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Concept: Molecular modelling


BACKGROUND: Recently, various metallocenes were synthesized and analyzed by biological activity point of view (such as antiproliferative properties): ruthenocenes, cobaltoceniums, titanocenes, zirconocenes, vanadocenes, niobocenes, molibdocenes etc. Two main disadvantages of metallocenes are the poor hydrosolubility and the hydrolytic instability. These problems could be resolved in two ways: synthetically modifying the structure or finding new formulations with enhanced properties. The aqueous solubility of metallocenes with cytostatic activities could be enhanced by molecular encapsulation in cyclodextrins, as well as the hydrolytic instability of these compounds could be reduced. RESULTS: This study presents a theoretical approach on the nanoencapsulation of a series of titanocenes with cytotoxic activity in alpha-, beta-, and gamma-cyclodextrin. The HyperChem 5.11 package was used for building and molecular modelling of titanocene and cyclodextrin structures, as well as for titanocene/cyclodextrin complex optimization. For titanocene/cyclodextrin complex optimization experiments, the titanocene and cyclodextrin structures in minimal energy conformations were set up at various distances and positions between molecules (molecular mechanics functionality, MM+). The best interaction between titanocene structures and cyclodextrins was obtained in the case of beta- and gamma-cyclodextrin, having the hydrophobic moieties oriented to the secondary face of cyclodextrin. The hydrophobicity of titanocenes (logP) correlate with the titanocene-cyclodextrin interaction parameters, especially with the titanocene-cyclodextrin interaction energy; the compatible geometry and the interaction energy denote that the titanocene/beta- and gamma-cyclodextrin complex can be achieved. Valuable quantitative structure-activity relationships (QSARs) were also obtained in the titanocene class by using the same logP as the main parameter for the in vitro cytotoxic activity against HeLa, K562, and Fem-x cell lines. CONCLUSIONS: According to our theoretical study, the titanocene/cyclodextrin inclusion compounds can be obtained (high interaction energy; the encapsulation is energetically favourable). Further, the most hydrophobic compounds are better encapsulated in beta- and gamma-cyclodextrin molecules and are more stable (from energetically point of view) in comparison with alpha-cyclodextrin case. This study suggests that the titanocene / beta- and gamma-cyclodextrin complexes (or synthetically modified cyclodextrins with higher water solubility) could be experimentally synthesized and could have enhanced cytotoxic activity and even lower toxicity.

Concepts: Molecule, Chemistry, Solubility, Computational chemistry, Experiment, Supramolecular chemistry, Molecular modelling, Cyclodextrin


Chemical cross-links identified by mass spectrometry generate distance restraints that reveal low-resolution structural information on proteins and protein complexes. The technology to reliably generate such data has become mature and robust enough to shift the focus to the question of how these distance restraints can be best integrated into molecular modeling calculations. Here, we introduce three workflows for incorporating distance restraints generated by chemical cross-linking and mass spectrometry into ROSETTA protocols for comparative and de novo modeling and protein-protein docking. We demonstrate that the cross-link validation and visualization software Xwalk facilitates successful cross-link data integration. Besides the protocols we introduce XLdb, a database of chemical cross-links from 14 different publications with 506 intra-protein and 62 inter-protein cross-links, where each cross-link can be mapped on an experimental structure from the Protein Data Bank. Finally, we demonstrate on a protein-protein docking reference data set the impact of virtual cross-links on protein docking calculations and show that an inter-protein cross-link can reduce on average the RMSD of a docking prediction by 5.0 Å. The methods and results presented here provide guidelines for the effective integration of chemical cross-link data in molecular modeling calculations and should advance the structural analysis of particularly large and transient protein complexes via hybrid structural biology methods.

Concepts: Protein, Protein structure, Bioinformatics, Molecular biology, Protein Data Bank, Molecular modelling, Cross-link, Docking


Lysozyme is a well-studied enzyme that hydrolyzes the β-(1,4)-glycosidic linkage of N-acetyl-β-glucosamine (NAG)(n) oligomers. The active site of hen egg-white lysozyme (HEWL) is believed to consist of six subsites, A-F that can accommodate six sugar residues. We present studies exploring the use of polarizable force fields in conjunction with all-atom molecular dynamics (MD) simulations to analyze binding structures of complexes of lysozyme and NAG trisaccharide, (NAG)(3) . MD trajectories are applied to analyze structures and conformation of the complex as well as protein-ligand interactions, including the hydrogen-bonding network in the binding pocket. Two binding modes (ABC and BCD) of (NAG)(3) are investigated independently based on a fixed-charge model and a polarizable model. We also apply molecular mechanics with generalized born and surface area (MM-GBSA) methods based on MD using both nonpolarizable and polarizable force fields to compute binding free energies. We also study the correlation between root-mean-squared deviation and binding free energies of the wildtype and W62Y mutant; we find that for this prototypical system, approaches using the MD trajectories coupled with implicit solvent models are equivalent for polarizable and fixed-charge models. © 2012 Wiley Periodicals, Inc.

Concepts: Protein, Molecular dynamics, Computational chemistry, Force, Molecular modelling, Implicit solvation, Molecular mechanics, Water model


New series of bioactive 7-oxycoumarin derivatives were synthesized and tested for their in vitro and in vivo monoamine oxidase (MAO) A and B inhibitory effect. In vitro studies revealed exceptionally potent and selective MAO-A inhibitors with K(i) values on a picomolar range. The acetohydrazide (3b) and the dioxopyrrolidine derivative (7b) showed the most potent in vitro and in vivo MAO inhibition activity. Moreover, molecular modeling study of the synthesized compounds into MAO-A (PDB: 2Z5X) and MAO-B (PDB: 2XFN) binding sites exhibited direct correlation between AutoDock binding affinity and% inhibition MAO-A (pM) and MAO-B (μM). In addition, the results of in vivo MAO inhibiting properties (ED(50)) of the tested compounds revealed better direct correlation.

Concepts: In vivo, In vitro, Neurotransmitter, Inhibitor, Xanthine oxidase inhibitor, Monoamine oxidase, Molecular modelling, Monoamine oxidase A


Hepatitis C virus inhibitors based on benzoxazole scaffold were designed based on molecular modeling simulation study including docking into the NS5B polymerase active site. Several compounds showed significant high simulation docking scores relative to the assigned benzimidazole lead compound. The designed compounds were synthesized, structurally elucidated and their antiviral activity was evaluated through cell-based replicon in cultured Huh 5-2 cells. A number of the synthesized compounds showed significant inhibitory activity ranging from (52.2% inhibition up to 98% at<50 µg/mL). N-Benzyl-2-phenylbenzo[1,3]oxazole-5-carboxamide (8b) and N-Phenethyl-2-phenylbenzo[1,3] oxazole-5-carboxamide (8c) demonstrated genuine HCV inhibitory activity with EC50 values of 41.6 and 24.5 µg/mL respectively.

Concepts: DNA, Computational chemistry, Enzyme inhibitor, Hepatitis C, Hepatitis B, Chemical compound, Hepatitis C virus, Molecular modelling


Thirteen 2-[2-(5-methyl-2-benzoxazolinone-3-yl)acetyl]-¾/5-substituted benzylidenehydrazine derivatives were synthesized by reacting 2-(5-methyl-2-benzoxazolinone-3-yl)acetylhydrazine and substituted benzaldehydes in neutral and acid/base catalyzed conditions, and a comparison was made in terms of their yields and reaction times. The structures of all compounds were confirmed by IR, (1)H NMR, (13)C NMR, mass spectral data, and elemental analyses. All the compounds were investigated for their ability to selectively inhibit MAO isoforms by in vitro tests and were found to inhibit recombinant human MAO-B selectively and reversibly in a competitive manner. Among the compounds examined, compound 16 was found to be more selective than selegiline, a known MAO-B inhibitor, in respect to the K ( i ) values experimentally found. Additionally, compounds 9 and 15 showed moderate MAO-B inhibitor activity. The interaction of compounds with MAO isoforms was investigated by molecular docking studies using recently published crystallographic models of MAO-A and MAO-B. The results obtained from the docking studies were found to be in good agreement with the experimental values.

Concepts: Chemical reaction, Computational chemistry, Enzyme inhibitor, Neurotransmitter, Xanthine oxidase inhibitor, Monoamine oxidase, Molecular modelling, Molecular mechanics


Monoamine oxidase B (MAO-B) is an important drug target for the treatment of neurological disorders. A series of 6-nitrobenzothiazole-derived semicarbazones were designed, synthesized, and evaluated as inhibitors of the rat brain MAO-B isoenzyme. Most of the compounds were found to be potent inhibitors of MAO-B, with IC(50) values in the nanomolar to micromolar range. Molecular docking studies were performed with AutoDock 4.2 to deduce the affinity and binding mode of these inhibitors toward the MAO-B active site. The free energies of binding (ΔG) and inhibition constants (K(i) ) of the docked compounds were calculated by the Lamarckian genetic algorithm (LGA) of AutoDock 4.2. Good correlations between the calculated and experimental results were obtained. 1-[(4-Chlorophenyl)(phenyl)methylene]-4-(6-nitrobenzothiazol-2-yl)semicarbazide emerged as the lead MAO-B inhibitor, with top ranking in both the experimental MAO-B assay (IC(50) : 0.004±0.001 μM) and in computational docking studies (K(i) : 1.08 μM). Binding mode analysis of potent inhibitors suggests that these compounds are well accommodated by the MAO-B active site through stable hydrophobic and hydrogen bonding interactions. Interestingly, the 6-nitrobenzothiazole moiety is stabilized in the substrate cavity with the aryl or diaryl residues extending up into the entrance cavity of the active site. According to our results, docking experiments could be an interesting approach for predicting the activity and binding interactions of this class of semicarbazones against MAO-B. Thus, a binding site model consisting of three essential pharmacophoric features is proposed, and this can be used for the design of future MAO-B inhibitors.

Concepts: Bioinformatics, Neurology, Enzyme inhibitor, Neurotransmitter, Inhibitor, Monoamine oxidase, Molecular modelling, Monoamine oxidase B


In accordance with our antiviral drug development attempt, acylhydrazone derivatives bearing amino acid side chains were synthesized for the evaluation of their antiviral activity against various types of viruses. Among these compounds, 8(S) , 11(S) , and 12(S) showed anti-HIV-1 activity with a 50% inhibitory concentration (IC(50) ) = 123.8 µM (selectivity index, SI > 3), IC(50)  = 12.1 µM (SI > 29), IC(50)  = 17.4 µM (SI > 19), respectively. Enantiomers 8® , 11® , and 12® were inactive against the HIV-1 strain III(B) . Hydrazones 8(S) , 11(S) , and 12(S) which were active against HIV-1 wild type showed no inhibition against a double mutant NNRTI-resistant strain (K103N;Y181C). Molecular docking calculations of R- and S-enantiomers of 8, 11, and 12 were performed using the hydrazone-bound novel site of HIV-1 RT.

Concepts: Gene, Amino acid, Virus, Influenza, Computational chemistry, Enzyme inhibitor, Molecular modelling, Molecular mechanics


The interaction of pepsin with chlorogenic acid (CHA) was investigated using fluorescence, UV/vis spectroscopy and molecular modeling methods. Stern-Volmer analysis indicated that the fluorescence quenching of pepsin by CHA resulted from a static mechanism, and the binding constant was 1.1846 × 10(5) and 1.1587 × 10(5) L/mol at 288 and 310 K, respectively. The distance between donor (pepsin) and acceptor (CHA) was calculated to be 2.39 nm and the number of binding sites for CHA binding on pepsin was ~ 1. The results of synchronous fluorescence and three-dimensional fluorescence showed that binding of CHA to pepsin could induce conformational changes in pepsin. Molecular docking experiments found that CHA bonded with pepsin in the area of the hydrophobic cavity with Van der Waals' forces or hydrogen bonding interaction, which were consistent with the results obtained from the thermodynamic parameter analysis. Furthermore, the binding of CHA can inhibit pepsin activity in vitro. Copyright © 2013 John Wiley & Sons, Ltd.

Concepts: Fluorescence, Spectroscopy, Oxygen, Hydrogen, Atom, Computational chemistry, Molecular modelling, Molecular mechanics


DNA is an important target for the treatment of multiple pathologies, most notably cancer. In particular, DNA intercalators have often been used as anti-cancer drugs. However, despite their relevance to drug discovery, only a few systematic computational studies were performed on DNA-intercalator complexes. In this work we have analyzed ligand binding sites preferences in 63 high resolution DNA-intercalator complexes available in the PDB and found that ligands bind preferentially between G and C and between the C and A base pairs (70% and 11% respectively). Next, we examined the ability of AUTODOCK to accurately dock ligands into pre-formed intercalation sites. Following the optimization of the docking protocol, AUTODOCK was able to generate conformations with RMSD values < 2.00 Å with respect to crystal structures in ~80% of the cases while focusing on the pre-formed binding site (small grid box) or on the entire DNA structure (large grid box). In addition, a top ranked conformation with an RMSD < 2.00 Å was identified in 75% and 60% of the cases using small and large docking boxes respectively. Moreover, under the large docking box setting AUTODOCK was able to successfully distinguish between the intercalation site and the minor groove site. However, in all cases the crystal structures and poses tightly clustered around it, had a lower score than the best scoring poses suggesting a potential scoring problem with AUTODOCK. A close examination of all cases where the top ranked pose had an RMSD value > 2.00 Å suggests that AUTODOCK may over emphasize the hydrogen bonding term. A decision tree was built to identify ligands which are likely to be accurately docked based on their characteristics. This analysis revealed that AUTODOCK performs best for intercalators characterized by a large number of aromatic rings, low flexibility, high molecular weight and a small number of hydrogen bond acceptors. Finally, for canonical B-DNA structures (where pre-formed sites are unavailable), we demonstrated that intercalation sites could be formed by inserting an anthracene moiety between the (anticipated) site-flanking base pairs and by relaxing the structure using either energy minimization or preferably molecular dynamics simulations. Such sites were suitable for the docking of different intercalators by AUTODOCK.

Concepts: DNA, Protein, Base pair, Molecule, Chemical bonding, Hydrogen bond, Binding site, Molecular modelling