Assessing protein–ligand docking for the binding of organometallic compounds to proteins

Organometallic compounds are increasingly used as molecular scaffolds in drug development projects; their structural and electronic properties offering novel opportunities in protein–ligand complementarities. Interestingly, while protein–ligand dockings have long become a spearhead in computer assisted drug design, no benchmarking nor optimization have been done for their use with organometallic compounds. Pursuing our efforts to model metal mediated recognition processes, we herein present a systematic study of the capabilities of the program GOLD to predict the interactions of protein with organometallic compounds. The study focuses on inert systems for which no alteration of the first coordination sphere of the metal occurs upon binding. Several scaffolds are used as test systems with different docking schemes and scoring functions. We conclude that ChemScore is the most robust scoring function with ASP and ChemPLP providing with good results too and GoldScore slightly underperforming. This study shows that current state‐of‐the‐art protein‐ligand docking techniques are reliable for the docking of inert organometallic compounds binding to protein. © 2013 Wiley Periodicals, Inc.     

A flexible docking procedure for the exploration of peptide binding selectivity to known structures and homology models of PDZ domains

PDZ domains are important scaffolding modules that typically bind to the C-termini of their interaction partners. Several structures of such complexes have been solved, revealing a conserved binding site in the PDZ domain and an extended conformation of the bound peptide. A compendium of information regarding PDZ complexes demonstrates that dissimilar C-terminal peptides bind to the same PDZ domain, and different PDZ domains can bind the same peptides. A detailed understanding of the PDZ-peptide recognition is needed to elucidate this complexity. To this end, we have designed a family of docking protocols for PDZ domains (termed PDZ-DocScheme) that is based on simulated annealing molecular dynamics and rotamer optimization, and is applicable to the docking of long peptides (20-40 rotatable bonds) to both known PDZ structures and to the more complicated problem of homology models of these domains. The resulting protocol reproduces the structures of PDZ complexes with peptides 4-8 amino acids long within 1-2 A from the experimental structure when the docking is performed to the original structure. If the structure of the target PDZ domain is an apo structure or a homology model, the docking protocol yields structures within 3 A in 9 out of 12 test cases. The automated docking procedure PDZ-DocScheme can serve in the generation of a structural context for validation of PDZ domain specificity from mutagenesis and ligand binding data.     

Fluorescence quenching and molecular docking study on the binding of four hydroxyanthraquinones to FTO

In this work, the binding of four hydroxyanthraquinones (HAQs) to fat mass and obesity-associated (FTO) protein has been studied using fluorescence, UV-vis absorption and circular dichroism spectroscopy as well as molecular docking analysis. Analysis of fluorescence data showed that the binding of HAQs to FTO occurred via a static quenching mechanism. Thermodynamic analysis and molecular docking results suggested that hydrophobic force played a major role in stabilising the HAQ-FTO complex. Circular dichroism spectra indicated that the secondary structure of FTO was changed by the addition of HAQs. Results also showed that emodin had the strongest quenching and binding ability among four HAQs.     

CEC separation of aromatic compounds and proteins on hexylamine-functionalized N-acryloxysuccinimide monoliths

Reactive organic polymer monoliths were prepared in fused-silica capillaries by UV-initiated free radical polymerization of N-acryloxysuccinimide (NAS) as reactive monomer, ethylene dimethacrylate as crosslinker, azobisisobutyronitrile as initiator, and toluene as porogen. In a second synthetic step, chemical derivatization of the activated-ester moieties was performed in situ through alkylation reaction with alkylamines to afford monolithic stationary phases with potential reversed-phase properties. A correlation between the synthesis conditions--composition of the reactive solution--chemical characteristics of the reactive polymer monoliths--nitrogen/NAS content--and the reversed-phase separation properties of the functionalized monolithic columns--selectivity towards homologous series of akylbenzenes--was clearly established. This finding offers the possibility of adjusting the experimental conditions with respect to the target applications. The monolithic stationary phases with optimized chemical and porous structures were used for the CEC separation of alkylbenzenes, phenols, anilines, organic acids, amino acids, and proteins. The data indicate that depending on the nature of the analytes (charge, hydrophobic/hydrophilic balance, size) reversed-phase or mixed modes may account for the observed separation.     

Theoretical study on the adsorption of aromatic compounds on platinum clusters

B3 LYP hybrid functional with LACVP* pseudopotential was applied for the optimization of geometries of complexes resulting from interaction of benzene, pyridine, naphthalene, and quinoline with Pt_n (n = 4, 7) clusters. For benzene‐containing complexes, the most stable form corresponds to a bridge adsorption, with benzene undergoing considerable geometric distortions, assuming a boat‐like conformation. C? H bonds are bended upward from the plane of the cluster. C? C bonds stretch, especially when they form π‐complexes with low coordinated Pt atoms. Some arrangements for pyridine complexes involving the N atom of the organic moiety undergo further distortions, apparently preserving a formal C? N π bond. Except for that distortion, the behavior of any heteroaromatic complex is similar to that of benzene in the same arrangement. The quinoline–Pt₇ complex can suitably be used for simulation of the cinchonidine (CD) anchorage over Pt. © 2003 Wiley Periodicals, Inc. Int J Quantum Chem, 2003     

Influence of composition of reaction mixture on selectivity in oxidation of aromatic compounds on oxide catalysts

A general outline is given of a kinetic model of oxidation of a hydrocarbon under the conditions of coexistence on the catalyst surface of sections of different oxidation levels. An analytical dependence has been obtained of the selectivity of the process and conversion on the composition of the reaction mixture. A qualitative agreement has been established between the theoretical and experimental dependences of selectivity and conversion on the ratio of the benzene and oxygen concentrations in the reaction mixture.Translated from Teoreticheskaya i Éksperimental'naya Khimiya, Vol. 21, No. 1, pp. 105–108, January–February, 1985.     

Improvement of selectivity of electrochemical detection for the determination of compounds with chloro aromatic rings

Summary Pharmaceuticals containing a thiazide ring or chlorinated aromatic ring were investigated with respect to enhanced selectivity in determination. Oxidative electrochemical detection coupled with HPLC was used to study the influence of the pH of the mobile phase under conditions of photolysis. To cover a pH range 3.9–12, the employment of a polymer column stable in alkaline media was necessary. The method offers the great advantage of derivatization without chemicals at low operating potentials, thereby providing high selectivity.     

A computational docking study on the pH dependence of peptide binding to HLA-B27 sub-types differentially associated with ankylosing spondylitis

A single amino acid difference (Asp116His), having a key role in a pathogenesis pathway, distinguishes HLA-B*27:05 and HLA-B*27:09 sub-types as associated and non-associated with ankylosing spondylitis, respectively. In this study, molecular docking simulations were carried out with the aim of comprehending the differences in the binding behavior of both alleles at varying pH conditions. A library of modeled peptides was formed upon single point mutations aiming to address the effect of 20 naturally occurring amino acids at the binding core peptide positions. For both alleles, computational docking was applied using Autodock 4.2. Obtained free energies of binding (FEB) were compared within the peptide library and between the alleles at varying pH conditions. The amino acid preferences of each position were studied enlightening the role of each on binding. The preferred amino acids for each position of pVIPR were found to be harmonious with experimental studies. Our results indicate that, as the pH is lowered, the capacity of HLA-B*27:05 to bind peptides in the library is largely lost. Hydrogen bonding analysis suggests that the interaction between the main anchor positions of pVIPR and their respective binding pocket residues are affected from the pH the most, causing an overall shift in the FEB profiles.     

A vanadium-51 NMR study of the binding of vanadate and peroxovanadate to proteins

51V quadrupolar central transition NMR spectra of buffered (pH 7.6-8.0) solutions of bovine apo-transferrin (Tf) and bovine prostatic acid phosphatase (Pp) treated with vanadate show normal features (chemical shifts between -515 and -542 ppm) corresponding to the complexation of VO2+ to the Tf binding site and the Pp active centre, respectively. Addition of H2O2 leads to the temporary formation of complexed VO(O2)+ (delta approximately -595). Vanadate-dependent bromoperoxidase from the alga Ascophyllum nodosum exhibits an unusually high shielding both for the native (delta = -931) and the peroxo form (delta = -1135) of the enzyme. A resonance at -471 ppm is traced back to an inactive form with oxovanadium(V) in a trigonal-bipyramidal array.     

Screening drug-like compounds by docking to homology models: a systematic study

In the absence of an experimentally solved structure, a homology model of a protein target can be used instead for virtual screening of drug candidates by docking and scoring. This approach poses a number of questions regarding the choice of the template to use in constructing the model, the accuracy of the screening results, and the importance of allowing for protein flexibility. The present study addresses such questions with compound screening calculations for multiple homology models of five drug targets. A central result is that docking to homology models frequently yields enrichments of known ligands as good as that obtained by docking to a crystal structure of the actual target protein. Interestingly, however, standard measures of the similarity of the template used to build the homology model to the targeted protein show little correlation with the effectiveness of the screening calculations, and docking to the template itself often is as successful as docking to the corresponding homology model. Treating key side chains as mobile produces a modest improvement in the results. The reasons for these sometimes unexpected results, and their implications for future methodologic development, are discussed.     

Analysis of aromatic compounds in gasoline with flow-switching comprehensive two-dimensional gas chromatography

A comprehensive two-dimensional gas chromatography (GC x GC) instrument has been created by coupling a flow-switching modulator and a standard gas chromatograph. The instrument was used to characterize the aromatic composition of gasoline. The high-resolution separation produced by flow-switching GC x GC allowed gasoline aromatics to be fully resolved from saturated components. The aromatic compounds were further separated into groups having the same carbon number. A standard gasoline sample was analyzed to evaluate the quantitative accuracy and precision of this technique. The data show that flow-switching GC x GC produces results that are comparable to gas chromatography-mass spectrometry (GC-MS) and thermal modulation GC x GC. The simple, low-cost, and robust nature of flow-switching GC x GC makes it an ideal technique for the routine analysis of aromatic compounds in gasoline.     

Backflush HPLC for the isolation of polycyclic aromatic compounds — A comparative study

Summary Semipreparative HPLC utilizing a polar bonded phase was applied to the isolation of polycyclic aromatic compounds (PAC) from complex samples using a backflush technique. Aminopropyl- and cyanopropyl-modified silica was tested. Aminopropyl-modified silica was found to be superior in achieving rapid, selective and non discriminating isolation of PAC. This was compared with the most commonly used isolation methods, dimethylsulfoxide (DMSO), dimethylformamide (DMF) and nitromethane liquid-liquid extractions, and silica and SephadexLH-20 open column chromatography. Strong discrimination of alkylated PAC and polycyclic aromatic nitrogen heterocyclics (PANH) was found for the liquid-liquid extractions and the LH-20 column chromatography. These comparisions were made using both standard compounds and a sample of used crankcase oil, indicating the necessity of using a real sample for evaluation of extraction methods. Recoveries of 42 PACs are reported.     

Extended-ensemble docking to probe dynamic variation of ligand binding sites during large-scale structural changes of proteins

Proteins can sample a broad landscape as they undergo conformational transition between different functional states. At the same time, as key players in almost all cellular processes, proteins are important drug targets. Considering the different conformational states of a protein is therefore central for a successful drug-design strategy. Here we introduce a novel docking protocol, termed extended-ensemble docking, pertaining to proteins that undergo large-scale (global) conformational changes during their function. In its application to multidrug ABC-transporter P-glycoprotein (Pgp), extensive non-equilibrium molecular dynamics simulations employing system-specific collective variables are first used to describe the transition cycle of the transporter. An extended set of conformations (extended ensemble) representing the full transition cycle between the inward- and the outward-facing states is then used to seed high-throughput docking calculations of known substrates, non-substrates, and modulators of the transporter. Large differences are predicted in the binding affinities to different conformations, with compounds showing stronger binding affinities to intermediate conformations compared to the starting crystal structure. Hierarchical clustering of the binding modes shows all ligands preferably bind to the large central cavity of the protein, formed at the apex of the transmembrane domain (TMD), whereas only small binding populations are observed in the previously described R and H sites present within the individual TMD leaflets. Based on the results, the central cavity is further divided into two major subsites, first preferably binding smaller substrates and high-affinity inhibitors, whereas the second one shows preference for larger substrates and low-affinity modulators. These central subsites along with the low-affinity interaction sites present within the individual TMD leaflets may respectively correspond to the proposed high- and low-affinity binding sites in Pgp. We propose further an optimization strategy for developing more potent inhibitors of Pgp, based on increasing its specificity to the extended ensemble of the protein, instead of using a single protein structure, as well as its selectivity for the high-affinity binding site. In contrast to earlier in silico studies using single static structures of Pgp, our results show better agreement with experimental studies, pointing to the importance of incorporating the global conformational flexibility of proteins in future drug-discovery endeavors.

Functional states of P-glycoprotein formed during its full transition cycle (red to blue), captured by molecular dynamics simulations, form a structural framework for extended-ensemble docking of small-molecule ligands of diverse activities.     

Antagonist binding in the rat muscarinic receptor A study by docking and X-ray crystallography

A series of agonists to the rat muscarinic receptor have been docked computationally to the active site of a homology model of rat M1 muscarinic receptor. The agonists were modelled on the X-ray crystal structure of atropine, which is reported here and the docking studies are shown to reproduce correctly the order of experimental binding affinities for the agonists as well as indicate where there appear to be inconsistencies in the experimental data. The crystal and molecular structure of atropine (tropine tropate; -[hydroxymethyl]benzeneacetic acid 8-methyl[3.2.1]oct-3-yl ester C₁₇H₂₃NO₃) has been determined by X-ray crystallography using an automated Patterson search method, and refined by full-matrix least-squares to a final R of 0.0452 for 2701 independent observed reflections and 192 parameters using Mo K radiation, λ = 0.71073 Å at 150 K. The compound crystallises in space group Fdd2 with Z = 16 molecules per unit cell.     

A route to fluoroalkyl-substituted aromatic compounds involving fluoroalkylcopper intermediates

Interaction of iodofluoroalkanes, iodoaromatic compounds and copper in polar aprotic solvents at 110–130° leads to good yields of (fluoroalkyl)aromatic compounds. The iodofluoroalkanes and iodoaromatic compounds can bear a wide variety of substituents (carboxyl, nitro, amino, hydroxyl, etc). The reactions proceed via fluoroalkylcopper compounds which are markedly more stable than their non-fluorinated analogues.     

A kinetics study of the reactions of OH with several aromatic and olefinic compounds

The reactions of hydroxyl radicals with eight substituted aromatic hydrocarbons and four olefins were studied utilizing the flash photolysis–resonance fluorescence technique. The rate constants were measured at 298°K using either Ar or He as the diluent gas. The values of the rate constants (k × 10¹²) in the units of cm³/molec. sec are

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