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PubMed2002

The receptor docking segment and S-adenosyl-L-homocysteine bind independently to the methyltransferase of bacterial chemotaxis.

To mediate adaptation to stimuli, the methyltransferase (CheR) catalyzes methyl group transfer from S-adenosyl-L-methionine (SAM) to glutamyl residues in the transmembrane receptors of the bacterial chemosensory signaling pathway. The interaction between receptors and CheR occurs at two sites: a methylation site-active site interaction, and a 'docking' site interaction that is separated both from the methylation sites and the CheR active site. It is not certain if the docking site interaction functions merely to localize the transferase in close proximity to the methylation sites, or if it also increases CheR catalytic activity. Isothermal titration calorimetry experiments are conducted to test for allosteric interactions between the docking and active sites on CheR, which are expected to be present if docking activates CheR. The binding parameters (DeltaG, DeltaH, DeltaS) of a substrate analog of SAM, S-adenosyl-L-homocysteine (SAH), are measured both in the absence and presence of saturating concentrations of a pentapeptide (NWETF) that defines the docking receptor docking segment. SAH binding is unaffected by the presence of saturating NWETF, providing evidence that an allosteric activation of CheR does not take place upon docking, and thus supports the idea that the CheR-NWETF interaction merely functions to localize CheR near the sites of methylation.

Binding Sites↗
PubMed1999

Docking experiments in the flexible non-nucleoside inhibitor binding pocket of HIV-1 reverse transcriptase.

Docking experiments were undertaken using a number of published crystal structures of HIV-1 reverse transcriptase complexes with various non-nucleoside inhibitors. The docking method was validated by successfully docking each ligand, in the conformation found in the crystal structure of the complex with the enzyme, back into its binding pocket in the right orientation and position. Each ligand was then subjected to conformational searching and a database of unique low-energy conformations of all ligands established. Docking this database into each of the reverse transcriptase binding pockets showed that all inhibitors could be fitted into each different pocket, without alteration of the pocket geometry. This contradicts findings from earlier docking investigations and implies that the conformation of the binding pocket in each different complex is conserved sufficiently to allow particular uniform ligand binding modes. The inhibitor conformations selected by this docking process are mostly the same as the one the ligand adopts in its own pocket and the selected conformations and orientations exhibit an impressive degree of similarity in the arrangement of their steric and electronic features. A correlation has also been observed between inhibitor flexibility and tightness of fit into the pockets with the more flexible inhibitors achieving a tighter fit and thus fewer favourable orientations upon docking.

Binding Sites↗
PubMed2000

Single-coordinate-driving method for molecular docking: application to modeling of guest inclusion in cyclodextrin.

An extension of the computer program CICADA has been developed that allows us to use the single-coordinate-driving (SCD) method for flexible molecular docking. The docking procedure is composed of three independent space rotations, three independent translations, and the torsions selected by the user. One of the coordinates is driven; the other coordinates are relaxed. This procedure follows low-energy wells on the potential energy surface of the entire system. The program allows us to dock more than one ligand molecule to the receptor. We ran two test examples, docking N,N-dimethylformamide into alpha-cyclodextrin and R-phenoxypropionic acid into beta-cyclodextrin. The test examples showed that the SCD approach is able to overcome high-energy barriers and to cover the entire box within which the search is performed. The limitations of molecular dynamics docking in comparison with our approach also are discussed. The philosophy of the newly developed approach is not only to find the best dock for the receptor-ligand(s) system, but also to describe all the important binding modes and provide a good starting point for studying the dynamics within the cavity during the docking process.

Carbohydrate Conformation↗
PubMed2003

Docking studies of matrix metalloproteinase inhibitors: zinc parameter optimization to improve the binding free energy prediction.

Docking of metalloproteinase inhibitors remains a challenge due to the zinc multiple coordination geometries and the lack of appropriate force field parameters to model the metal/ligand interactions. In this study, we explore the docking accuracy and scoring reliability for the docking of matrix metalloproteinase (MMP) inhibitors using AutoDock 3.0. Potential problems associated with zinc ion were investigated by docking 16 matrix metalloproteinase ligands to their crystal structures. A good coordination between the zinc binding group (ZBG) and the zinc was shown to be a prerequisite for the ligand to fit the binding site. A simplex optimization of zinc parameters, including zinc radius, well depth, and zinc charges, was performed utilizing the 14 MMP complexes with good docking. The use of optimized zinc parameters (zinc radius: 0.87 A; well depth: 0.35 kcal/mol; and zinc charges: +0.95 e) shows improvement in both docking accuracy at the zinc binding site and the prediction of binding free energies. Although further improvement in the docking procedure, particularly the scoring function is needed, optimization of zinc parameters provides an efficient way to improve the performance of AutoDock as a drug discovery tool.

Binding Sites↗
PubMed2002

Molecular docking and high-throughput screening for novel inhibitors of protein tyrosine phosphatase-1B.

High-throughput screening (HTS) of compound libraries is used to discover novel leads for drug development. When a structure is available for the target, computer-based screening using molecular docking may also be considered. The two techniques have rarely been used together on the same target. The opportunity to do so presented itself in a project to discover novel inhibitors for the enzyme protein tyrosine phosphatase-1B (PTP1B), a tyrosine phosphatase that has been implicated as a key target for type II diabetes. A corporate library of approximately 400 000 compounds was screened using high-throughput experimental techniques for compounds that inhibited PTP1B. Concurrently, molecular docking was used to screen approximately 235 000 commercially available compounds against the X-ray crystallographic structure of PTP1B, and 365 high-scoring molecules were tested as inhibitors of the enzyme. Of approximately 400 000 molecules tested in the high-throughput experimental assay, 85 (0.021%) inhibited the enzyme with IC50 values less than 100 microM; the most active had an IC50 value of 4.2 microM. Of the 365 molecules suggested by molecular docking, 127 (34.8%) inhibited PTP1B with IC50 values less than 100 microM; the most active of these had an IC50 of 1.7 microM. Structure-based docking therefore enriched the hit rate by 1700-fold over random screening. The hits from both the high-throughput and docking screens were dissimilar from phosphotyrosine, the canonical substrate group for PTP1B; the two hit lists were also very different from each other. Surprisingly, the docking hits were judged to be more druglike than the HTS hits. The diversity of both hit lists and their dissimilarity from each other suggest that docking and HTS may be complementary techniques for lead discovery.

Benzene Derivatives↗
PubMed2003

Information decay in molecular docking screens against holo, apo, and modeled conformations of enzymes.

Molecular docking uses the three-dimensional structure of a receptor to screen a small molecule database for potential ligands. The dependence of docking screens on the conformation of the binding site remains an open question. To evaluate the information loss that occurs as the active site conformation becomes less defined, a small molecule database was docked against the holo (ligand bound), apo, and homology modeled structures of 10 different enzyme binding sites. The holo and apo representations were crystallographic structures taken from the Protein Data Bank (PDB), and the homology-modeled structures were taken from the publicly available resource ModBase. The database docked was the MDL Drug Data Report (MDDR), a functionally annotated database of 95000 small molecules that contained at least 35 ligands for each of the 10 systems. In all sites, at least 99% of the molecules in the MDDR were treated as nonbinding decoys. For each system, the holo, apo, and modeled structures were used to screen the MDDR, and the ability of each structure to enrich the known ligands for that system over random selection was evaluated. The best overall enrichment was produced by the holo structure in seven systems, the apo structure in two systems, and the modeled structure in one system. These results suggest that the performance of the docking calculation is affected by the particular representation of the receptor used in the screen, and that the holo structure is the one most likely to yield the best discrimination between known ligands and decoy molecules, but important exceptions to this rule also emerge from this study. Although each of the holo, apo, and modeled conformations led to enrichment of known ligands in all systems, the enrichment did not always rise to a level judged to be sufficient to justify the effort of a docking screen. Using a 20-fold enrichment of known ligands over random selection as a rough guideline for what might be enough to justify a docking screen, the holo conformation of the enzyme met this criterion in eight of 10 sites, whereas the apo conformation met this criterion in only two sites and the modeled conformation in three.

Animals↗
PubMed2004

Prediction of HIV-1 integrase/viral DNA interactions in the catalytic domain by fast molecular docking.

This study details the separate analyses of binding specificity of HIV-1 integrase (IN) and viral B-DNA forms through ligand-receptor docking studies by means of a fast molecular docking method. The application of solvated electrostatics with the University of Houston Brownian Dynamics Program (UHBD) and configurational sampling by the Daughter of Turnip (DOT) docking program resulted in the computation of energies of more than 113 billion configurations for each ligand-receptor docking study, a procedure considered computationally intractable a few years ago. A specific binding pattern of viral DNA to the IN catalytic domain region has been predicted as a result of these calculations. In a representative docked configuration, we observe the 3'-hydroxyl of the conserved deoxyadenosine to be close to one of the two divalent metal ions that are necessary for catalysis. A superimposition of our energy-minimized docked complex on representative structures from a molecular dynamics (MD) simulation of a crystallographically resolved IN/inhibitor complex revealed an overlap of viral DNA with the inhibitor, indicating that the bound inhibitor might operate by blocking substrate binding. The DOT docking calculation also identified a second, adjacent DNA-binding site, which we believe is the nonspecific host DNA binding site. The binding pattern predicted by DOT complements previous electrostatics, MD simulation, photo-cross-linking, and mutagenesis studies and also provides a further refinement of the IN/viral DNA binding interaction as a basis for new structure-based design efforts.

Catalytic Domain↗
PubMed2002

Flexible docking under pharmacophore type constraints.

FLEXX-PHARM, an extended version of the flexible docking tool FLEXX, allows the incorporation of information about important characteristics of protein-ligand binding modes into a docking calculation. This information is introduced as a simple set of constraints derived from receptor-based type pharmacophore features. The constraints are determined by selected FLEXX interactions and inclusion volumes in the receptor active site. They guide the docking process to produce a set of docking solutions with particular properties. By applying a series of look-ahead checks during the flexible construction of ligand fragments within the active site, FLEXX-PHARM determines which partially built docking solutions can potentially obey the constraints. Solutions that will not obey the constraints are deleted as early as possible, often decreasing the calculation time and enabling new docking solutions to emerge. FLEXX-PHARM was evaluated on various individual protein-ligand complexes where the top docking solutions generated by FLEXX had high root mean square deviations (RMSD) from the experimentally observed binding modes. FLEXX-PHARM showed an improvement in the RMSD of the top solutions in most cases, along with a reduction in run time. We also tested FLEXX-PHARM as a database screening tool on a small dataset of molecules for three target proteins. In two cases, FLEXX-PHARM missed one or two of the active molecules due to the constraints selected. However, in general FLEXX-PHARM maintained or improved the enrichment shown with FLEXX, while completing the screen in considerably less run time.

Algorithms↗
PubMed2002

Sensitivity of molecular docking to induced fit effects in influenza virus neuraminidase.

Many proteins undergo small side chain or even backbone movements on binding of different ligands into the same protein structure. This is known as induced fit and is potentially problematic for virtual screening of databases against protein targets. In this report we investigate the limits of the rigid protein approximation used by the docking program, GOLD, through cross-docking using protein structures of influenza neuraminidase. Neuraminidase is known to exhibit small but significant induced fit effects on ligand binding. Some neuraminidase crystal structures caused concern due to the bound ligand conformation and GOLD performed poorly on these complexes. A 'clean' set, which contained unique, unambiguous complexes, was defined. For this set, the lowest energy structure was correctly docked (i.e. RMSD < 1.5 A away from the crystal reference structure) in 84% of proteins, and the most promiscuous protein (1mwe) was able to dock all 15 ligands accurately including those that normally required an induced fit movement. This is considerably better than the 70% success rate seen with GOLD against general validation sets. Inclusion of specific water molecules involved in water-mediated hydrogen bonds did not significantly improve the docking performance for ligands that formed water-mediated contacts but it did prevent docking of ligands that displaced these waters. Our data supports the use of a single protein structure for virtual screening with GOLD in some applications involving induced fit effects, although care must be taken to identify the protein structure that performs best against a wide variety of ligands. The performance of GOLD was significantly better than the GOLD implementation of ChemScore and the reasons for this are discussed. Overall, GOLD has shown itself to be an extremely good, robust docking program for this system.

Algorithms↗
PubMed2002

Distilling the essential features of a protein surface for improving protein-ligand docking, scoring, and virtual screening.

For the successful identification and docking of new ligands to a protein target by virtual screening, the essential features of the protein and ligand surfaces must be captured and distilled in an efficient representation. Since the running time for docking increases exponentially with the number of points representing the protein and each ligand candidate, it is important to place these points where the best interactions can be made between the protein and the ligand. This definition of favorable points of interaction can also guide protein structure-based ligand design, which typically focuses on which chemical groups provide the most energetically favorable contacts. In this paper, we present an alternative method of protein template and ligand interaction point design that identifies the most favorable points for making hydrophobic and hydrogen-bond interactions by using a knowledge base. The knowledge-based protein and ligand representations have been incorporated in version 2.0 of SLIDE and resulted in dockings closer to the crystal structure orientations when screening a set of 57 known thrombin and glutathione S-transferase (GST) ligands against the apo structures of these proteins. There was also improved scoring enrichment of the dockings, meaning better differentiation between the chemically diverse known ligands and a approximately 15,000-molecule dataset of randomly-chosen small organic molecules. This approach for identifying the most important points of interaction between proteins and their ligands can equally well be used in other docking and design techniques. While much recent effort has focused on improving scoring functions for protein-ligand docking, our results indicate that improving the representation of the chemistry of proteins and their ligands is another avenue that can lead to significant improvements in the identification, docking, and scoring of ligands.

Algorithms↗
PubMed2003

Automated docking of ligands to an artificial active site: augmenting crystallographic analysis with computer modeling.

The W191G cavity of cytochrome c peroxidase is useful as a model system for introducing small molecule oxidation in an artificially created cavity. A set of small, cyclic, organic cations was previously shown to bind in the buried, solvent-filled pocket created by the W191G mutation. We docked these ligands and a set of non-binders in the W191G cavity using AutoDock 3.0. For the ligands, we compared docking predictions with experimentally determined binding energies and X-ray crystal structure complexes. For the ligands, predicted binding energies differed from measured values by +/- 0.8 kcal/mol. For most ligands, the docking simulation clearly predicted a single binding mode that matched the crystallographic binding mode within 1.0 A RMSD. For 2 ligands, where the docking procedure yielded an ambiguous result, solutions matching the crystallographic result could be obtained by including an additional crystallographically observed water molecule in the protein model. For the remaining 2 ligands, docking indicated multiple binding modes, consistent with the original electron density, suggesting disordered binding of these ligands. Visual inspection of the atomic affinity grid maps used in docking calculations revealed two patches of high affinity for hydrogen bond donating groups. Multiple solutions are predicted as these two sites compete for polar hydrogens in the ligand during the docking simulation. Ligands could be distinguished, to some extent, from non-binders using a combination of two trends: predicted binding energy and level of clustering. In summary, AutoDock 3.0 appears to be useful in predicting key structural and energetic features of ligand binding in the W191G cavity.

Automation↗
PubMed2000

A conserved docking motif in MAP kinases common to substrates, activators and regulators.

Mitogen-activated protein kinases (MAPKs) are specifically phosphorylated and activated by the MAPK kinases, phosphorylate various targets such as MAPK-activated protein kinases and transcription factors, and are inactivated by specific phosphatases. Recently, docking interactions via the non-catalytic regions of MAPKs have been suggested to be important in regulating these reactions. Here we identify docking sites in MAPKs and in MAPK-interacting enzymes. A docking domain in extracellular-signal-regulated kinase (ERK), a MAPK, serves as a common site for binding to the MAPK kinase MEK1, the MAPK-activated protein kinase MNK1 and the MAPK phosphatase MKP3. Two aspartic acids in this domain are essential for docking, one of which is mutated in the sevenmaker mutant of Drosophila ERK/Rolled. A corresponding domain in the MAPKs p38 and JNK/SAPK also serves as a common docking site for their MEKs, MAPK-activated protein kinases and MKPs. These docking interactions increase the efficiency of the enzymatic reactions. These findings reveal a hitherto unidentified docking motif in MAPKs that is used in common for recognition of their activators, substrates and regulators.

Amino Acid Motifs↗
PubMed2002

Modular structure of a docking surface on MAPK phosphatases.

Mitogen-activated protein kinases (MAPKs) must be precisely inactivated to achieve proper functions in the cells. Ten members of dual specificity phosphatases specifically acting on MAPKs, termed MAPK phosphatases (MKPs), have been reported. Each member has its own substrate specificity that should be tightly regulated. However, the molecular mechanism underlying the regulation of the specificity is largely unknown. In the MAPK signaling pathways, docking interactions, which are different from transient enzyme-substrate interaction, are known to regulate the enzymatic specificity. Here we have identified and characterized a docking surface of MKPs. Our results show that a docking surface is composed of a tandem alignment of three subregions (modules): a cluster of positively charged amino acids, a cluster of hydrophobic amino acids, and a cluster of positively charged amino acids (positive-hydrophobic-positive). This modular structure well fits the docking groove on MAPKs that we have previously identified and may contribute to regulating the docking specificity of the MKP family. The position, number, and species of charged amino acids in each module including the central hydrophobic subregion are important factors in regulation of docking to specific MAPKs. This modular structure in the docking interaction may define a novel model of protein-protein interaction that would also regulate other systems.

Amino Acid Sequence↗
PubMedDate not supplied

Methodology and problems of protein-ligand docking: case study of dihydroorotate dehydrogenase, thymidine kinase, and phosphodiesterase 4.

The docking methodology was applied to three different therapeutically interesting enzymes: human dihydroorotate dehydrogenase (DHODH), Herpes simplex virus type I thymidine kinase (HSV1 TK) and human phosphodiesterase 4 (PDE4). Programs FlexX, AutoDock and DOCK where used. The three targets represent three distinct cases. For DHODH and HSV1 TK, the binding modes of substrate and inhibitors within the active site are known, while the binding orientation of cAMP within PDE4 has been solely hypothesized. Active site of DHODH is mainly hydrophobic and the binding mode of the inhibitor brequinar was used as a template for evaluating the docking strategies. The presence of cofactors revealed to be crucial for the definition of the docking site. The HSV1 TK active site is small and polar and contains crystal water molecules and ATP. Docking of thymidine and aciclovir (ACV) within the active site was analyzed by keeping or removing water molecules. It showed the crucial role of water in predicting the binding of pyrimidines and purines. The crystal structure of PDE4 contains magnesium and zinc cations as well as catalytic water molecule but no ligand. Several docking experiments of cAMP and rolipram were performed and the results showed clear-cut dependence between the ligand orientation and the presence of metals in the active site. All three cases show specific problems of the docking methodology, depending on the character of the active site.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1997

Docking of yeast vacuoles is catalyzed by the Ras-like GTPase Ypt7p after symmetric priming by Sec18p (NSF).

Vacuole inheritance in yeast involves the formation of tubular and vesicular "segregation structures" which migrate into the bud and fuse there to establish the daughter cell vacuole. Vacuole fusion has been reconstituted in vitro and may be used as a model for an NSF-dependent reaction of priming, docking, and fusion. We have developed biochemical and microscopic assays for the docking step of in vitro vacuole fusion and characterized its requirements. The vacuoles must be primed for docking by the action of Sec17p (alpha-SNAP) and Sec18p (NSF). Priming is necessary for both fusion partners. It produces a labile state which requires rapid docking in order to lead productively to fusion. In addition to Sec17p/Sec18p, docking requires the activity of the Ras-like GTPase Ypt7p. Unlike Sec17p/Sec18p, which must act before docking, Ypt7p is directly involved in the docking process itself.

Adenosine Triphosphatases↗
PubMed2004

PEX3 functions as a PEX19 docking factor in the import of class I peroxisomal membrane proteins.

PEX19 is a chaperone and import receptor for newly synthesized, class I peroxisomal membrane proteins (PMPs). PEX19 binds these PMPs in the cytoplasm and delivers them to the peroxisome for subsequent insertion into the peroxisome membrane, indicating that there may be a PEX19 docking factor in the peroxisome membrane. Here we show that PEX3 is required for PEX19 to dock at peroxisomes, interacts specifically with the docking domain of PEX19, and is required for recruitment of the PEX19 docking domain to peroxisomes. PEX3 is also sufficient to dock PEX19 at heterologous organelles and binds PEX19 via a conserved motif that is essential for this docking activity and for PEX3 function in general. Not surprisingly, transient inhibition of PEX3 abrogates class I PMP import but has no effect on class II PMP import or peroxisomal matrix protein import. Taken together, these results suggest that PEX3 plays a selective, essential, and direct role in PMP import as a docking factor for PEX19.

Amino Acid Motifs↗
PubMed1996

Cosmetic tail docking of dogs.

The anatomy of the canine tail and its relationship to the physiological functions of the tail are described and the effect of tail docking on these is discussed. Current knowledge on the physiology and anatomy of pain is described with particular reference to cosmetic tail docking in the neonatal puppy. Recent advances in knowledge about pain and the changes in approach to pain management, refute the premise that 'puppies do not feel pain therefore tail docking is not inhumane' and also the premise that 'the pain and the effects of tail docking are insignificant.' Six criteria to test the 'necessity' to dock dogs are presented; this article shows that the reasons advanced for tail docking do not satisfy these criteria and so that docking dogs' tails cannot be justified.

Amputation, Surgical↗
PubMed1995

Evaluation of the respiratory health of dock workers who load grain cargoes in British Columbia.

OBJECTIVES: To investigate the respiratory health of dock workers who load grain cargoes. METHODS: The respiratory health of 118 dock workers who load grain cargoes in the ports of Vancouver and Prince Rupert was compared with that of 555 grain elevator workers from the same regions. 128 civic workers were used as an unexposed control group. RESULTS: The prevalences of chronic cough and phlegm were at least as high in dock workers as those found in the elevator workers, and when adjusted for differences in duration of employment and smoking, dock workers had an eightfold higher risk of developing chronic phlegm than did civic workers. Symptoms of eye and skin irritation that were experienced at least monthly were highest for dock workers. Average percentage of the predicted FEV1 and FVC for dock workers (mean 100.6% and 105.3% respectively) were similar to the civic workers but significantly higher than those found for elevator workers. Higher subjective estimates of duration of exposure to grain dust (hours/day) were associated with lower values of FEV1. CONCLUSIONS: The more intermittent grain dust exposure patterns of dock workers may have allowed for some recovery of lung function, but chronic respiratory symptoms were less labile.

Adult↗