Prediction of the binding mode of N2-phenylguanine derivative inhibitors to herpes simplex virus type 1 thymidine kinase

The probable binding mode of the herpes simplex virus thymidine kinase (HSV1 TK) N²-[substituted]-phenylguanine inhibitors is proposed. A computational experiment was designed to check some qualitative binding parameters and to calculate the interaction binding energies of alternative binding modes of N²-phenylguanines. The known binding modes of the HSV1 TK natural substrate deoxythymidine and one of its competitive inhibitors ganciclovir were used as templates. Both the qualitative and quantitative parts of the computational experiment indicated that the N²-phenylguanine derivatives bind to the HSV1 TK active site in the deoxythymidine-like binding mode. An experimental observation that N²-phenylguanosine derivatives are not phosphorylated during the interaction with the HSV1 TK gives support to the proposed binding mode.     

Computer-aided active-site-directed modeling of the Herpes Simplex Virus 1 and human thymidine kinase

Summary Thymidine kinase (TK), which is induced by Herpes Simplex Virus 1 (HSV1), plays a key role in the antiviral activity of guanine derivatives such as aciclovir (ACV). In contrast, ACV shows only low affinity to the corresponding host cell enzyme. In order to define the differences in substrate binding of the two enzymes on molecular level, models for the three-dimensional (3-D) structures of the active sites of HSV1-TK and human TK were developed. The reconstruction of the active sites started from primary and secondary structure analysis of various kinases. The results were validated to homologous enzymes with known 3-D structures. The models predict that both enzymes consist of a central core -sheet structure, connected by loops and -helices very similar to the overall structure of other nucleotide binding enzymes. The phosphate binding is made up of a highly conserved glycine-rich loop at the N-terminus of the proteins and a conserved region at the C-terminus. The thymidine recognition site was found about 100 amino acids downstream from the phosphate binding loop. The differing substrate specificity of human and HSV1-TK can be explained by amino-acid substitutions in the homologous regions.To achieve a better understanding of the structure of the active site and how the thymidine kinase proteins interact with their substrates, the corresponding complexes of thymidine and dihydroxypropoxyguanine (DHPG) with HSV1 and human TK were built. For the docking of the guanine derivative, the X-ray structure of Elongation Factor Tu (EF-Tu), co-crystallized with guanosine diphosphate, was taken as reference. Fitting of thymidine into the active sites was done with respect to similar interactions found in thymidylate kinase. To complement the analysis of the 3-D structures of the two kinases and the substrate enzyme interactions, site-directed mutagenesis of the thymidine recognition site of HSV1-TK has been undertaken, changing Asp¹⁶² in the thymidine recognition site into Asn. First investigations reveal that the enzymatic activity of the mutant protein is destroyed.     

Synthesis and Molecular Docking Studies of Novel 2‐Phenyl‐4‐Substituted Oxazole Derivatives as Potential Anti‐cancer Agents

A novel series of 2,4‐disubstituted oxazole derivatives were synthesized, screened for their anti‐tumor activity against three cell lines MCF‐ 7 , TK‐10, and UACC‐62. Molecular docking study was carried out against epidermal growth factor receptor. A new series of 2‐phenyl‐4‐substituted oxazole derivatives were synthesized. A series of chiral α‐amino acid derivatives 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 were synthesized by coupling various l ‐acylated amino acid azide 3. The synthesized compounds were tested for their in vitro antitumor activity against MCF‐7, TK‐10, and UACC‐62 cell lines. Compound 6 exhibited the strongest inhibitory activity against TK cell lines, while compound 12 showed the highest activity against MCF‐7 cell lines. Compound 14 was the most active against UACC‐62 cell lines. Furthermore, a molecular docking study of the most active compounds was carried out using epidermal growth factor receptor X‐ray 3D structure (protein data bank ID 1 M17). Docking results revealed that compound 6 showed the highest binding energy of ΔG = ?78.17 Kcal/mol.     

An Organocatalyzed Efficient One‐pot Synthesis,Biological Evaluation,and Molecular Docking Studies of 4,4′‐(Arylmethylene)bis‐(3‐methyl‐1‐phenyl‐1H‐pyrazol‐5‐ols)

The synthesis of 4,4′‐(arylmethylene)bis‐(3‐methyl‐1‐phenyl‐1H‐pyrazol‐5‐ol) derivatives catalyzed by ʟ‐proline is a simple, versatile, and efficient method. In vitro antioxidant, anti‐inflammatory, and antimicrobial activities of compounds 4a , 4b , 4c , 4d , 4e , 4f , 4g , 4h , 4i , 4j were studied. Furthermore, to rationalize the observed anti‐inflammatory activity data, molecular docking study has been performed against COX‐2 enzyme which revealed a good binding affinity for these molecules and could provide an insight into the various bonded and non‐bonded interactions guiding their binding affinity.     

A Bioorthogonal Chemical Reporter of Viral Infection

Pathogen‐selective labeling was achieved by using the novel gemcitabine metabolite analogue 2′‐deoxy‐2′,2′‐difluoro‐5‐ethynyluridine (dF‐EdU) and click chemistry. Cells infected with Herpes Simplex Virus‐1 (HSV‐1), but not uninfected cells, exhibit nuclear staining upon the addition of dF‐EdU and a fluorescent azide. The incorporation of the dF‐EdU into DNA depends on its phosphorylation by a herpes virus thymidine kinase (TK). Crystallographic analyses revealed how dF‐EdU is well accommodated in the active site of HSV‐1 TK, but steric clashes prevent dF‐EdU from binding human TK. These results provide the first example of pathogen‐enzyme‐dependent incorporation and labeling of bioorthogonal functional groups in human cells.     

Synthesis and Cytotoxicity Evaluation of Novel Andrographolide‐1,2,3‐Triazole Derivatives

A series of new andrographolide‐1,2,3‐triazole derivatives, 3a , 3b , 3c , 3d , 3e , 3f , 3g , 3h , 3i , 3j , 3k , were synthesized from a natural bioactive labdane type diterpenoid, andrographolide. All the derivatives were screened against human cancer cell lines MCF7, MDA‐MB‐231, COLO205, HepG2, K562, Hela, and HEK293 to evaluate their cytotoxic activity. All the compounds showed anticancer activity selectively against K562 cell line, with IC₅₀ values ranging from 8.00 to 17.11 µM, and are inactive against the rest of the cell lines. Compounds 3c and 3d showed significant cytotoxicity among the synthesized derivatives. The in silico docking studies revealed compounds 3b and 3d with high binding affinity against the cancer target, transient receptor potential vanilloid 1.     

Docking Study and Three‐Dimensional Quantitative Structure‐Activity Relationship (3D‐QSAR) Analyses and Novel Molecular Design of a Series of 4‐Aminoquinazolines as Inhibitors of Aurora B Kinase

The Aurora proteins are critical regulators of major mitotic events and attractive targets for anticancer therapy. 3D‐QSAR studies based on molecular docking were performed on a dataset of 40 4‐aminoquinazolines compounds. The CoMSIA model produced significantly better results than CoMFA model, with q²=0.652 and r²=0.991. The contours analysis provides useful information about the structural requirements for 4‐aminoquinazolines for inhibiting Aurora B. Scaffold hopping method was used to generate new structures based on the maximum common substructure of the training and test set compounds. The ADMET property, binding affinity and inhibitory activity of the new designed compounds were predicted, respectively. Finally 16 compounds were identified as the novel inhibitors for Aurora B kinase.     

取代脱氧脲苷的量子化学计算及分子对接

5取代6氮杂2’脱氧脲苷是一类疱疹单纯一型病毒胸苷激酶(ＨＳＶ1ＴＫ)抑制剂.研究此类化合物的合成、结构、杀菌活性及构效关系一直为科学界所关注[1-3].ＨＳＶ1ＴＫ可以催化胸苷的磷酸化反应,使生成胸苷磷酸脂,在ＤＮＡ合成的控制中起着重要的作用.其晶体结构的发表[4],使得我们能从分子水平上研究此类酶抑制剂与酶活性中心的作用机制,模拟其作用方式,从而实现ＨＳＶ1ＴＫ抑制剂的全新设计.本文从化合物(Ｉ)和(ＩＩ)(见图1)晶体结构出发,使用美国Ｔｒｉｐｏｓ公司开发的三维分子模拟软件包ＳＹＢＹＬ63[5],采用ＭＯＰＡＣ界面中ＰＭ3[6]程…     

Oligonucleotides Containing Novel 4′‐C‐ or 3′‐C‐(Aminoalkyl)‐Branched Thymidines

The synthesis of four novel 3′‐C‐branched and 4′‐C‐branched nucleosides and their transformation into the corresponding 3′‐O‐phosphoramidite building blocks for automated oligonucleotide synthesis is reported. The 4′‐C‐branched key intermediate 11 was synthesized by a convergent strategy and converted to its 2′‐O‐methyl and 2′‐deoxy‐2′‐fluoro derivatives, leading to the preparation of novel oligonucleotide analogues containing 4′‐C‐(aminomethyl)‐2′‐O‐methyl monomer X and 4′‐C‐(aminomethyl)‐2′‐deoxy‐2′‐fluoro monomer Y (Schemes 2 and 3). In general, increased binding affinity towards complementary single‐stranded DNA and RNA was obtained with these analogues compared to the unmodified references (Table 1). The presence of monomer X or monomer Y in a 2′‐O‐methyl‐RNA oligonucleotide had a negative effect on the binding affinity of the 2′‐O‐methyl‐RNA oligonucleotide towards DNA and RNA. Starting from the 3′‐C‐allyl derivative 28 , 3′‐C‐(3‐aminopropyl)‐protected nucleosides and 3′‐O‐phosphoramidite derivatives were synthesized, leading to novel oligonucleotide analogues containing 3′‐C‐(3‐aminopropyl)thymidine monomer Z or the corresponding 3′‐C‐(3‐aminopropyl)‐2′‐O,5‐dimethyluridine monomer W (Schemes 4 and 5). Incorporation of the 2′‐deoxy monomer Z induced no significant changes in the binding affinity towards DNA but decreased binding affinity towards RNA, while the 2′‐O‐methyl monomer Z induced decreased binding affinity towards DNA as well as RNA complements (Table 2).     

Synthesis,Docking, ADME‐Tox Study of 2‐(2‐(2‐Chlorophenyl)quinoline‐4‐carbonyl)‐N‐substituted hydrazinecarbothioamide Derivatives and Their Biological Evaluation

A series of 2‐(2‐(2‐chlorophenyl)quinoline‐4‐carbonyl)‐N‐substituted hydrazinecarbothioamide derivatives were synthesized by facile and efficient conventional method. The structures of the compounds were elucidated with the aid of an elemental analysis, IR, ESI‐MS, ¹H‐NMR, and ¹³C‐NMR spectral data. The synthesized compounds were evaluated for their in vitro antibacterial, antifungal, antimalarial, and antituberculosis activity against standard drugs. The bacterial studies were determined against gram‐positive and negative bacteria. These compounds were found to a broad spectrum of activity against the screened bacteria, but poor activity was observed against Pseudomonas aeruginosa and Escherichia coli. Compounds 8d , 8f , 8i , 8l , and 8n showed the potent activity against Staphylococcus aureus. Compounds 8d , 8g , 8k , 8l , and 8q show the potent activity against antimalarial as compared with the standard drugs Chloroquine, Quinine and compounds 8h , 8n , and 8o shows mild activity against H37Rv strain. Molecular docking revealed that synthesized derivatives and target proteins were actively involved in a binding pattern and had a significant corelation with biological activity. We have also performed a molecular dynamics and ADME‐Tox parameters for the synthesized compounds.     

Synthesis,Antiproliferative, and c‐Src Kinase Inhibitory Activities of 4‐Oxo‐4H‐1‐benzopyran Derivatives

A new class of 4‐oxo‐4H‐1‐benzopyran derivatives were synthesized and their antiproliferative activity examined against a panel of three human cancer cell lines, that is, breast carcinoma (MDA‐MB‐468), ovarian adenocarcinoma (SK‐OV‐3), and colorectal adenocarcinoma (HT‐29). Two compounds, that is, 3‐hexyl‐7,8‐dihydroxy‐4‐oxo‐4H‐1‐benzopyran and (E)‐ethyl 3‐(7‐methoxy‐4‐oxo‐4H‐1‐benzopyran‐3‐yl)acrylate were found to be potent against all three cancer cell lines studied at 50 μM concentration. Also, the inhibitory potency of the compounds was evaluated against active Src kinase. A few of these compounds exhibited modest Src kinase inhibitory activity (IC₅₀ = 52–57 μM). Structure‐activity relationship studies with respect to the nature and position of substituents on the lead compounds could be further exploited for the design and development of more potent antiproliferative agents and/or Src kinase inhibitors.     

Glycerol Mediated Synthesis,Biological Evaluation,and Molecular Docking Study of 4‐(1H‐pyrazol‐4‐yl)‐polyhydroquinolines as Potent Antitubercular Agents

A series of 4‐(1H‐pyrazol‐4‐yl)‐polyhydroquinolines were synthesized through one‐pot four‐component Hantzsch condensation of 1,3‐diphenyl‐1H‐pyrazole‐4‐carbaldehydes, ammonium acetate, dimedone, and alkyl acetoacetate in glycerol as a green reaction medium. The structures of the compounds are verified by spectroscopic methods and screened for their antimicrobial activity against Mycobacterium tuberculosis H37RV strain. Almost all the synthesized derivatives reveal excellent antitubercular activity based on minimum inhibitory concentration. Especially the compounds 5h and 5k exhibit outstanding antitubercular activity with minimum inhibitory concentration 1.6 μg/mL. In addition, molecular docking study of synthesized scaffolds against enoyl‐acyl carrier protein reductase from M. tuberculosis was performed to propose the binding modes.     

Design and Synthesis of Antimicrobial Active (E)‐(3‐(Substituted‐styryl)‐7H‐furo[2,3‐f]chromen‐2‐yl)(phenyl)methanone Derivatives and Their In Silico Molecular Docking Studies

Nine new (E)‐(3‐(substituted‐styryl)‐7H‐furo[2,3‐f]chromen‐2‐yl)(phenyl)methanone derivatives, 7 ( a – i ), with an efficient microwave‐assisted synthetic method was achieved by reacting with (E)‐3‐(aryl)‐1‐(5‐hydroxy‐2H‐chromen‐6‐yl)prop‐2‐en‐1‐ones and 2‐bromo‐1‐(4‐bromophenyl)ethanone. The microwave irradiation method was found to be best with high yields and with shorter reaction times compared with the conventional method. All the new products structural assignments were confirmed by spectral data like FTIR, ¹H NMR, ¹³C NMR, ESI MS, and analytical data. Moreover, these newly synthesized compounds were tested in vitro for their antimicrobial activity against various bacterial and fungal strains. Some of these new chromen derivatives like 7b , 7c , and 7d exhibits good antibacterial and antifungal activities. Furthermore, these biological evolution results were a good correlation with molecular docking studies performed based on their computational DFT minimized structures exhibited high binding energies.     

Synthesis and Docking Studies of Some 1,2,3‐Benzotriazine‐4‐one Derivatives as Potential Anticancer Agents

Newly synthesized 1,2,3‐benzotriazine‐4‐one derivatives substituted at position‐3 were characterized by various analytical and spectral techniques. The in vitro antitumor activity was evaluated against three different cell lines (liver cells cancer, colorectal cancer, and breast cancer), where compounds 7b , 15 , and 25 showed strong antitumor activity with IC₅₀ ranging from 5.54 to 16.26 μM. In addition, molecular modeling studies using MOE were performed to investigate their binding modes to the C‐Met kinase active site. Docking results demonstrated that all new compounds recognized the active sites of C‐Met kinase and form different types of bonding interactions with key active site amino acid residues.     

A pseudoreceptor modelling study of the varicella-zoster virus and human thymidine kinase binding sites

Summary A representative range of pyrimidine nucleoside analogues that are known to inhibit herpes simplex virus (HSV) replication have been used to construct receptor binding site models for the varicella-zoster virus (VZV), thymidine kinase (TK) and human TK1. Given a set of interacting ligands, superimposed in such a manner as to define a pharmacophore, the pseudoreceptor modelling technique Yak provides a means of building binding site models of macromolecules for which no three-dimensional experimental structures are available. Once the models have been evaluated by their ability to reproduce experimental binding data [Vedani et al., J. Am. Chem. Soc., 117 (1995) 4987], they can be used for predictive purposes. Calculated and experimental values of relative binding affinity are compared. Our models suggest that the substitution of one residue may be sufficient to determine ligand subtype affinity.     

Synthesis,Anticancer Evaluation,and Molecular Docking Studies of Novel (4‐Hydroxy‐2‐Thioxo‐3,4‐Dihydro‐2H‐[1,3]Thiazin‐6‐Yl)‐Chromen‐2‐Ones via a Multicomponent Approach

A series of coumarin‐substituted 1,3‐thiazine‐2‐thione derivatives ( 4a–m ) were synthesized via the multicomponent reaction of 3‐chloro‐3‐(2‐oxo‐2H‐chromen‐3‐yl)acrylaldehyde ( 1 ) carbon disulfide ( 2 ), and various primary amines ( 3 ), in presence of triethylamine and acetonitrile under stirring with good yields. The structures of all the synthesized compounds were characterized by analytical and spectral studies. Further, the synthesized compounds were screened for their in vitro antiproliferative activities against different cancer cell lines (A549, MDA‐MB‐231, MCF7, HeLa, and B16F10). Studies on the molecular interactions to recognize the hypothetical binding motif of the title compounds with the target Hsp 100 were carried out employing the Schrodinger software. Compounds 4a , 4c and 4m showed activity against all the five cell lines compared with the reference drug, and 4a exhibited the least IC₅₀ concentration of 7.56 ± 1.07 μg/mL against MCF7. This in vitro anticancer result was supported by in silico docking and in silico ADME (absorption, distribution, metabolism, and excretion) studies as well.     

Synthesis and Antioxidant Properties of New Substituted 8‐Methyl‐6‐phenyl‐5,6‐dihydro‐4H‐1,3,2‐benzodioxaphosphocine‐2‐oxide Derivatives

A new route for the synthesis of substituted 8‐methyl‐6‐phenyl‐5,6‐dihydro‐4H‐1,3,2‐benzodioxaphosphocine‐2‐oxide derivatives has been developed by using cinnamic acid and p‐cresol via condensation, reduction, and followed by phosphorylation steps. The title compounds were characterized by IR, ¹H, ¹³C, ³¹P, and mass spectral studies and elemental analysis. The title compounds have been investigated for their antioxidant activity with respect to their IC₅₀ values using 2,2‐diphenyl‐1‐picrylhydrazyl, NO radical scavenging activities, and reducing power assay. The results obtained from the aforementioned methods revealed that 2‐phenylamino derivatives have shown greater free radical scavenging activity when compared with those of the phenoxy derivatives and is attributed to the presence of secondary amino group, which is able to produce free radicals easily.     

Novel Delta‐Opioid‐Receptor‐Selective Ligands in the 14‐Alkoxy‐Substituted Indolo‐ and Benzofuromorphinan Series

Several new indolo‐ and benzofuromorphinans substituted at the positions 5 and 14 were prepared and tested in vitro by means of opioid‐receptor binding and functional ([³⁵S]GTPγS binding) assays. All compounds 1 – 11 displayed high affinity for δ opioid‐binding sites (Table 1). Compound 4 proved to be an agonist, and all other compounds were antagonists. The presence of a Me group at position 5 induced no change in δ affinity (see 1 vs. 3 ), but decreased the μ and κ affinities. An EtO group at position 14 conferred a very high affinity and also high selectivity to δ opioid receptors (see 2 and 10 ). Chain elongation of the 14‐alkoxy group resulted in compounds with reduced δ affinity and selectivity (see 4 and 11 and also 5 – 9 ). The results of the present study indicate that the 5‐ and 14‐positions of indolo‐ and benzofuromorphinans represent critical sites that could be a trigger to develop new compounds with increased δ affinity and/or selectivity.     

Synthesis of Novel 1,2,4‐Triazole‐3‐thione Derivatives as Influenza Neuraminidase Inhibitors

A series of 1,2,4‐triazole‐3‐thione derivatives ( 6a – 6t ) were synthesized and evaluated against influenza viruses (H1N1) neuraminidase (NA) in vitro. Eighteen compounds exhibited inhibitory potency with IC₅₀ values ranging from 14.68 ± 0.49 to 39.85 ± 4.23 μg/mL. Among them, compounds 6e and 6h showed significant inhibitory activity with IC₅₀ values of 14.97 ± 0.70 and 14.68 ± 0.49 μg/mL, respectively. Structure activity relationships were established. Molecular docking studies were performed to understand the binding interaction between active compounds and NA.