bioisosteres of the biologically labile β-diketoacid pharmacophores have also been synthesized from reactions of the corresponding diketo acids with o-phenylenediamine. The structures of all diketo acid （ester） and quinoxalone derivatives were confirmed by 1^H NMR, 13^C NMR, IR, HRMS and/or MS （ESI）. X-ray crystallographic analysis of 11b demonstrates a similar arrangement of the side chain of quinoxalone derivatives with the parent diketoacids due to the intramolecular hydrogen bond （O…H-N） and the sp^2 hybridization configuration of the two nitrogen atoms of the quinoxalone ring.     

Screening of new non-nucleoside reverse transcriptase inhibitors of HIV-1 based on traditional Chinese medicines database

HIV-1 RT is an important target for the treatment of AIDS.There are two major classes of antiviral agents that inhibit HIV-1 RT have been identified,nucleoside RT inhibitors(NRTIs) and non-nucleoside RT inhibitors(NNRTIs).In this report,a noval class of non-nucleoside compound with potential RT inhibitory activity were found from the traditional Chinese medicines database (TCMD) using a combination of virtual screening,docking,molecular dynamic simulations,where results were ranked by scoring function of...     

Building the Pharmacophore Model of HIV-1 Integrase Strand Transfer Inhibitors and Studying Their Inhibition Mechanism

The replication of HIV-1 requires the integration of its cyclic DNA into host DNA by HIV-1 integrase (IN), which includes two important reactions, 3'-processing and strand transfer, both catalyzed by HIV-1 IN. Disrupting either of the reactions will fulfill the purpose of inhibiting the replication of HIV-1. In this paper, pharmacophore modeling and molecular docking are employed to investigate the inhibition mechanism of the HIV-1 IN strand transfer inhibitors (INSTIs). Based on the results, we suggest that the inhibition mechanism of INSTIs involves the inhibitor chelating the cofactors Mg2+ and its forming hydrogen bonds with some crucial residues adjacent to the DDE active center.     

Synthesis and anti-HIV-1 activity of the conjugates of gossypol with oligopeptides and D-glucosamine

A series of novel gossypol derivatives were synthesized and screened for their in vitro anti-HIV- 1I activity. The results showed that replacing the aldehyde groups of gossypol with certain oligopeptides and Dglucosamine not only reduced the cytotoxicity of gossypol derivatives but also enhanced their antiviral activity against HIV-1. Interestingly, D-glucosamine derivative of gossypol that lacked the COONa group also exhibited the same potent anti-HIV-1 activity as oligopeptide derivatives with the COONa group. These compounds blocked the entry of HIV-1ⅢB into target cell. which was similar to T20. Furthermore, the molecular docking analysis rationalized their anti-HIV-1 activity. The results also implied that certain oligopeptides and D-glucosamine were important moities to prepare gossypol derivatives as HIV- 1 entry inhibitors besides certain amino acids.     

Study on the drug resistance and the binding mode of HIV-1 integrase with LCA inhibitor

Human immunodeficiency virus type 1 (HIV-1) integrase (IN) is an essential enzyme in the lifecycle of this virus and also an important target for the study of anti-HIV drugs. The binding mode of the wild type IN core domain and its G140S mutant with L-Chicoric acid (LCA) inhibitor were investigated by using multiple conformation molecular docking and molecular dynamics (MD) simulation. Based on the binding modes, the drug resistance mechanism was explored for the G140S mutant of IN with LCA. The results indicate that the binding site of the G140S mutant of IN core domain with LCA is different from that of the core domain of the wild type IN, which leads to the partial loss of inhibition potency of LCA. The flexibility of the IN functional loop region and the interactions between Mg2 ion and the three key residues (i.e., D64, D116, E152) stimulate the biological operation of IN. The drug resistance also lies in several other important effects, such as the repulsion between LCA and E152 in the G140S mutant core domain, the weakening of K159 binding with LCA and Y143 pointing to the pocket of the G140S mutant. All of the above simulation results agree well with experimental data, which provide us with some helpful information for designing the drug of anti-HIV based on the structure of IN.     

Drug Design,Molecular Docking,and ADMET Prediction of CCR5 Inhibitors Based on QSAR Study

The chemokine receptor CCR5 is a main and necessary co-receptor for which HIV can recognize and enter the cells, and has been identified as a potential new target for the design of new anti-HIV therapeutic drugs. Highly active CCR5 inhibitors can prevent HIV-1 from entering target cells and block the process of infection. In this study, HQSAR and Topomer Co MFA methods were used to establish QSAR models for 75 1-(3,3-diphenylpropyl)-piperidinyl and urea derivatives, and cross-validation and non-...     

EXPRESSION OF SURFACE ANTIGEN GENE OF HUMAN HEPATITIS B VIRUS SEROTYPE adr IN Escherichia coli

The construction of an expression plasmid of hepatitis B virus surface antigen (HBsAg) gone from the cloned hepatitis B virus (HBV) genome subtype adr is reported. The expression products of this plasmid in E. coli were detected by means of radioimmunoassay in competitive suppression and polyacrylamide-SDS gel electrophoresis. The presence of a fusion protein containing HBsAg was confirmed.     

Design and synthesis of new 7, 8-dimethoxy-α-naphthoflavones as CYP1A1 inhibitors

The flavonoids as inhibitors of CYP1Al exhibit chemopreventive effects against certain procarcinogens and have been considered as the promising cancer preventive agents.A series of novel 7,8-dimethoxy-αnaphthoflavones as the substrate analogs were designed and prepared.The enzyme assay suggested that all of these new flavones were stronger inhibitors of CYP1 Al than the lead compoundα-naphthoflavone. Among the tested ones,3h showed the most potent inhibitory effects.     

A Novel Protoilludane Sesquiterpene from the Wood of Xanthoceras sorbifolia

In the course of our searching for anti-HIV agents from natural sources, we have isolated a triterpene and a doubly linked proanthocyanidin dimer as HIV-1 protease inhibitors from the wood of Xanthoceras sorbifolia Bunge (Sapindaceae)1. Further investigation of this plant has led to the isolation of a protoilludane sesquiterpene (1). The present paper describes the isolation and structural determination of this novel sesquiterpene. The EtOH eluate of a MeOH extract of the wood of X. so…     

Synthesis,biochemical evaluation and computational simulations of new cytochrome bc1 complex inhibitors based on N-(4-aryloxyphenyl) phthalimides

A series of N-(4-aryloxyphenyl)phthalimides were synthesized and identified as new inhibitors of the cytochrome bc1 complex. Furthermore, results obtained from computational simulations indicated that 3e' should bind to the Q_o site of the bc1 complex.     

Studies on Sulfation of Lycium barbarum Polysaccharides

Polysaccharides can anti-virus, such as human immunodeficiency virus (HIV-1),[1] herpes simplex virus (HSV-1,HSV-2) and cytomegalovirus. Some of them are sulfates, e.g. dextran sulfate, heparin, sulfonation of chitosan and sulfated derivatives of Lentinan. Our results showed that sulfated derivatives of Lycium barbarum polysaccharides (LBP)have anti-HIV activity. Because the anti-HIV activity of LBP was deeply dependent on the molecular weight, the sulfation pattern and glycosidic branches besides degree of sulfation (DS), so we emphasized our work on the factors of DS.     

Design and synthesis of á, á-trehalose derivatives bearing guanidino groups as inhibitors for the Tat Protein-TAR RNA interaction of HIV-1

Replication of human immunodeficiency virus type 1 (HIV-1) requires specific interactions of Tat protein with the transactivation responsive region (TAR) RNA. Disruption of Tat-TAR RNA interaction could inhibit HIV-1 replication. Here four target compounds were designed and synthesized to bind to TAR RNA for blocking the interaction of Tat-TAR RNA. The core molecule 6,6'-diamino-6,6' -dideoxy-α,α-trehalose was obtained from selective bromination of α,α-trehalose at C-6,6', fo…     

Synthesis and Biological Activity of New Pyrethroid Acid Oxime－esters Containing Pyrazole Ring

A series of compounds containing oxime-ester linkage and pyrazole ring(in place of the ester linkage and the alcohol moiety in pyrethroid ester) was designed and synthesized. The structures of all the compounds prepared were confirmed by IH NMR and MS spectroscopy as well as elemental analyses. The binassay data of those compounds against tobacco mosaic virus (TMV), cucumber mosaic virus(CMV), potato virus X (PVX) and potato virus Y(PVY) were presented. Among them compound 6i was found to possess significant plant antiviral activities. But all the compounds showed low insecticidal and acaricidal activities.