SEARCH · PubMed Health

Results for “Molecular Docking Simulation”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 325 records · Page 18Linked to original sources

PubMedDate not supplied

Tetraethylammonium binding to the outer mouth of the KcsA potassium channel: implications for ion permeation.

Extracellular tetraethylammonium (TEA+) inhibits the current carried out by K+ ions in potassium channels. Structural models of wild-type (WT) and Y82C KcsA K+ channel/TEA+ complexes are here built using docking procedures, electrostatics calculations and molecular dynamics simulations. The calculations are based on the structure determined by Doyle et al. (11) Our calculations suggest that in WT, the TEA+ cation turns binds at the outer mouth of the selectivity filter, stabilized by electrostatic and hydrophobic interactions with the four Tyr82 side chains. Replacement of Tyr82 with Cys causes a decrease of the affinity of the cation for the channel, consistently with the available site-directed mutagenesis data (16). An MD simulation in which K+ replaces TEA+ provides evidence that TEA+ binding site can accommodate a potassium ion, in agreement with the high-resolution structure recently reported by Zhou et al. (20)

Bacterial Proteins↗

PubMed2005

Partial agonism, neutral antagonism, and inverse agonism at the human wild-type and constitutively active cholecystokinin-2 receptors.

Cholecystokinin receptor-2 (CCK2R) is a G protein receptor that regulates a number of physiological functions. Activation of CCK2R and/or expression of a constitutively active CCK2R variant may contribute to human diseases, including digestive cancers. Search for antagonists of the CCK2R has been an important challenge during the last few years, leading to discovery of a set of chemically distinct compounds. However, several early-discovered antagonists turned out to be partial agonists. In this context, we carried out pharmacological characterization of six CCK2R antagonists using COS-7 cells expressing the human CCK2R or a CCK2R mutant having a robust constitutive activity on inositol phosphates production, and we investigated the molecular mechanisms which, at a CCK2R binding site, account for these features. Results indicated that three compounds, 3R(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl)urea (L365,260), 4-{[2-[[3-(lH-indol-3-yl)-2-methyl-1-oxo-2-[[[1.7.7-trimethyl-bicyclo[2.2.1]hept-2-yl)-oxy]carbonyl]amino]propyl]amino]-1-phenylethyl]amino-4-oxo-[lS-la.2[S*(S*)]4a]}-butanoate N-methyl-D-glucamine (PD135,158), and (R)-1-naphthalenepropanoic acid, b-[2-[[2-(8-azaspiro-[4.5]dec-8-ylcarbonyl)-4,6-dimethylphenyl]amino]-2-oxoethyl] (CR2945), were partial agonists; one molecule, 1-[(R)-2,3-dihydro-1-(2,3-dihydro-1-(2-methylphenacyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(3-methylphenyl)urea (YM022), was a neutral antagonist; and two compounds, N-(+)-[1-(adamant-1-ylmethyl)-2,4-dioxo-5-phenyl2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl]-N'-phenylurea (GV150,013X) and ([(N-[methoxy-3 phenyl] N-[N-methyl N-phenyl carbamoylmethyl], carbomoyl-methyl)-3 ureido]-3-phenyl)2-propionic acid (RPR101,048), were inverse agonists. Furthermore, target- and pharmacophore-based docking of ligands followed by molecular dynamic simulation experiments resulted in consistent motion of aromatic residues belonging to a network presumably important for activation, thus providing the first structural explanations for the different pharmacological profiles of tested compounds. This study confirms that several referenced so-called antagonists are in fact partial agonists, and because of this undesired activity, we suggest that newly generated molecules should be preferred to efficiently block CCK2R-related physiological effects. Furthermore, data on the structural basis for the different pharmacological features of CCK2R ligands will serve to further clarify CCK2R mechanism of activation.

Animals↗

PubMed2005

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.

Models, Molecular↗

PubMed1999

Docking of cationic antibiotics to negatively charged pockets in RNA folds.

The binding of aminoglycosides to RNA provides a paradigm system for the analysis of RNA-drug interactions. The electrostatic field around three-dimensional RNA folds creates localized and defined negatively charged regions which are potential docking sites for the cationic ammonium groups of aminoglycosides. To explore in RNA folds the electronegative pockets suitable for aminoglycoside binding, we used calculations of the electrostatic field and Brownian dynamics simulations of cation diffusion. We applied the technique on those RNA molecules experimentally known to bind aminoglycosides, namely, two tobramycin aptamers (Wang, Y.; Rando, R. R. Chem. Biol. 1995, 2, 281-290): the aminoglycoside-binding region in 16S ribosomal RNA (Moazed, S.; Noller, H. F. Nature 1987, 327, 389-394) and the TAR RNA from human immunodeficiency virus (Mei, H.-Y.; et al. Bioorg. Med. Chem. Lett. 1995, 5, 2755-2760). For the aptamers and ribosomal RNA, for which the binding sites of the aminoglycosides are known, a good agreement between negatively charged pockets and the binding positions of the drugs was found. On the basis of variations between neomycin-like and kanamycin-like aminoglycosides in the interaction with the electrostatic field of ribosomal RNA, we propose a model for the different binding specificities of these two classes of drugs. The spatial congruence between the electronegative pockets in RNA folds and binding positions of aminoglycosides was used to dock aminoglycosides to ribosomal and TAR RNAs. Molecular dynamics simulations were used to analyze possible RNA-drug interactions. Aminoglycosides inhibit the binding of the viral Tat protein to TAR RNA; however, the drug-binding sites are still unknown. Thus, our docking approach provides first structural models for TAR-aminoglycoside complexes. The RNA-drug interactions observed in the modeled complexes support the view that the antibiotics might lock TAR in a conformation with low affinity for the Tat protein, explaining the experimentally found aminoglycoside inhibition of the Tat-TAR interaction (Mei, H.-Y.; et al. Bioorg. Med. Chem. Lett. 1995, 5, 2755-2760).

Anti-Bacterial Agents↗

PubMed1990

Automated docking of substrates to proteins by simulated annealing.

The Metropolis technique of conformation searching is combined with rapid energy evaluation using molecular affinity potentials to give an efficient procedure for docking substrates to macromolecules of known structure. The procedure works well on a number of crystallographic test systems, functionally reproducing the observed binding modes of several substrates.

Acetylglucosamine↗

PubMed2006

Prediction of binding for a kind of non-peptic HCV NS3 serine protease inhibitors from plants by molecular docking and MM-PBSA method.

In the study, molecular dynamics simulations combined with MM-PBSA (Molecular Mechanics and Poisson-Boltzmann Surface Area) technique were applied to predict the binding mode of the polyphenol inhibitor in the binding pocket of the HCV NS3 serine protease for which the ligand-protein crystal structure is not available. The most favorable geometry of three candidates from molecular docking had a binding free energy about 3 and 6kcal/mol more favorable than the other two candidates, respectively, and was identified as the correct binding mode. In the mode, the correlation of the calculated and experimental binding affinities of all five polyphenol compounds is satisfactory indicated by r(2)=0.92. The most favorable binding mode suggests that two galloyl residues at 3 and 4 positions of the glucopyranose ring of the inhibitors interact with SER139, GLY137, ALA157, and ASP81 by hydrogen bond interaction and with ALA156 and HIE57 by hydrophobic interaction and are essential for the activities of the studied inhibitors.

Binding Sites↗

PubMed1991

Molecular modelling of protein-carbohydrate interactions. Docking of monosaccharides in the binding site of concanavalin A.

A general procedure is described for addressing the computer simulation of protein-carbohydrate interactions. First, a molecular mechanical force field capable of performing conformational analysis of oligosaccharides has been derived by the addition of new parameters to the Tripos force field; it is also compatible with the simulation of protein. Second, a docking procedure which allows for a systematic exploration of the orientations and positions of a ligand into a protein cavity has been designed. This so-called 'crankshaft' method uses rotations and variations about/of virtual bonds connecting, via dummy atoms, the ligand to the protein binding site. Third, calculation of the relative stability of protein ligand complexes is performed. This strategy has been applied to search for all favourable interactions occurring between a lectin [concanavalin A (ConA)] and methyl alpha-D-mannopyranoside or methyl alpha-D-glucopyranoside. For each monosaccharide, different stable orientations and positions within the binding site can be distinguished. Among them, one corresponds to very favourable interactions, not only in terms of hydrogen bonding, but also in terms of van der Waals interactions. It corresponds precisely to the binding mode of methyl alpha-D-mannopyranoside into ConA as revealed by the 2.9 A resolution of the crystalline complex (Derewenda et al., 1989). Some implications of the present modelling study with respect to the molecular basis of the specificity of the interaction of lectins with various monosaccharides are presented.

Binding Sites↗

PubMed2003

Molecular modelling studies on the ORL1-receptor and ORL1-agonists.

The ORLI (opioid receptor like 1)- receptor is a member of the family of rhodopsin-like G protein-coupled receptors (GPCR) and represents an interesting new therapeutical target since it is involved in a variety of biomedical important processes, such as anxiety, nociception, feeding, and memory. In order to shed light on the molecular basis of the interactions of the GPCR with its ligands, the receptor protein and a dataset of specific agonists were examined using molecular modelling methods. For that purpose, the conformational space of a very potent non-peptide ORL1-receptor agonist (Ro 64-6198) with a small number of rotatable bonds was analysed in order to derive a pharmacophoric arrangement. The conformational analyses yielded a conformation that served as template for the superposition of a set of related analogues. Structural superposition was achieved by employing the program FlexS. Using the experimental binding data and the superposition of the ligands, a 3D-QSAR analysis applying the GRID/GOLPE method was carried out. After the ligand-based modelling approach, a 3D model of the ORL1-receptor has been constructed using homology modelling methods based on the crystal structure of bovine rhodopsin. A representative structure of the model taken from molecular dynamics simulations was used for a manual docking procedure. Asp-130 and Thr-305 within the ORL1-receptor model served as important hydrophilic interaction partners. Furthermore, a hydrophobic cavity was identified stabilizing the agonists within their binding site. The manual docking results were supported using FlexX, which identified the same protein-ligand interaction points.

Amino Acid Sequence↗

PubMed2006

Prenylflavonoids as nonsteroidal phytoestrogens and related structure-activity relationships.

In the search for estrogen receptor (ER) modulators, a series of prenylflavonoids were found to be widely distributed amongst tonic herbal medicines and to possess estrogen-like activity in MCF-7/BOS cells, as evaluated by an estrogen-screening assay. Cell-cycle analysis revealed that the stimulatory effects of these compounds toward cell proliferation were elicited at the G1-S checkpoint and could significantly increase the S-phase population of MCF-7 cells under hormone-free conditions. ER-responsive gene (PS2, PgR) and protein (PgR) expression was also detected; mRNA and protein-expression levels for PS2 and PgR were up-regulated by the compounds in a dose-dependent manner. These effects could be inhibited by the pure ER antagonist ICI 182,780 ((7alpha-[9-{4,4,5,5,5-pentafluoropentyl}sulfinyl]nonyl)estra-1,3,5(10)-triene-3,17beta-diol). It was therefore concluded that the estrogen-like effects of these prenylflavonoids were mediated primarily through ERs. Furthermore, to explore the structure-activity relationship based on the estrogen receptor and detailed molecular mechanisms among the prenylflavonoids, protein-ligand docking simulations were carried out by using the DS-MODELING software package. The binding affinity of each prenylflavonoid toward ERalpha was scored, and the receptor-ligand interaction was also analyzed to provide the simulation characteristics of virtual molecular recognition mechanisms.

Base Sequence↗

PubMed2002

Mutating a critical lysine in ShK toxin alters its binding configuration in the pore-vestibule region of the voltage-gated potassium channel, Kv1.3.

The voltage-gated potassium channel in T lymphocytes, Kv1.3, an important target for immunosuppressants, is blocked by picomolar concentrations of the polypeptide ShK toxin and its analogue ShK-Dap22. ShK-Dap22 shows increased selectivity for Kv1.3, and our goal was to determine the molecular basis for this selectivity by probing the interactions of ShK and ShK-Dap22 with the pore and vestibule of Kv1.3. The free energies of interactions between toxin and channel residues were measured using mutant cycle analyses. These data, interpreted as approximate distance restraints, guided molecular dynamics simulations in which the toxins were docked with a model of Kv1.3 based on the crystal structure of the bacterial K(+)-channel KcsA. Despite the similar tertiary structures of the two ligands, the mutant cycle data imply that they make different contacts with Kv1.3, and they can be docked with the channel in configurations that are consistent with the mutant cycle data for each toxin but quite distinct from one another. ShK binds to Kv1.3 with Lys22 occupying the negatively charged pore of the channel, whereas the equivalent residue in ShK-Dap22 interacts with residues further out in the vestibule, producing a significant change in toxin orientation. The increased selectivity of ShK-Dap22 is achieved by strong interactions of Dap22 with His404 and Asp386 on Kv1.3, with only weak interactions between the channel pore and the toxin. Potent and specific blockade of Kv1.3 apparently occurs without insertion of a positively charged residue into the channel pore. Moreover, the finding that a single residue substitution alters the binding configuration emphasizes the need to obtain consistent data from multiple mutant cycle experiments in attempts to define protein interaction surfaces using these data.

Binding Sites↗

PubMed1999

Computer simulation of the interaction of non-steroidal anti-inflammatory drugs: indoprofen and NS398 with cyclooxygenase.

We have applied computer simulation technique to study interaction of two anti-inflammatory drugs (NSAIDs) indoprofen and NS398 with cyclooxygenase (COX-1 and COX-2) enzymes. We have also investigated conformational flexibility of the two drugs by systematic search and simulated annealing molecular dynamics (SAMD) methods. Both the drugs were docked in the cyclooxygenase channel using in house docking program IMF1. The complexes were energy minimised by molecular mechanics (MM) method. These were heated for 30 picoseconds (ps), equilibrated for 110 ps at 300K and subjected to 'production simulation' for 110 ps by molecular dynamics (MD) method using Sanderís module of AMBER 5.0 package and united atom force field mostly from PARM96.DAT. Integration was carried out with time step of 0.001 ps, distance dependent di-electric constant with scaling factor 2.0 for 1-4 interaction and cut-off distance for non-bonded pair-list equal to 8A. The non-bonded pair-list was upgraded after every 20 cycles. The coordinate output from MD trajectories is analysed using analysis package of AMBER 5.0, MOLMOL, P-CURVES 3.0 and in house packages: ANALMD, ANALP1. We have observed perturbative changes in COX-1 and COX-2 structures due to indoprofen and NS398. In case of indoprofen specific changes between COX-1 and COX-2 were noted in helix D, H6, S6 and helix H8 in the cyclooxygenase cavity. In case of NS398 these were in helix B in membrane binding domain, helix H6, S8 and S10 in cyclooxygenase cavity and helices H14-H16 in small lobe close to haem binding region. Implications of these results in enzyme selectivity by NSAIDs is discussed here.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2006

Molecular docking studies on 4-thiazolidinones as HIV-1 RT inhibitors.

Flexible docking simulations were performed on two series of 4-thiazolidinones as HIV-1 reverse transcriptase (HIV-1 RT) inhibitors. This was done by analyzing the interaction of these compounds with the allosteric site of the HIV-1 reverse transcriptase enzyme. The binding scores for these compounds were also congruent with their anti-HIV activity. A good correlation between the predicted binding free energies and the experimentally observed inhibitory activities (EC(50)) suggest that the identified binding conformations of these inhibitors are reliable. The results of docking studies provide an insight into the pharmacophoric structural requirements for the HIV-1 RT inhibitory activity of this class of molecules.

Allosteric Site↗

PubMed2004

Computational prediction of structure, substrate binding mode, mechanism, and rate for a malaria protease with a novel type of active site.

The histo-aspartic protease (HAP) from the malaria parasite P. falciparum is one of several new promising targets for drug intervention. The enzyme possesses a novel type of active site, but its 3D structure and mechanism of action are still unknown. Here we use a combination of homology modeling, automated docking searches, and molecular dynamics/reaction free energy profile simulations to predict the enzyme structure, conformation of bound substrate, catalytic mechanism, and rate of the peptide cleavage reaction. We find that the computational tools are sufficiently reliable both for identifying substrate binding modes and for distinguishing between different possible reaction mechanisms. It is found that the favored pathway only involves direct participation by the catalytic aspartate, with the neighboring histidine providing critical stabilization (by a factor of approximately 10000) along the reaction. The calculated catalytic rate constant of about 0.1 s(-1) for a hexapeptide substrate derived from the alpha chain of human hemoglobin is in excellent agreement with experimental kinetic data for a similar peptide fragment.

Animals↗

PubMed2005

Experimental validation of the docking orientation of Cdc25 with its Cdk2-CycA protein substrate.

Cdc25 phosphatases are key activators of the eukaryotic cell cycle and compelling anticancer targets because their overexpression has been associated with numerous cancers. However, drug discovery targeting these phosphatases has been hampered by the lack of structural information about how Cdc25s interact with their native protein substrates, the cyclin-dependent kinases. Herein, we predict a docked orientation for Cdc25B with its Cdk2-pTpY-CycA protein substrate by a rigid-body docking method and refine the docked models with full-scale molecular dynamics simulations and minimization. We validate the stable ensemble structure experimentally by a variety of in vitro and in vivo techniques. Specifically, we compare our model with a crystal structure of the substrate-trapping mutant of Cdc25B. We identify and validate in vivo a novel hot-spot residue on Cdc25B (Arg492) that plays a central role in protein substrate recognition. We identify a hot-spot residue on the substrate Cdk2 (Asp206) and confirm its interaction with hot-spot residues on Cdc25 using hot-spot swapping and double mutant cycles to derive interaction energies. Our experimentally validated model is consistent with previous studies of Cdk2 and its interaction partners and initiates the opportunity for drug discovery of inhibitors that target the remote binding sites of this protein-protein interaction.

Binding Sites↗

PubMed2002

A model of the human M2 muscarinic acetylcholine receptor.

The M2 muscarinic acetylcholine receptor belongs to the family of rhodopsin like G-Protein Coupled Receptors. This subtype of muscarinic receptors is of special interest because it bears, aside from an orthosteric binding site, also an allosteric binding site. Based on the X-ray structure of bovine rhodopsin a complete homology model of the human M2 receptor was developed. For the orthosteric binding site point mutations and binding studies with different agonists and antagonists are available. This knowledge was utilized for an initial verification of the M2 model. Allosteric modulation of activity is mediated by structurally different ligands such as gallamine, caracurine V salts or W84 (a hexamethonium-derivative). Caracurine V derivatives with different affinities to M2 were docked using GRID-fields. Subsequent molecular dynamics simulations yielded different binding energies based on diverse electrostatic and lipophilic interactions. The calculated affinities are in good agreement to experimentally determined affinities.

Allosteric Site↗

PubMed2006

Modeling the structure of the StART domains of MLN64 and StAR proteins in complex with cholesterol.

Steroidogenic acute regulatory protein-related lipid transfer (StART) domains are ubiquitously involved in intracellular lipid transport and metabolism and other cell-signaling events. In this work, we use a flexible docking algorithm, comparative modeling, and molecular dynamics (MD) simulations to generate plausible three-dimensional atomic models of the StART domains of human metastatic lymph node 64 (MLN64) and steroidogenic acute regulatory protein (StAR) proteins in complex with cholesterol. Our results show that cholesterol can adopt a similar conformation in the binding cavity in both cases and that the main contribution to the protein-ligand interaction energy derives from hydrophobic contacts. However, hydrogen-bonding and water-mediated interactions appear to be important in the fine-tuning of the binding affinity and the position of the ligand. To gain insights into the mechanism of binding, we carried out steered MD simulations in which cholesterol was gradually extracted from within the StAR model. These simulations indicate that a transient opening of loop Omega1 may be sufficient for uptake and release, and they also reveal a pathway of intermediate states involving residues known to be crucial for StAR activity. Based on these observations, we suggest specific mutagenesis targets for binding studies of cholesterol and its derivatives that could improve our understanding of the structural determinants for ligand binding by sterol carrier proteins.

Algorithms↗

PubMed2004

SDOCKER: a method utilizing existing X-ray structures to improve docking accuracy.

This paper introduces a new strategy for structure-based drug design that combines high-quality docking with data from existing ligand-protein cocrystal X-ray structures. The main goal of SDOCKER, a new algorithm that implements this strategy, is docking accuracy improvement. In this new paradigm, simulated annealing molecular dynamics is used for conformational sampling and optimization and an additional similarity force is applied on the basis of the positions of ligands from X-ray data that focus the sampling on relevant regions of the active site. Because the structural information from both the ligand and protein active site is included, this approach is more effective in finding the optimal conformation for a ligand-protein complex than the classical docking or similarity overlays. Interestingly, it was found that a 3D similarity-only approach gives comparable docking accuracy to the regular force field approach used in classical docking, given the final structures are minimized in the presence of the protein. The combination of both, as implemented in SDOCKER, is shown here to be more accurate. A significant improvement in docking accuracy has been observed for three different test systems. Specifically an improvement of 10%, 17.5%, and 10% is seen for 37 HIV-1 protease, 32 thrombin, and 23 CDK2 ligands, respectively, compared to docking using the force field alone. In addition, SDOCKER's accuracy performance dependence on the similarity template is discussed. The strategy of utilizing existing ligand X-ray information should prove effective in light of the multitude of structures available from structural genomics approaches.

Algorithms↗

PubMed2004

A hybrid method of molecular dynamics and harmonic dynamics for docking of flexible ligand to flexible receptor.

We have developed a new docking method to consider receptor flexibility, a hybrid method of molecular dynamics and harmonic dynamics. The global motions of the whole receptor were approximately introduced into those of the receptor in the docking simulation as harmonic dynamics. On the other hand, the local flexibility of the side chains was also considered by conventional molecular dynamics. We confirmed that this new method can reproduce the fluctuations of the whole receptor by making a comparison of the directions and amplitudes of the global fluctuations. Then this method was applied to the docking of HIV-1 protease and its ligand. As a result, we observed a docking process where the ligand enters into the binding pocket well, which implies that this method is effective enough to reproduce a molecular complex formation.

Algorithms↗