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At least 199 records · Page 11Linked to original sources
PubMed2005

An evaluation of automated in silico ligand docking of amino acid ligands to Family C G-protein coupled receptors.

Family C G-protein coupled receptors (GPCRs) consist of the metabotropic glutamate receptors (mGluRs), the calcium-sensing receptor (CaSR), the T1R taste receptors, the GABA(B) receptor, the V2R pheromone receptors, and several chemosensory receptors. A common feature of Family C receptors is the presence of an amino acid binding pocket. The objective of this study was to evaluate the ability of the automatic docking program FlexX to predict the favored amino acid ligand at several Family C GPCRs. The docking process was optimized using the crystal structure of mGluR1 and the 20 amino acids were docked into homology models of the CaSR, the 5.24 chemosensory receptor, and the GPRC6A amino acid receptor. Under optimized docking conditions, glutamate was docked in the binding pocket of mGluR1 with a root mean square deviation of 1.56 angstroms from the co-crystallized glutamate structure and was ranked as the best ligand with a significantly better FlexX score compared to all other amino acids. Ligand docking to a homology model of the 5.24 receptor gave generally correct predictions of the favored amino acids, while the results obtained with models of GPRC6A and the CaSR showed that some of the favored amino acids at these receptors were correctly predicted, while a few other top scoring amino acids appeared to be false positives. We conclude that with certain caveats, FlexX can be successfully used to predict preferred ligands at Family C GPCRs.

Amino Acids↗
PubMed2006

Efficient restraints for protein-protein docking by comparison of observed amino acid substitution patterns with those predicted from local environment.

The discovery that the functions of most eukaryotic gene products are mediated through multi-protein complexes makes the prediction of protein interactions one of the most important current challenges in structural biology. Rigid-body docking methods can generate a large number of alternative candidates, but it is difficult to discriminate the near-native interactions from the large number of false positives. Many different scoring functions have been developed for this purpose, but in most cases, experimental and biological information is still required for accurate predictions. We explore here the use of evolutionary restraints in evaluating rigid-body docking geometries. In order to identify potential interface residues we identify functional residues based on the comparison of observed amino acid substitutions with those predicted from local environment. The interface residues identified by this method are correctly located in 85% of the cases. These predicted interface residues are used to define distance restraints that help to score rigid-body docking solutions. We have developed the pyDockRST software, which uses the percentage of satisfied distance restraints, together with the electrostatics and desolvation binding energy, to identify correct docking orientations. This methodology dramatically improves the docking results when compared to the use of energy criteria alone, and is able to find the correct orientation within the top 20 docking solutions in 80% of the cases.

Amino Acid Substitution↗
PubMed2006

Flexible protein-protein docking.

Predicting the structure of protein-protein complexes using docking approaches is a difficult problem whose major challenges include identifying correct solutions, and properly dealing with molecular flexibility and conformational changes. Flexibility can be addressed at several levels: implicitly, by smoothing the protein surfaces or allowing some degree of interpenetration (soft docking) or by performing multiple docking runs from various conformations (cross or ensemble docking); or explicitly, by allowing sidechain and/or backbone flexibility. Although significant improvements have been achieved in the modeling of sidechains, methods for the explicit inclusion of backbone flexibility in docking are still being developed. A few novel approaches have emerged involving collective degrees of motion, multicopy representations and multibody docking, which should allow larger conformational changes to be modeled.

Binding Sites↗
PubMed2002

A model binding site for testing scoring functions in molecular docking.

Prediction of interaction energies between ligands and their receptors remains a major challenge for structure-based inhibitor discovery. Much effort has been devoted to developing scoring schemes that can successfully rank the affinities of a diverse set of possible ligands to a binding site for which the structure is known. To test these scoring functions, well-characterized experimental systems can be very useful. Here, mutation-created binding sites in T4 lysozyme were used to investigate how the quality of atomic charges and solvation energies affects molecular docking. Atomic charges and solvation energies were calculated for 172,118 molecules in the Available Chemicals Directory using a semi-empirical quantum mechanical approach by the program AMSOL. The database was first screened against the apolar cavity site created by the mutation Leu99Ala (L99A). Compared to the electronegativity-based charges that are widely used, the new charges and desolvation energies improved ranking of known apolar ligands, and better distinguished them from more polar isosteres that are not observed to bind. To investigate whether the new charges had predictive value, the non-polar residue Met102, which forms part of the binding site, was changed to the polar residue glutamine. The structure of the resulting Leu99Ala and Met102Gln double mutant of T4 lysozyme (L99A/M102Q) was determined and the docking calculation was repeated for the new site. Seven representative polar molecules that preferentially docked to the polar versus the apolar binding site were tested experimentally. All seven bind to the polar cavity (L99A/M102Q) but do not detectably bind to the apolar cavity (L99A). Five ligand-bound structures of L99A/M102Q were determined by X-ray crystallography. Docking predictions corresponded to the crystallographic results to within 0.4A RMSD. Improved treatment of partial atomic charges and desolvation energies in database docking appears feasible and leads to better distinction of true ligands. Simple model binding sites, such as L99A and its more polar variants, may find broad use in the development and testing of docking algorithms.

Algorithms↗
PubMed1999

Pak functions downstream of Dock to regulate photoreceptor axon guidance in Drosophila.

The SH2/SH3 adaptor protein Dock has been proposed to transduce signals from guidance receptors to the actin cytoskeleton in Drosophila photoreceptor (R cell) growth cones. Here, we demonstrate that Drosophila p21-activated kinase (Pak) is required in a Dock pathway regulating R cell axon guidance and targeting. Dock and Pak colocalize to R cell axons and growth cones, physically interact, and their loss-of-function phenotypes are indistinguishable. Normal patterns of R cell connectivity require Pak's kinase activity and binding sites for both Dock and Cdc42/Rac. A membrane-tethered form of Pak (Pak(myr) acts as a dominant gain-of-function protein. Retinal expression of Pak(myr) rescues the R cell connectivity phenotype in dock mutants. These data establish Pak as a critical regulator of axon guidance and a downstream effector of Dock in vivo.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Molecular docking and 3-D-QSAR studies on the possible antimalarial mechanism of artemisinin analogues.

Artemisinin (Qinghaosu) is a natural constituent found in Artemisia annua L, which is an effective drug against chloroquine-resistant Plasmodium falciparum strains and cerebral malaria. The antimalarial activities of artemisinin and its analogues appear to be mediated by the interactions of the drugs with hemin. In order to understand the antimalarial mechanism and the relationship between the physicochemical properties and the antimalarial activities of artemisinin analogues, we performed molecular docking simulations to probe the interactions of these analogues with hemin, and then performed three-dimensional quantitative structure-activity relationship (3-D-QSAR) studies on the basis of the docking models employing comparative molecular force fields analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). Molecular docking simulations generated probable 'bioactive' conformations of artemisinin analogues and provided a new insight into the antimalarial mechanism. The subsequent partial least squares (PLS) analysis indicates that the calculate binding energies correlate well with the experimental activity values. The CoMFA and CoMSIA models based on the bioactive conformations proved to have good predictive ability and in turn match well with the docking result, which further testified the reliability of the docking model. Combining these results, that is molecular docking and 3-D-QSAR, together, the binding model and activity of new synthesized artemisinin derivatives were well explained.

Antimalarials↗
PubMed2002

Lead discovery using molecular docking.

As the structures of more and more proteins and nucleic acids become available, molecular docking is increasingly considered for lead discovery. Recent studies consider the hit-rate enhancement of docking screens and the accuracy of docking structure predictions. As more structures are determined experimentally, docking against homology-modeled targets also becomes possible for more proteins. With more docking studies being undertaken, the 'drug-likeness' and specificity of docking hits is also being examined.

Animals↗
PubMed2001

A base change in the catalytic core of the hairpin ribozyme perturbs function but not domain docking.

The hairpin ribozyme is a small endonucleolytic RNA motif with potential for targeted RNA inactivation. It optimally cleaves substrates containing the sequence 5'-GU-3' immediately 5' of G. Previously, we have shown that tertiary structure docking of its two domains is an essential step in the reaction pathway of the hairpin ribozyme. Here we show, combining biochemical and fluorescence structure and function probing techniques, that any mutation of the substrate base U leads to a docked RNA fold, yet decreases cleavage activity. The docked mutant complex shares with the wild-type complex a common interdomain distance as measured by time-resolved fluorescence resonance energy transfer (FRET) as well as the same solvent-inaccessible core as detected by hydroxyl-radical protection; hence, the mutant complex appears nativelike. FRET experiments also indicate that mutant docking is kinetically more complex, yet with an equilibrium shifted toward the docked conformation. Using 2-aminopurine as a site-specific fluorescent probe in place of the wild-type U, a local structural rearrangement in the substrate is observed. This substrate straining accompanies global domain docking and involves unstacking of the base and restriction of its conformational dynamics, as detected by time-resolved 2-aminopurine fluorescence spectroscopy. These data appear to invoke a mechanism of functional interference by a single base mutation, in which the ribozyme-substrate complex becomes trapped in a nativelike fold preceding the chemical transition state.

2-Aminopurine↗
PubMed2004

Heterotrimeric type I collagen C-telopeptide conformation as docked to its helix receptor.

The amino (N-telo) and carboxyl (C-telo) telopeptides of type I collagen play crucial roles, in vivo and in vitro, in the assembly of collagen fibrils, regulating the axial alignment of the molecules within a fibril, azimuthal orientations of neighboring molecules, and cross-link formation. High-resolution structures of the telopeptides are not available from X-ray diffraction studies, but computational methods permitted prediction of the N-telo structure within a fibril. Here, using a suite of molecular modeling software, the more complex heterotrimeric C-telo of human type I collagen has been built from the correct sequences and energy minimized and the energy minimum confirmed by molecular dynamics. The receptor triple helix was modeled on the basis of the Protein Data Bank coordinates of a collagen-like sequence. Docking of the heterotrimeric C-telopeptide to its receptor showed that hydrophobic interactions involving the short alpha2 C-telopeptide are crucial determinants of its azimuthal orientation within the docked structure. A docked C-telo can interact with only one neighboring helix. The two alpha1(I) C-telo chains in the alpha1(Alpha)-alpha2-alpha1(B) chain stagger do not have identical docked conformations, and one of the alpha1(I) C-telo chains appears to be favored for formation of a cross-link between its K(16C) and a helix K87. Prior studies showed that a docked N-telopeptide can interact with two adjacent collagen monomers, forming a tightly packed region. A recent X-ray analysis showed the N- and C-telo regions pack differently, with the C-telo region being less densely packed than N-telo regions. This difference between N- and C-telopeptide docked structures demonstrates how unique and specific packing can occur in the fibril at each boundary of the type I collagen gap region.

Amino Acid Sequence↗
PubMed2006

CheA Kinase of bacterial chemotaxis: chemical mapping of four essential docking sites.

The chemotaxis pathway of Escherichia coli and Salmonella typhimurium is the paradigm for the ubiquitous class of 2-component signaling pathways in prokaryotic organisms. Chemosensing begins with the binding of a chemical attractant to a transmembrane receptor on the cell surface. The resulting transmembrane signal regulates a cytoplasmic, multiprotein signaling complex that controls cellular swimming behavior by generating a diffusible phosphoprotein. The minimal functional unit of this signaling complex, termed the core complex, consists of the transmembrane receptor, the coupling protein CheW, and the histidine kinase CheA. Though the structures of individual components are largely known and the core complex can be functionally reconstituted, the architecture of the assembled core complex has remained elusive. To probe this architecture, the present study has utilized an enhanced version of the protein-interactions-by-cysteine-modification method (PICM-beta) to map out docking surfaces on CheA essential for kinase activity and for core complex assembly. The approach employed a library of 70 single, engineered cysteine residues, scattered uniformly over the surfaces of the five CheA domains in a cysteine-free CheA background. These surface Cys residues were further modified by the sulfhydryl-specific alkylating agent, 5-fluorescein-maleimide (5FM). The functional effects of individual Cys and 5FM-Cys surface modifications were measured by kinase assays of CheA activity in both the free and core complex-associated states, and by direct binding assays of CheA associations with CheW and the receptor. The results define (i) two mutual docking surfaces on the CheA substrate and catalytic domains essential for the association of these domains during autophosphorylation, (ii) a docking surface on the CheA regulatory domain essential for CheW binding, and (iii) a large docking surface encompassing regions of the CheA dimerization, catalytic, and regulatory domains proposed to bind the receptor. To test the generality of these findings, a CheA sequence alignment was analyzed, revealing that the newly identified docking surfaces are highly conserved among CheA homologues. These results strongly suggest that the same docking sites are widely utilized in prokaryotic sensory pathways. Finally, the results provide new structural constraints allowing the development of improved models for core complex architecture.

Amino Acid Substitution↗
PubMed1998

Identification of the basic residues of cytochrome f responsible for electrostatic docking interactions with plastocyanin in vitro: relevance to the electron transfer reaction in vivo.

The prominent basic patch seen in the atomic structure of the lumen-side domain of turnip cytochrome f, consisting of Arg209 and Lys187, 58, 65, and 66, was proposed to be an electrostatically complementary docking site for its physiological electron acceptor, plastocyanin [Martinez, S. E., Huang, D., Szczepaniak, A., Cramer, W. A., and Smith, J. L. (1994) Structure 2, 95-105]. This proposal agrees with solution studies on the cytochrome f/plastocyanin electron-transfer reaction that showed a major contribution of electrostatic interactions to the docking, but not with studies on the oxidation rate of cyt f in vivo using mutants in which the basic patch of cyt f was neutralized. The apparent contradiction might be explained by an unknown electron acceptor protein for cyt f. However, (i) flash-induced oxidation of cyt f is absent in a PC-deficient mutant. (ii) Lys58, 65, and 66 in the large domain and Lys188 and 189 in the small domain are major contributors to the ionic strength dependence of the electron-transfer reaction in solution. Replacement of Lys58 and 65 by neutral residues and of Lys66 by the acidic residue Glu66 resulted in a >10-fold decrease in the rate of electron transfer in solution and complete loss of its ionic strength dependence. Replacement of Lys188 and Lys189 in the small domain of cyt f resulted in a 3-4-fold decrease in the second-order rate constant and a smaller dependence of the overall rate of electron transfer on ionic strength, corresponding to a loss of two positive charges. (iii) Acidification of the thylakoid lumen cannot explain the absence of electrostatic interactions. (iv) Changing the five lysines to acidic residues did not result in any significant retardation of the rate of cyt f oxidation in vivo. If the docking of cyt f and plastocyanin in vivo is mediated by basic residues of cyt f, they are different from those that mediate electron transfer in vitro or that are implicated by simulations of electrostatic interactions of the docking. Alternatively, docking of cyt f/PC in vivo is limited by spatial constraints or release of PC from P700 that precludes a rate-limiting mediation of the cyt f/PC reaction by specific electrostatic interactions. The cyt f/PC system in Chlamydomonas reinhardtii is the first electron-transfer couple for which the role of electrostatics in mediating the docking reaction has been studied both in vitro and in vivo.

Animals↗
PubMedDate not supplied

A comprehensive docking study on the selectivity of binding of aromatic compounds to proteins.

Generally, computer-aided drug design is focused on screening of ligand molecules for a single protein target. The screening of several proteins for a ligand is a relatively new application of molecular docking. In the present study, complexes from the Brookhaven Protein Databank were used to investigate a docking approach of protein screening. Automated molecular docking calculations were applied to reproduce 44 protein-aromatic ligand complexes (31 different proteins and 39 different ligand molecules) of the databank. All ligands were docked to all different protein targets in altogether 12090 docking runs. Based on the results of the extensive docking simulations, two relative measures, the molecular interaction fingerprint (MIF) and the molecular affinity fingerprint (MAF), were introduced to describe the selectivity of aromatic ligands to different proteins. MIF and MAF patterns are in agreement with fragment and similarity considerations. Limitations and future extension of our approach are discussed.

Animals↗
PubMedDate not supplied

Synergistic use of compound properties and docking scores in neural network modeling of CYP2D6 binding: predicting affinity and conformational sampling.

Cytochrome P450 2D6 (CYP2D6) is used to develop an approach for predicting affinity and relevant binding conformation(s) for highly flexible binding sites. The approach combines the use of docking scores and compound properties as attributes in building a neural network (NN) model. It begins by identifying segments of CYP2D6 that are important for binding specificity, based on structural variability among diverse CYP enzymes. A family of distinct, low-energy conformations of CYP2D6 are generated using simulated annealing (SA) and a collection of 82 compounds with known CYP2D6 affinities are docked. Interestingly, docking poses are observed on the backside of the heme as well as in the known active site. Docking scores for the active site binders, along with compound-specific attributes, are used to train a neural network model to properly bin compounds as strong binders, moderate binders, or nonbinders. Attribute selection is used to preselect the most important scores and compound-specific attributes for the model. A prediction accuracy of 85+/-6% is achieved. Dominant attributes include docking scores for three of the 20 conformations in the ensemble as well as the compound's formal charge, number of aromatic rings, and AlogP. Although compound properties were highly predictive attributes (12% improvement over baseline) in the NN-based prediction of CYP2D6 binders, their combined use with docking score attributes is synergistic (net increase of 23% above baseline). Beyond prediction of affinity, attribute selection provides a way to identify the most relevant protein conformation(s), in terms of binding competence. In the case of CYP2D6, three out of the ensemble of 20 SA-generated structures are found to be the most predictive for binding.

Algorithms↗
PubMed2002

Studying enzyme binding specificity in acetylcholinesterase using a combined molecular dynamics and multiple docking approach.

A combined molecular dynamics simulation and multiple ligand docking approach is applied to study the binding specificity of acetylcholinesterase (AChE) with its natural substrate acetylcholine (ACh), a family of substrate analogues, and choline. Calculated docking energies are well correlated to experimental k(cat)/K(M) values, as well as to experimental binding affinities of a related series of TMTFA inhibitors. The "esteratic" and "anionic" subsites are found to act together to achieve substrate binding specificity. We find that the presence of ACh in the active site of AChE not only stabilizes the setup of the catalytic triad but also tightens both subsites to achieve better binding. The docking energy gained from this induced fit is 0.7 kcal/mol for ACh. For the binding of the substrate tailgroup to the anionic subsite, both the size and the positive charge of the tailgroup are important. The removal of the positive charge leads to a weaker binding of 1 kcal/mol loss in docking energy. Substituting each tail methyl group with hydrogen results in both an incremental loss in docking energy and also a decrease in the percentage of structures docked in the active site correctly set up for catalysis.

Acetophenones↗
PubMed2003

Ligand binding in a docking site of cytochrome C oxidase: a time-resolved step-scan Fourier transform infrared study.

The description of reaction regulation in enzymes responsible for activating and catalyzing small molecules (O(2), NO) requires identification of ligand movement into the binding site and out of the enzyme through specific channels and docking sites. We have used time-resolved step-scan Fourier transform infrared spectroscopy on CO-photolyzed cytochrome c oxidase ba(3) from T. thermophilus, which is responsible for the activation and reduction of both O(2) and NO, to gain insight into the structure of ligand-binding intermediates at ambient temperature. We show that, upon dissociation, the photolyzed CO becomes trapped within a ligand docking site located near the ring A propionate of heme a(3). The 2131 cm(-1) mode of the "docked" CO we have detected corresponds to the B(1) state of Mb and persists for 35 micros. The release of CO from the docking site is not followed by recombination to the heme a(3) Fe. Our analysis indicates that this behavior reflects a mechanism in which the protein near ring A of heme a(3) propionate reorganizes about the released CO from the docking site, and establishes a transient barrier that inhibits the recombination process to the heme a(3) Fe for a few milliseconds. Rebinding to heme a(3) occurs with k(2) = 29.5 s(-1). These results have implications for understanding the role of ligand binding/escape through docking sites and channels in heme-copper oxidases and, thus, in respiration.

Bacterial Proteins↗
PubMed2005

Representing receptor flexibility in ligand docking through relevant normal modes.

Inspired by the current representation of the ligand-receptor binding process, a normal-mode-based methodology is presented to incorporate receptor flexibility in ligand docking and virtual screening. However, the systematic representation of the deformation space grows geometrically with the number of modes, and furthermore, midscale loop rearrangements like those found in protein kinase binding pockets cannot be accounted for with the first lowest-frequency modes. We thus introduced a measure of relevance of normal modes on a given region of interest and showed that only very few modes in the low-frequency range are necessary and sufficient to describe loop flexibility in cAMP-dependent protein kinase. We used this approach to generate an ensemble of representative receptor backbone conformations by perturbing the structure along a combination of relevant modes. Each ensemble conformation is complexed with known non-native binders to optimize the position of the binding-pocket side chains through a full flexible docking procedure. The multiple receptor conformations thus obtained are used in a small-scale virtual screening using receptor ensemble docking. We evaluated this algorithm on holo and apo structures of cAMP-dependent protein kinase that exhibit backbone rearrangements on two independent loop regions close to the binding pocket. Docking accuracy is improved, since the ligands considered in the virtual screening docked within 1.5 A to at least one of the structures. The discrimination between binders and nonbinders is also enhanced, as shown by the improvement of the enrichment factor. This constitutes a new step toward the systematic integration of flexible ligand-flexible receptor docking tools in structure-based drug discovery.

Algorithms↗
PubMed2003

Construction and assessment of models of CYP2E1: predictions of metabolism from docking, molecular dynamics, and density functional theoretical calculations.

3D models of CYP2E1 were constructed for the purpose of structure-based prediction of 2E1 metabolism of diverse substrates based on configuration sampling of ligand-atom-oxyferryl center distances and quantum chemical criteria. Models were constructed on the basis of sequence alignments of 2E1 with templates of known structure, including rabbit CYP2C5 (3LVdH) and bacterial CYP450s. Following geometric and energetic assessments, the utility of the model was tested in structure-based predictions of metabolism. Autodock was used to dock chlorzoxazone, p-nitrophenol, N-nitrosodimethylamine, acetominophen, caffeine, theophylline, and methoxyflurane into the model CYP2E1 employing a model oxyferryl heme with charges based on density functional theoretical parametrization. In all cases, the lowest energy bound docked configurations corresponded to ones with the substrate intimately associated with the oxyferryl center. Configurations among the lowest energy docked forms of each of the ligands had orientations relative to the oxyferryl center consistent with the experimentally observed metabolites. Docking of long-chain dialkylnitrosoamines revealed no heme binding site bound configurations, in agreement with the negligible metabolism of these ligands. The lowest energy docked configurations of chlorzoxazone, p-nitrophenol, and N-nitrosodimethylamine, high-affinity substrates of 2E1, were used to initiate 300 ps molecular dynamics (MD) trajectories. The MD-sampled ligand-oxyferryl heme reactant configurations were in good accord with density functional theoretical (DFT) optimized oxyferryl-heme-ligand geometries. Analysis of the MD-sampled ligand-2E1 configurations from multiple docked orientations indicates the configurations with closest exposure of reactive centers to the oxyferryl heme to be correlated with observed metabolites with proper consideration of H-abstraction energetics. DFT assessment of relative radical energetics is directly compared with differential H-abstraction activation energetics by compound I and by a p-nitrosophenoxy radical compound I surrogate for the specific case of methoxyflurane and is shown to be in good agreement.

Amino Acid Sequence↗
PubMed2004

Ph4Dock: pharmacophore-based protein-ligand docking.

The development and validation of the program Ph4Dock is presented. Ph4Dock is a novel automated ligand docking program that makes best use of pharmacophoric features both in a ligand and at concave portions of a protein. By mapping of pharmacophores of the ligand to the pharmacophoric features that represent the concaves of the target protein, Ph4Dock realizes an efficient and accurate prediction of the binding modes between the ligand and the protein. To validate the potential of this unique docking algorithm, we have selected 43 reliable crystal structures of protein-ligand complexes. All of the ligands are druglike, and they are varied in nature. The diffraction-component precision index (DPI) originally used in crystallography was applied in this study in order to evaluate the docking results quantitatively. The root-mean-square deviation (rmsd) between non-hydrogen atoms of the ligand in the prediction and experimental results were analyzed using DPI. The rmsd values for 25 structures, consisting of almost 60% of the dataset, are less than three times of the corresponding DPI values. It means that the precision of docking results obtained by Ph4Dock is mostly equivalent to the experimental error in these cases. The present study has demonstrated that Ph4Dock can accurately reproduce the experimentally determined docking modes if the reliable crystal structures are used. Normally the success rate of the docking is judged using rmsd < or = 2.0 A as the criterion. The Ph4Dock marked an appreciably good success rate of 86% based on this criterion.

Binding Sites↗