-
[show abstract]
[hide abstract]
ABSTRACT: Database survey in this study revealed that about one-third of the protein structures deposited in the Protein Data Bank (PDB) contain arginine-arginine (Arg-Arg) pairing with a carbon···carbon (CZ···CZ) interaction distance less than 5 Å. All the Arg-Arg pairings were found to bury in a polar environment composed of acidic residues, water molecules, and strong polarizable or negatively charged moieties from binding site or bound ligand. Most of the Arg-Arg pairings are solvent exposed and 68.3% Arg-Arg pairings are stabilized by acidic residues, forming Arg-Arg-Asp/Glu clusters. Density functional theory (DFT) was then employed to study the effect of environment on the pairing structures. It was revealed that Arg-Arg pairings become thermodynamically stable (about -1 kcal/mol) as the dielectric constant increases to 46.8 (DMSO), in good agreement with the results of the PDB survey. DFT calculations also demonstrated that perpendicular Arg-Arg pairing structures are favorable in low dielectric constant environment, while in high dielectric constant environment parallel structures are favorable. Additionally, the acidic residues can stabilize the Arg-Arg pairing structures to a large degree. Energy decomposition analysis of Arg-Arg pairings and Arg-Arg-Asp/Glu clusters showed that both solvation and electrostatic energies contribute significantly to their stability. The results reported herein should be very helpful for understanding Arg-Arg pairing and its application in drug design.
The Journal of Physical Chemistry B 04/2013; · 3.70 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Tuberculosis (TB) is an infectious disease caused by the pathogen Mycobacterium tuberculosis (M. tuberculosis), killing about two million people worldwide each year. An increase in the prevalence of drug-resistant strains of M. tuberculosis in the past decades has renewed focus on the development of new drugs that can treat both drug-sensitive and resistant TB infections. M. tuberculosis evades the host immune system and drug regimes by entering dormant phase within macrophage. As a consequence, there is a pressing need for new vaccines and antimicrobials to treat persistent infections. As clinically used antibiotics target very few essential functions of mycobacterium, it is rational that identification of new targets that are essential for bacterial growth and survival can serve as starting point for designing of novel drugs to cure both drug-sensitive and resistant TB infections. With the development of molecular biology and structural biology and the availability of the genome sequence of M. tuberculosis, some success has been achieved in the identification of new targets in M. tuberculosis and their relevant inhibitors. This review summarizes about ninety important targets that participate in a range of diverse physiological processes in M. tuberculosis and seven new drugs currently in clinical phase 2 or 3 trials. In addition, promising inhibitors with novel mechanisms of action and clinical vaccine candidates are highlighted.
Current drug targets 04/2013; · 3.93 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: In recent years, several specific imidazolium-based ionic liquids with halogen substituents on the imidazole ring as well as on the alkyl chains have been reported. In this work, noncovalent interactions in four halogenated ionic liquids, i.e. 2-bromo-/iodo- and 4,5-dibromo-/diiodo-1,3-dimethylimidazolium trifluoromethanesulfonates, were systematically investigated using density functional theory calculations. The structural and energetic properties of the ion pairs for such ionic liquids have been fully examined and compared with the non-halogenated ones. It was found that C-XO halogen bonds, C-HO hydrogen bonds, and electrostatic interactions with the anion located over the imidazole ring in the ion pairs. In addition, the structures and energetics of two ion pairs for such ionic liquids were also explored to reproduce experimental observations. The halogen-bonded ring structures and the conformers with the concurrent C-HO and C-XO contacts were predicted, consistent with the X-ray crystal structures of corresponding organic salts. Finally, the implications of the observed structural and energetic features of ion pairs on the design of halogen-bonding ionic liquids were discussed. The results presented herein should provide useful information in the development of novel halogenated ionic liquids used for specific tasks ranging from organic synthesis to gas absorption.
Physical Chemistry Chemical Physics 02/2013; 15(12):4405-14. · 3.57 Impact Factor
-
Enguang Feng,
Woo-Jin Shin,
Xuelian Zhu,
Jian Li,
Deju Ye,
Jiang Wang,
Mingyue Zheng,
Jian-Ping Zuo,
Kyoung Tai No,
Xian Liu, Weiliang Zhu,
Wei Tang,
Baik-Lin Seong,
Hualiang Jiang,
Hong Liu
[show abstract]
[hide abstract]
ABSTRACT: In order to exploit the 430-cavity in the active sites of neuraminidases, 20 zanamivir analogs with C-1 and C-4-modification were synthesized, and their inhibitory activities against both group-1 (H5N1, H1N1) and group-2 neuraminidases (H3N2) were determined. Compound 9f exerts the most potency, with IC(50) value of 0.013, 0.001 and 0.09 μM against H3N2, H5N1 and H1N1, which is similar to that of zanamivir (H3N2: IC(50) 0.0014 μM, H5N1: IC(50) 0.012 μM, H1N1: IC(50) 0.001 μM). Pharmacokinetic studies of compound 9f in rats showed a much longer plasma half-life (t1/2) than that of zanamivir following oral administration. Molecular modeling provided information about the binding model between these new inhibitors and neuraminidase, with the elongated groups at the C-1 position being projected towards the 430-loop region. This study may represent a novel starting point for the future development of improved anti-flu agents.
Journal of Medicinal Chemistry 01/2013; · 4.80 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Two conserved histidine residues are located near the mid-point of the conduction channel of ammonium transport proteins. The role of these histidines in ammonia and methylamine transport was evaluated by using a combination of in vivo studies, molecular dynamics (MD) simulation, and potential of mean force (PMF) calculations. Our in vivo results showed that a single change of either of the conserved histidines to alanine leads to the failure to transport methylamine but still facilitates good growth on ammonia, whereas double histidine variants completely lose their ability to transport both methylamine and ammonia. Molecular dynamics simulations indicated the molecular basis of the in vivo observations. They clearly showed that a single histidine variant (H168A or H318A) of AmtB confines the rather hydrophobic methylamine more strongly than ammonia around the mutated sites, resulting in dysfunction in conducting the former but not the latter molecule. PMF calculations further revealed that the single histidine variants form a potential energy well of up to 6 kcal/mol for methylamine, impairing conduction of this substrate. Unlike the single histidine variants, the double histidine variant, H168A/H318A, of AmtB was found to lose its unidirectional property of transporting both ammonia and methylamine. This could be attributed to a greatly increased frequency of opening of the entrance gate formed by F215 and F107, in this variant compared to wild-type, with a resultant lowering of the energy barrier for substrate to return to the periplasm.
PLoS ONE 01/2013; 8(5):e62745. · 4.09 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Phase I metabolism is an important consideration in drug discovery because it profoundly affects the toxicity and activity profile of a drug candidate. In these metabolic processes, CYP450 family is responsible for the majority of biotransformation events. However, it is still an important challenge to predict sites of metabolism (SOM) of a new chemical entity due to the complex reaction mechanism and variety in CYP450 enzymes. SOMEViz is an online service designed for predicting and visualizing human cytochromes P450 (CYP450)-mediated sites of metabolism (SOM) of a molecule, on the basis of a previously reported model. The service provides an access for predicting sites of metabolism of molecules with reasonable accuracy, and predicted results are shown in a user-friendly as well as interactive way, which may help chemists explore metabolism properties of chemicals in the early stage of drug discovery. The web-based GUI of SOMEViz offers user a straightforward way to manage and visualize the sites of metabolism (SOM) prediction results. The service and examples are available free of charge at http://www.dddc.ac.cn/some.
Protein and Peptide Letters 09/2012; 19(9):905-9. · 1.94 Impact Factor
-
Xiangqian Kong,
Jie Qin,
Zeng Li,
Adina Vultur,
Linjiang Tong,
Enguang Feng,
Geena Rajan,
Shien Liu,
Junyan Lu,
Zhongjie Liang,
Mingyue Zheng, Weiliang Zhu,
Hualiang Jiang,
Meenhard Herlyn,
Hong Liu,
Ronen Marmorstein,
Cheng Luo
[show abstract]
[hide abstract]
ABSTRACT: Oncogenic mutations in critical nodes of cellular signaling pathways have been associated with tumorigenesis and progression. The B-Raf protein kinase, a key hub in the canonical MAPK signaling cascade, is mutated in a broad range of human cancers and especially in malignant melanoma. The most prevalent B-Raf(V600E) mutant exhibits elevated kinase activity and results in constitutive activation of the MAPK pathway, thus making it a promising drug target for cancer therapy. Herein, we describe the development of novel B-Raf(V600E) selective inhibitors via multi-step virtual screening and hierarchical hit optimization. Nine hit compounds with low micromolar IC(50) values were identified as B-Raf(V600E) inhibitors through virtual screening. Subsequent scaffold-based analogue searching and medicinal chemistry efforts significantly improved both the inhibitor potency and oncogene selectivity. In particular, compounds 22f and 22q possess nanomolar IC(50) values with selectivity for B-Raf(V600E)in vitro and exclusive cytotoxicity against B-Raf(V600E) harboring cancer cells.
Organic & Biomolecular Chemistry 08/2012; 10(36):7402-17. · 3.70 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Carcinogenicity is an important toxicological endpoint that poses high concern to drug discovery. In this study, we developed a method to extract structural alerts (SAs) and modulating factors of carcinogens on the basis of statistical analyses. First, the Gaston algorithm, a frequent subgraph mining method, was used to detect substructures that occurred at least six times. Then, a molecular fragments tree was built and pruned to select high-quality SAs. The p-value of the parent node in the tree and that of its children nodes were compared, and the nodes that had a higher statistical significance in binomial tests were retained. Finally, modulating factors that suppressed the toxic effects of SAs were extracted by three self-defining rules. The accuracy of the 77 SAs plus four SA/modulating factor pairs model for the training set, and the test set was 0.70 and 0.65, respectively. Our model has higher predictive ability than Benigni's model, especially in the test set. The results highlight that this method is preferable in terms of prediction accuracy, and the selected SAs are useful for prediction as well as interpretation. Moreover, our method is convenient to users in that it can extract SAs from a database using an automated and unbiased manner that does not rely on a priori knowledge of mechanism of action.
Journal of Chemical Information and Modeling 07/2012; 52(8):1994-2003. · 4.68 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: In this study for searching novel B-Raf(V600E) inhibitors, pharmacophore-based virtual screening identified 1 as a hit bearing 5-benzylidene-2-thioxodihydropyrimidine-4,6(1H,5H)-dione. Based on 1, scaffold hopping inspired by molecular docking discovered 5-(furan-2-ylmethylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-dione as a new and better scaffold. Substructure search with the new scaffold identified 28 active compounds, among which 12 compounds (42.9%) showed IC(50) less than 1 μM. Especially, compound 3o, which is 10-fold more potent than the hit 1, is a potent inhibitor comparable to that of the marketed drug vemurafenib.
Bioorganic & medicinal chemistry letters 07/2012; 22(17):5428-37. · 2.65 Impact Factor
-
Deju Ye,
Woo-Jin Shin,
Ning Li,
Wei Tang,
Enguang Feng,
Jian Li,
Pei-Lan He,
Jian-Ping Zuo,
Hanjo Kim,
Ky-Youb Nam, Weiliang Zhu,
Baik-Lin Seong,
Kyoung Tai No,
Hualiang Jiang,
Hong Liu
[show abstract]
[hide abstract]
ABSTRACT: With the introduction of bioisosteres of the guanidinium group together with scaffold hopping, 35 zanamivir analogs with C-4-modification were synthesized, and their inhibitory activities against both group-1 and group-2 neuraminidase (H5N1 and H3N2) were determined. Compound D26 exerts the most potency, with IC(50) values of 0.58 and 2.72 μM against N2 and N1, respectively. Further preliminary anti-avian influenza virus (AIV, H5N1) activities against infected MDCK cells were evaluated, and D5 exerts ∼58% protective against AIV infection, which was comparable to zanamivir (∼67%). In a rat pharmacokinetic study, compound D5 showed an increased plasma half-life (t(1/2)) compared to zanamivir following either intravenous or oral administration. This study may represent a new start point for the future development of improved anti-AIV agents.
European journal of medicinal chemistry 06/2012; 54:764-70. · 3.27 Impact Factor
-
Jing Deng,
Ning Li,
Hongchuan Liu,
Zhili Zuo,
Oi Wah Liew,
Weijun Xu,
Gang Chen,
Xiankun Tong,
Wei Tang,
Jin Zhu,
Jianping Zuo,
Hualiang Jiang,
Cai-Guang Yang,
Jian Li, Weiliang Zhu
[show abstract]
[hide abstract]
ABSTRACT: By virtual screening, compound 1 was found to be active against NS2B-NS3 protease (IC(50) = 13.12 ± 1.03 μM). Fourteen derivatives (22) of compound 1 were synthesized, leading to the discovery of four new inhibitors with biological activity. In order to expand the chemical diversity of the inhibitors, small-molecule-based scaffold hopping was performed on the basis of the common scaffold of compounds 1 and 22. Twenty-one new compounds (23, 24) containing quinoline (new scaffold) were designed and synthesized. Protease inhibition assays revealed that 12 compounds with the new scaffold are inhibitors of NS2B-NS3 protease. Taken together, 17 new compounds were discovered as NS2B-NS3 protease inhibitors with IC(50) values of 7.46 ± 1.15 to 48.59 ± 3.46 μM, and 8 compounds belonging to two different scaffolds are active to some extent against DENV based on luciferase reporter replicon-based assays. These novel chemical entities could serve as lead structures for discovering therapies against DENV.
Journal of Medicinal Chemistry 06/2012; 55(14):6278-93. · 4.80 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: According to our survey of the Cambridge Structural Database (CSD), a great number of crystal structures, in which halogen bonds and aromatic stacking interactions are present and play an important role in crystal packing, have been extracted. In this work, ab initio calculations at the MP2 level of theory were performed to investigate the mutual influence between halogen bonds and π-π stacking interactions. Different energetic effects are observed in the studied complexes where the two kinds of noncovalent interactions coexist, which can be rationalized by the direction of charge transfer for the two interactions. These effects have been analyzed in detail in terms of the structural, energetic, and charge transfer properties of the complexes. In addition, the quantum theory of atoms in molecules (QTAIM) was also employed to characterize the interactions and to examine the strengthening or weakening of the interactions, depending on the variations of electron density on the bond and cage critical points. Finally, certain crystal structures retrieved from the CSD have been selected to provide experimental evidence of the combination of the two interactions.
Physical Chemistry Chemical Physics 06/2012; 14(28):9948-55. · 3.57 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Drug metabolism is a major consideration for modifying drug clearance and also a primary source for drug metabolite-induced toxicity. Cytochromes P450 (CYPs) are the major enzymes involved in drug metabolism and bioactivation, accounting for almost 75% of the total drug metabolism. Predicting the sites of cytochrome P450-mediated metabolism of drug-like molecules using in silico methods would be highly beneficial and time efficient. An ideal system would enable researchers to make a confident elimination decision based purely on the structure of a new compound. In this review, several tools and models for predicting probable site of metabolism (SOM) have been compared and discussed. The methods are generally based on enzyme structure, ligand structure, and combined methods. Although all the methods have certain accuracy and considerable progress has been made, the results of the calculations still need careful inspection.
Protein and Peptide Letters 05/2012; · 1.94 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Human neutrophil elastase (HNE) has been implicated as a major contributor in the pathogenesis of diseases, such as pulmonary emphysema, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and other inflammatory diseases. Therefore, searching for appropriate and potential human neutrophil elastase inhibitors (HNEI) that would restore the balance between the free enzyme and the endogenous inhibitors would be of therapeutic interest. ONO-5046 is the first specific HNEI to improve respiratory function and protect lung tissues against various lung injuries. However, the mechanism of ONO-5046 to HNE is still unclear. In this study, the binding properties of ONO-5046 were investigated through (1)H NMR, molecular docking, and bioassay methods to understand the effect of ONO-5046 to HNE. The proton spin-lattice relaxation rate and molecular rotational correlation time results indicated that ONO-5046 has higher affinity with HNE. The molecular docking study showed that ONO-5046 is perfectly matched for the primary enzyme specificity pocket (S1 pocket), and is tightly bound to this pocket of HNE through hydrophobic and hydrogen bonding interactions. The results of both methods were validated through analysis of the HNE inhibitory activity bioassay of ONO-5046 with an IC(50) value of 87.05 nM. Our data suggested that ONO-5046 could bind to HNE through direct interaction, and that molecular docking and NMR methods are valid approaches to survey new HNEI.
International journal of biological macromolecules 05/2012; 51(3):196-200. · 2.37 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The M2 protein from influenza A virus is a tetrameric ion channel. It was reported that the permeation of the ion channel
is correlated with the hydrogen bond network among His37 residues and the cation-π interactions between His37 and Trp41. In
the present study, the hydrogen bonding network of 4-methyl-imidazoles was built to mimic the hydrogen bonds between His37
residues, and the cation-π interactions between 4-methyl-imidazolium and indole systems were selected to represent the interactions
between His37 and Trp41. Then, quantum chemistry calculations at the MP2/6-311G** level were carried out to explore the properties
of the hydrogen bonds and the cation-π interactions. The calculation results indicate that the binding strength of the N-H…N
hydrogen bond between imidazole rings is up to −6.22 kcal·mol−1, and the binding strength of the strongest cation-π interaction is up to −18.8 kcal·mol−1 (T-shaped interaction) or −12.3 kcal·mol−1 (parallel stacking interaction). Thus, the calculated binding energies indicate that it is possible to control the permeation
of the M2 ion channel through the hydrogen bond network and the cation-π interactions by altering the pH values.
Science in China Series B Chemistry 04/2012; 51(8):768-775. · 1.20 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: INTRODUCTION: A large number of drugs and drug candidates in clinical development contain halogen substituents. For a long time, only the steric and lipophilic contributions of halogens were considered when trying to exploit their effects on ligand binding. However, the ability of halogens to form stabilizing interactions, such as halogen bonding, hydrogen bonding and multipolar interactions, in biomolecular systems was revealed recently. Halogen bonding, the non-covalent interaction in which covalently bound halogens interact with Lewis bases, has now been utilized in the context of rational drug design. AREAS COVERED: The purpose of this review is to show how halogen bonding could be used in drug design, and in particular, to stimulate researchers to apply halogen bonding in lead optimization. This review article covers the recent advances relevant to halogen bonding in drug discovery and biological design over the past decade, including database survey of this interaction in protein-ligand complexes, molecular mechanical investigations of halogen bonding in drug discovery and applications of this interaction in the development of halogenated ligands as inhibitors and drugs for protein kinases, serine protease factor Xa, HIV reverse transcriptase and so on. EXPERT OPINION: Halogen bonding should intentionally be used as a powerful tool, comparable with hydrogen bonding, to enhance the binding affinity and also influence the binding selectivity. Rational design of new and potent inhibitors against therapeutic targets through halogen bonding continues to be an exciting area, which will be further elucidated with the combination of various experimental techniques and theoretical calculations in the forthcoming years.
Expert Opinion on Drug Discovery 03/2012; 7(5):375-83. · 2.12 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The interplay between halogen bonds and cation-π interactions is investigated by ab initio calculations at the MP2 level of theory. Different energetic effects are observed in the studied complexes in which halogen bonds and cation-π interactions coexist, which can be ascribed to the direction of charge transfer for the two interactions. These effects are analyzed in detail in terms of the structural, energetic, and charge-transfer properties of the complexes. In addition, the quantum theory of atoms in molecules is employed to characterize the interactions and to examine their enhancement and attenuation in terms of the variations in electron density at the bond and cage critical points. Finally, experimental evidence for a combination of the two interactions is obtained from the Cambridge Structural Database.
ChemPhysChem 03/2012; 13(8):2154-61. · 3.41 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Energetic effects between halogen bonds and anion-π or lone pair-π interactions have been investigated by means of ab initio MP2 calculations. 1,4-diiodo-perfluorobenzene, a very effective building block for crystal engineering based on halogen bonding, is selected in this work both as electron-deficient π aromatic ring and as halogen bond donor. Additive and diminutive effects are observed when halogen bonds and anion-π/lone pair-π interactions coexist in the same complex, which can be ascribed to the same direction of charge transfer for the two interactions. These effects have been analyzed in detail by the structural, energetic, and AIM properties of the complexes. Finally, experimental evidence of the combination of the interactions has been obtained from the Cambridge Structural Database.
The Journal of Physical Chemistry A 02/2012; 116(10):2591-7. · 2.95 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Human African trypanosomiasis (HAT), caused by the protozoan parasite Trypanosoma brucei, is a neglected fatal disease. Leucyl-tRNA synthetase (LeuRS), which has been successfully applied in the development of antifungal agent, represents a potential antiprotozoal drug target. In this study, a 3D model of T. brucei LeuRS (TbLeuRS) synthetic active site was constructed and subjected to virtual screening using a combination of pharmacophore- and docking-based methods. A new 2-pyrrolinone scaffold was discovered and the structure-activity relationship (SAR) studies aided by the docking model and organic synthesis were carried out. Compounds with various substituents on R(1), R(2) and R(3) were synthesized and their SAR was discussed.
Bioorganic & medicinal chemistry 02/2012; 20(3):1240-50. · 2.82 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Chitinases belong to family 18 glycosyl hydrolases that can hydrolyze chitin by cleaving β-1,4-glycosidic bond, and are at key points in the life cycles of organism. The inhibitors of chitinases not only have chemotherapeutic potential against fungi, insects, but also hold anti-inflammatory efficacy against asthma and allergic disease in human. This review summarizes the structural characters of chitinases, the proposed catalytic mechanism, furthermore, also gives descriptions of currently existing inhibitors. In addition, computational studies of the interaction modes of chitinases with different inhibitors and substrates, as well as the inhibitor design of chitinases, are summarized so as to obtain an overall understanding for chitinases.
Current drug targets 01/2012; 13(4):502-11. · 3.93 Impact Factor
