Synthesis and HIV-1 Integrase Inhibitory Activity of Furanone Derivatives

Twenty novel furanone derivatives,based on the structure of raltegravir which was the first HIV-1 integrase(IN) inhibitor approved by the United States Food and Drug Administration(US FDA),were designed,synthesized and characterized by 1H NMR,IR and MS.The biological activities of these compounds against HIV-1 IN in vitro were evaluated.The assay results indicate that the replacement of pyrimidinone with furanone decreased the inhibitory activity of the compounds to HIV-1 IN.Compounds 3i,3j and 3t show mode...     

Synthesis of the C5-C30 fragment of cyclodidemniserinol trisulfate via I2-mediated deprotection and ring closure tandem reaction

The marine natural product cyclodidemniserinol trisulfate displayed moderate HIV-1 integrase inhibitory activity. Its novel structure triggered our interest to synthesize it. In our total synthesis effort, the natural product was dissected into four fragments based on the rational retrosynthetic analysis. All four fragments were successfully prepared with orthogonal protection. And the assembly of fragment A and B furnished the C₅-C₃₀ key subunit by employing the I₂-mediated deprotection and intramolecular ketal formation tandem reaction in the presence of NaHCO₃ in MeCN. Our work provided flexible and practical approaches to synthesize and derive the 3,5,7-trisubstituted 6,8-dioxabicyclo [3.2.1] octane based analogs to search for new structure HIV-1 integrase inhibitors.     

用分子对接方法预测HIV-1整合酶与金精三羧酸抑制剂的相互作用

用分子对接方法(Docking)研究了HIV-1整合酶与其抑制剂金精三羧酸的结合过程.为弄清金属离子在结合中所起的作用,选择含有一个Mg+2或不含Mg+2的两种不同的整合酶受体分别与金精三羧酸对接.结果表明, Mg+2对稳定配体与受体的结合起了重要作用. 金精三羧酸配体与含有一个金属Mg+2的整合酶受体对接,最优结合自由能为-45.19 kJ/mol. 当Mg+2失去后,整合酶的活性中心构象将发生变化,使金精三羧酸抑制剂与整合酶的结合自由能(-24.35 kJ/mol)明显增加. 预测了未知的HIV-1整合酶与其抑制剂金精三羧酸的复合物结构, 并可对基于结构的抗HIV-1整合酶的药物设计提供重要信息.     

HIV-1整合酶与抑制剂金精三羧酸复合物的分子动力学模拟

用分子对接程序(Autodock)将含有一个Mg²⁺的HIV-1整合酶核心区(以下简称IN-A)与抑制剂小分子金精三羧酸(简称Aurin)进行对接,预测其未知的复合物结构,然后用分子动力学(MD)方法对IN-A与Aurin的对接结果进行了950 ps的模拟.MD模拟结果发现,IN-A与Aurin形成了两个稳定的氢键,Mg²⁺也与Aurin上的氧原子形成了稳定的配键,IN-A与Aurin之间的静电相互作用能和范德华相互作用能的平均值分别为-205.8和-162.7 kJ/mol.根据MD模拟得到的IN-A与Aurin相互作用后的构象变化信息,我们对对接复合物结构进行了修正,给出了更加合理和稳定的复合物预测结构.本工作得到的HIV-1整合酶与抑制剂Aurin的结合模式信息将有助于设计和改造出效果更好的抗HIV-1整合酶的先导化合物.     

靶向整合过程不同步骤的HIV-1整合酶抑制剂的结构类型和研究进展

HIV-1整合酶是病毒复制所必需的三个基本酶之一, 为病毒所特有, 人体无对应的酶, 因此整合酶是理想的抗HIV药物设计的新靶标. HIV-1整合酶催化病毒DNA插入宿主染色体的过程涉及到整合酶与前病毒DNA形成整合前复合物、病毒DNA的3’末端切断和DNA链转移等步骤, 目前研究得最多的HIV-1整合酶抑制剂是抑制链转移反应的芳基二酮酸化合物, 其中的电子等排体衍生物Raltegravir (MK-0518)于2007年10月被美国食品药品管理局(FDA)批准上市, 而GS-9137处于三期临床试验, 此外还有多个处于临床前研究和临床阶段的药物. 根据抑制剂的不同作用机理, 本综述介绍了近年来所报道的HIV-1整合酶抑制剂的结构类型、药效团模型、研究进展及化学合成, 将整合酶抑制剂分为链转移反应抑制剂、整合酶-DNA结合抑制剂、整合酶3’端切除反应抑制剂、非专一性整合酶抑制剂以及多肽类抑制剂等几大类. 其中链转移反应抑制剂结构类型最丰富、发展最快. 整合酶抑制剂的出现丰富了高效抗逆转录病毒疗法(HAART), 为多重抗药性艾滋病患者提供了新的有效的治疗方案.     

Bovine Lactoferrampin,Human Lactoferricin,and Lactoferrin 1-11 Inhibit Nuclear Translocation of HIV Integrase

This study aimed to investigate fragments derived from human and bovine lactoferrins for ability to inhibit nuclear translocation of HIV-1 integrase. It was shown that human lactoferricin, human lactoferrin 1-11, and bovine lactoferrampin reduced nuclear distribution of HIV-1 integrase. Bovine lactoferrampin could inhibit both the activity and nuclear translocation of HIV-1 integrase. Human lactoferrampin, bovine lactoferricin, and bovine lactoferrin 1-11 had no effect on HIV-1 integrase nuclear translocation. Human lactoferrampin which inhibited the activity of integrase did not prevent its nuclear translocation. Human lactoferricin and lactoferrin 1-11 did not inhibit HIV-1 integrase nuclear translocation despite their ability to attenuate the enzyme activity. The discrepancy between the findings on reduction of HIV-1 activity and inhibition of nuclear translocation of HIV-1 integrase was due to the different mechanisms involved. A similar reasoning can also be applied to the different inhibitory potencies of the milk peptides on different HIV enzymes, i.e., nuclear translocation.     

De novo design based identification of potential HIV-1 integrase inhibitors: A pharmacoinformatics study

In the present study, pharmacoinformatics paradigms include receptor-based de novo design, virtual screening through molecular docking and molecular dynamics (MD) simulation are implemented to identify novel and promising HIV-1 integrase inhibitors. The de novodrug/ligand/molecule design is a powerful and effective approach to design a large number of novel and structurally diverse compounds with the required pharmacological profiles. A crystal structure of HIV-1 integrase bound with standard inhibitor BI-224436 is used and a set of 80,000 compounds through the de novo approach in LigBuilder is designed. Initially, a number of criteria including molecular docking, in-silico toxicity and pharmacokinetics profile assessments are implied to reduce the chemical space. Finally, four de novo designed molecules are proposed as potential HIV-1 integrase inhibitors based on comparative analyses. Notably, strong binding interactions have been identified between a few newly identified catalytic amino acid residues and proposed HIV-1 integrase inhibitors. For evaluation of the dynamic stability of the protein-ligand complexes, a number of parameters are explored from the 100 ns MD simulation study. The MD simulation study suggested that proposed molecules efficiently retained their molecular interaction and structural integrity inside the HIV-1 integrase. The binding free energy is calculated through the Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) approach for all complexes and it also explains their thermodynamic stability. Hence, proposed molecules through de novo design might be critical to inhibiting the HIV-1 integrase.     

Structures and biological activity of cinnamoyl derivatives of coumarins and dehydroacetic acid and their boron difluoride complexes

Computer-assisted screening for Kohonen self-organizing maps in terms of the quantitative structure??activity relationship (QSAR) model revealed the high potential activity of cinnamoyl derivatives of coumarin and dehydroacetic acid and their boron difluoride complexes against a number of biological targets, including HIV-1 integrase. The pronounced inhibitory properties of dehydroacetic acid derivatives and their boron difluoride complexes against HIV-1 integrase were experimentally confirmed by in vitro testing of their antiviral activity with respect to HIV-infected cells. The data obtained suggests a correlation between the structure of the compounds studied and their biological activity.     

用分子模拟方法研究HIV-1整合酶与咖啡酰基类抑制剂的相互作用

用分子对接和分子动力学(MD)模拟方法研究了一类咖啡酰基和没食子酰基类HIV-1整合酶抑制剂与整合酶之间的相互作用模式, 结果表明该类抑制剂分子上的两个侧链基团(咖啡酰基或没食子酰基)与整合酶的DDE基序之间的相互作用对抑制整合酶活性起到关键作用. 当侧链基团为没食子酰基时, 可以提高该类抑制剂与整合酶的结合能力. 采用线性相互作用能方法(LIE)计算了该类抑制剂与整合酶之间的结合自由能, 预测值与实验值相吻合, 均方根偏差RMSD为1.39 kJ•mol^-1, 以上结果可为基于结构的HIV-1整合酶抑制剂设计提供有用的信息.     

Structure, stereochemistry, and biological activity of integramycin, a novel hexacyclic natural product produced by Actinoplanes sp. that inhibits HIV-1 integrase

[structure: see text] HIV-1 integrase is a critical enzyme for viral replication, and its inhibition is an emerging target for potential antiviral chemotherapy. We have discovered a novel inhibitor, integramycin, from screening of fermentation extracts using an in vitro assay. Integramycin possesses a hexacyclic ring system and exhibited an IC50 value of 4 microM against HIV-1 integrase (strand transfer). The isolation, structure elucidation, stereochemistry, conformation, and biological activity has been described.     

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.     

Two New Compounds from Lindera chunii Merr.

The root of Lindera chunii Merr. is a noble traditional Chinese medicine and frequently used as a substitute for L. aggregata to cure the chronic disease of rheumatoid arthritis1. In our previous paper, we have reported some components from the roots of L…     

HPLC Bioassay of Elvitegravir using a Molecularly Imprinted Polymer Based Solid Phase Extraction in RAT Plasma: Application to Pharmacokinetic Studies

Journal of Analytical Chemistry - A water-compatible molecularly imprinted polymer (MIP) was prepared for specific extraction of HIV-1 integrase inhibitor elvitegravir (EVG). It was prepared by a...     

Synthesis and HIV-1 integrase inhibition activity of some N-arylindoles

Eight simple N-arylindoles were designed, synthesized and evaluated as human immunodeficiency virus (HIV)-1 integrase inhibitors in vitro for the first time. Among these compounds, 3b, 3e and 3g demonstrated significant anti-HIV-1 integrase activity. Especially 3b showed the highest anti-HIV-1 integrase activity with EC50 value of 7.88 microg/ml and TI value of 24.61. Meantime, some structure-activity relationships were also observed and will provide a new lead for design and discovery of more potent N-arylindoles as HIV-1 integrase inhibitors.     

Sesquiterpenes and alkaloids from Lindera chunii and their inhibitory activities against HIV-1 integrase

Three new eudesmane type sesquiterpenoid lindenanolides E (1), F (2) and G (3), and two new aporphine alkaloid lindechunines A (18) and B (20) were isolated from roots of Lindera chunii MERR., together with seven known sesquiterpenes including a new naturally-occurring lindenanolide H (4) and eight known aporphine alkaloids. The structures of these compounds were determined by spectroscopic means. Of the isolated compounds, hernandonine (14), laurolistine (16), 7-oxohernangerine (17) and lindechunine A (18) showed significant anti-human immunodeficiency virus type 1 (HIV-1) integrase activity with IC(50) values of 16.3, 7.7, 18.2 and 21.1 microM, respectively. The major alkaloids presented in the roots of L. chunii were quantitatively analyzed by an HPLC method.     

Cyclodidemniserinol trisulfate, a sulfated serinolipid from the Palauan ascidian Didemnum guttatum that inhibits HIV-1 integrase

[structure--see text] Bioassay-guided fractionation of extracts of the Palauan ascidian Didemnum guttatum led to the isolation of cyclodidemniserinol trisulfate (1) as an inhibitor of HIV-1 integrase, which is an attractive target for anti-retroviral chemotherapy. The structure of cyclodidemniserinol trisulfate (1), the stereochemistry of which was only partially determined, was elucidated by interpretation of NMR and mass spectral data.     

Eigen value analysis of HIV-1 integrase inhibitors.

A three-dimensional quantitative structure activity relationship using the eigen value analysis (EVA) paradigm applied to 41 HIV-1 integrase inhibitors that inhibit integrase mediated cleavage (3'-processing step) and integration (3'-strand transfer step) in vitro was performed. The training set consisted of 35 molecules from five structurally diverse classes: salicylhydrazines, lichen acids, coumarins, quinones, and thiazolothiazepines. Models derived using semiempirical (MOPAC AM1 and PM3) calculated normal-mode frequencies were compared. The predictive ability of each resultant model was evaluated using a test set comprised of six molecules belonging to a different structural class: hydrazides. Models derived using AM1 method showed considerable internal as well as external predictivity (r(2)(cv) = 0.806, r(2)(pred) = 0.761 for 3'-processing and r(2)(cv) = 0.677, r(2)(pred) = 0.591 for 3'-strand transfer).