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Results for “Molecular Docking Simulation”

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PubMed2006

Homology modeling of the serotonin 5-HT1A receptor using automated docking of bioactive compounds with defined geometry.

This paper describes a rhodopsin-based model of 5-HT(1A) serotonin receptor. The flexibility of the receptor was considered by using large number of models for ligand dockings. Rearrangements of the heptahelical bundle were introduced, which resulted in the improvement of correlation between computational results and experimental data. The model was validated by automated docking of conformationally restricted arylpiperazines. Specific interactions, responsible for the recognition of arylpiperazine derivatives, were identified. An ionic bond was formed between the protonated amine of ligands and Asp3.32. The aromatic moiety and its substituents specifically interacted with Phe6.52 and Ser5.42, respectively, while the carbonyl groups of imide part of ligands formed hydrogen bonds with Asn7.39 and Tyr7.43. The model reproduced the binding affinity of the test group of ligands (correlation r = 0.8 between pK(i) and docking score). It also gave the enrichment in virtual screening-like experiment (100 compounds), in which 34 high-affinity compounds were found among 50 top-scored ligands.

Binding Sites↗

PubMed1994

Molecular dynamics simulations in solvent of the glucocorticoid receptor protein in complex with a glucocorticoid response element DNA sequence.

We investigated protein/DNA interactions, using molecular dynamics simulations computed in solvent, between the glucocorticoid receptor (GR) DNA binding domain (DBD) amino acids and DNA of a glucocorticoid receptor response element (GRE). We compared findings obtained from a fully solvated 80 Angstrom water droplet GR DBD/GRE model with those from a 10 Angstrom water layer GR DBD/GRE model. Hydrogen bonding interactions were monitored. In addition, van der Waals and electrostatic interaction energies were calculated. Molecular dynamics simulations from both models yielded similar findings; amino acids of the GR DBD DNA recognition helix formed both direct and water mediated hydrogen bonds at cognate codon/anticodon nucleotide base sites within the GRE right major groove halfsite. Likewise GR DBD amino acids in a beta strand structure adjacent to the DNA recognition helix formed both direct and water mediated hydrogen bonds at cognate codon/anticodon nucleotide base and backbone sites. We also investigated protein/DNA interactions with a 10 Angstrom water layer model consisting of the same GR DBD as above but with a predicted alpha helix attached to the carboxyl terminus of the GR DBD docked at the same GRE as above with additional flanking nucleotides. In this model, the interactions between amino acids of the DNA recognition helix and beta strand and nucleotides within the GRE right major groove halfsite were at cognate codon/anticodon nucleotide sites as found in the two models above. In addition, amino acids within the predicted alpha helix located on the carboxyl terminus of the GR DBD interacted at codon/anticodon nucleotide sites on the DNA backbone of the GRE flanking nucleotides. These interactions together induced breakage of Watson-Crick nucleotide base pairing hydrogen bonds, resulting in bending of the DNA, strand elongation and unwinding events similar to those described for helicases.

Amino Acid Sequence↗

PubMed2006

Impaired helix 12 dynamics due to proline 892 substitutions in the androgen receptor are associated with complete androgen insensitivity.

Structural studies of the ligand-binding domain (LBD) of several steroid receptors have revealed that the dynamic properties of the C-terminal helix 12 (H12) are the major determinant of the activation mode of these receptors. H12 exhibits high mobility and different conformations in the absence of ligand. Upon ligand binding, H12 is stabilized in a precise position to seal the ligand-binding pocket and finalize the assembly of the activation function (AF-2) domain. In this study, we investigated the role of the conserved proline 892 of the androgen receptor (AR) in directing the dynamic location and orientation of the AR-H12. We used a combined approach including kinetic and biochemical assays with molecular dynamic simulations to analyze two substitutions (P892A and P892L) identified in individuals with complete androgen insensitivity syndrome. Our analyses revealed distinct mechanisms by which these substitutions impair H12 function resulting in severely defective receptors. The AR-P892A receptor exhibited reduced ligand binding and transactivational potential because of an increased flexibility in H12. The AR-P892L substitution renders the receptor inactive due to a distorted, unstructured and misplaced H12. To confirm the mutants' inability to stabilize H12 in an active position, we have developed a novel in vivo assay to evaluate the accessibility of the H12-docking site on the AR-LBD surface. An extrinsic AR-H12 peptide was able to interact with wild-type and mutant LBDs in the absence of ligand. Ligand-induced proper positioning of the intrinsic H12 of wild-type AR prevented these interactions, whereas the misplacement of the mutants' H12 did not. Proline at this position may be critical for H12 dynamics not only in the AR, but also in other nuclear receptors where this proline is conserved.

Amino Acid Sequence↗

PubMed2005

Humanization of an anti-human TNF-alpha antibody by variable region resurfacing with the aid of molecular modeling.

The murine monoclonal antibody Z12 is of therapeutic interest for its neutralizing biological activity against human tumor necrosis factor-alpha (hTNF-alpha). We attempted to humanize Z12 with variable domain resurfacing guided by computer modeling. First, the genes of heavy and light chain variable region (VH, VL) of Z12 were cloned and the whole three-dimensional structure of Fv fragment was constructed by using homology-based modeling and molecular docking methods. Then the complex model of Fv interacting with hTNF-alpha whose crystal structure derived from PDB database was gained with computer-guided docking program. Based on this model, a humanized version was designed. The humanized Fab antibody was constructed, expressed and purified in the pComb3H vector system and it showed unaltered binding affinity to the antigen as determined by ELISA and atomic force microscopy (AFM). The method described here can be used to humanize other anti-hTNF-alpha antibodies.

Amino Acid Sequence↗

PubMed1999

The binding site for UCH-L3 on ubiquitin: mutagenesis and NMR studies on the complex between ubiquitin and UCH-L3.

The ubiquitin fold is a versatile and widely used targeting signal that is added post-translationally to a variety of proteins. Covalent attachment of one or more ubiquitin domains results in localization of the target protein to the proteasome, the nucleus, the cytoskeleton or the endocytotic machinery. Recognition of the ubiquitin domain by a variety of enzymes and receptors is vital to the targeting function of ubiquitin. Several parallel pathways exist and these must be able to distinguish among ubiquitin, several different types of polymeric ubiquitin, and the various ubiquitin-like domains. Here we report the first molecular description of the binding site on ubiquitin for ubiquitin C-terminal hydrolase L3 (UCH-L3). The site on ubiquitin was experimentally determined using solution NMR, and site-directed mutagenesis. The site on UCH-L3 was modeled based on X-ray crystallography, multiple sequence alignments, and computer-aided docking. Basic residues located on ubiquitin (K6, K11, R72, and R74) are postulated to contact acidic residues on UCH-L3 (E10, E14, D33, E219). These putative interactions are testable and fully explain the selectivity of ubiquitin domain binding to this enzyme.

Allosteric Site↗

PubMed2006

The structure of human ADP-ribosylhydrolase 3 (ARH3) provides insights into the reversibility of protein ADP-ribosylation.

Posttranslational modifications are used by cells from all kingdoms of life to control enzymatic activity and to regulate protein function. For many cellular processes, including DNA repair, spindle function, and apoptosis, reversible mono- and polyADP-ribosylation constitutes a very important regulatory mechanism. Moreover, many pathogenic bacteria secrete toxins which ADP-ribosylate human proteins, causing diseases such as whooping cough, cholera, and diphtheria. Whereas the 3D structures of numerous ADP-ribosylating toxins and related mammalian enzymes have been elucidated, virtually nothing is known about the structure of protein de-ADP-ribosylating enzymes. Here, we report the 3Dstructure of human ADP-ribosylhydrolase 3 (hARH3). The molecular architecture of hARH3 constitutes the archetype of an all-alpha-helical protein fold and provides insights into the reversibility of protein ADP-ribosylation. Two magnesium ions flanked by highly conserved amino acids pinpoint the active-site crevice. Recombinant hARH3 binds free ADP-ribose with micromolar affinity and efficiently de-ADP-ribosylates poly- but not monoADP-ribosylated proteins. Docking experiments indicate a possible binding mode for ADP-ribose polymers and suggest a reaction mechanism. Our results underscore the importance of endogenous ADP-ribosylation cycles and provide a basis for structure-based design of ADP-ribosylhydrolase inhibitors.

Adenosine Diphosphate Ribose↗

PubMed2003

A structure-activity relationship study of catechol-O-methyltransferase inhibitors combining molecular docking and 3D QSAR methods.

A panel of 92 catechol-O-methyltransferase (COMT) inhibitors was used to examine the molecular interactions affecting their biological activity. COMT inhibitors are used as therapeutic agents in the treatment of Parkinson's disease, but there are limitations in the currently marketed compounds due to adverse side effects. This study combined molecular docking methods with three-dimensional structure-activity relationships (3D QSAR) to analyse possible interactions between COMT and its inhibitors, and to incite the design of new inhibitors. Comparative molecular field analysis (CoMFA) and GRID/GOLPE models were made by using bioactive conformations from docking experiments, which yielded q2 values of 0.594 and 0.636, respectively. The docking results, the COMT X-ray structure, and the 3D QSAR models are in agreement with each other. The models suggest that an interaction between the inhibitor's catechol oxygens and the Mg2+ ion in the COMT active site is important. Both hydrogen bonding with Lys144, Asn170 and Glu199, and hydrophobic contacts with Trp38, Pro174 and Leu198 influence inhibitor binding. Docking suggests that a large R1 substituent of the catechol ring can form hydrophobic contacts with side chains of Val173, Leu198, Met201 and Val203 on the COMT surface. Our models propose that increasing steric volume of e.g. the diethylamine tail of entacapone is favourable for COMT inhibitory activity.

Animals↗

PubMed2005

1,5-Diarylpyrrole-3-acetic acids and esters as novel classes of potent and highly selective cyclooxygenase-2 inhibitors.

A small set of substituted 1,5-diarylpyrrole-3-acetic and -glyoxylic acid derivatives have been synthesized, and their cyclooxygenase (COX-1 and COX-2) inhibiting properties have been evaluated. Some compounds proved to be highly selective COX-2 inhibitors, and their affinity data have been rationalized through docking simulations in terms of interactions with a crystallographic model of the COX-2 binding site.

Acetates↗

PubMed2005

Naphtho[1,2-d]isothiazole acetic acid derivatives as a novel class of selective aldose reductase inhibitors.

Acetic acid derivatives of naphtho[1,2-d]isothiazole (NiT) were synthesized and tested as novel aldose reductase (ALR2) inhibitors. The parent compound 11 exhibited a fair inhibitory activity (IC(50) = 10 muM), which was enhanced by 2 orders of magnitude by introducing a second carboxylic group at position 4 (13 and 14: IC(50) = 0.55 and 0.14 muM, respectively). Substitution of the acetic acid function with an apolar group gave inactive (29) or poorly active (25, 26, 30) compounds, thus demonstrating that the 2-acetic group is involved in the enzyme pharmacophoric recognition while the 4-carboxylic moiety has only an accessory role. The potent compounds 11, 13, 14, 26 all proved to be selective for ALR2, since none of them inhibited aldehyde reductase, sorbitol dehydrogenase, or glutathione reductase. The isopropyl ester 31, a prodrug of 14, was found to be effective in preventing cataract development in severely galactosemic rats, when administered as an eyedrop solution. The theoretical binding mode of 13 and 14, obtained by docking simulations into the ALR2 crystal structure, was fully consistent with the structure-activity relationships in the NiT series.

Acetates↗

PubMedDate not supplied

Molecular therapeutic target for type-2 diabetes.

Many lines of evidences indicate that increased flux of glucose through the pathway, in which glutamine:fructose-6-phosphate amidotransferase (GFPT or GFAT) is a key catalyst while uridine-5'-diphosphate-N-acetylglucosamine (UDP-GlcNAc) functions as an energy sensor, can lead to the insulin resistance that is characteristic of Type-2 diabetes. In view of this, GFAT and its interaction mechanism with UDP-GlcNAc may become a novel therapeutic target for the treatment of type 2 diabetes. To stimulate the structure-based drug design, the three-dimensional structures of human GFAT1 monomer and dimer have been developed. It has been found by docking UDP-GlcNAc to the dimer (the smallest unit for catalyzing the substrate) that UDP-GlcNAc is bound to the interface of the dimer by 12 hydrogen bonds. On the basis of the docking results, a binding pocket of human GFAT1 dimer for UDP-GlcNAc is defined. All of these findings can serve as a reference or footing in developing new therapeutic strategy for the treatment of type-2 diabetes.

Amino Acid Sequence↗

PubMed2002

Understanding protein structure-function relationships in Family 47 alpha-1,2-mannosidases through computational docking of ligands.

Family 47 alpha-1,2-mannosidases are crucial enzymes involved in N-glycan maturation in the endoplasmic reticula and Golgi apparati of eukaryotic cells. High-resolution crystal structures of the human and yeast endoplasmic reticulum alpha-1,2-mannosidases have been recently determined, the former complexed with the inhibitors 1-deoxymannojirimycin and kifunensine, both of which bind in its active site in the unusual 1C4 conformation. However, unambiguous identification of the catalytic proton donor and nucleophile involved in glycoside bond hydrolysis was not possible from this structural information. In this work, alpha-D-galactose, alpha-D-glucose, and alpha-D-mannose were computationally docked in the active site in the energetically stable 4C1 conformation as well as in the 1C4 conformation to compare their interaction energetics. From these docked structures, a model for substrate and conformer selectivity based on the dimensions of the active site was proposed. Alpha-D-galactopyranosyl-(1-->2)-alpha-D-mannopyranose, alpha-D-glucopyranosyl-(1-->2)-alpha-D-mannopyranose, and alpha-D-mannopyranosyl-(1-->2)-alpha-D-mannopyranose were also docked into the active site with their nonreducing-end residues in the 1C4 and E4 (representing the transition state) conformations. Based on the docked structure of alpha-D-mannopyranosyl-E4-(1-->2)-alpha-D-mannopyranose, the catalytic acid and base are Glu132 and Glu435, respectively.

1-Deoxynojirimycin↗

PubMed1997

Development and validation of a genetic algorithm for flexible docking.

Prediction of small molecule binding modes to macromolecules of known three-dimensional structure is a problem of paramount importance in rational drug design (the "docking" problem). We report the development and validation of the program GOLD (Genetic Optimisation for Ligand Docking). GOLD is an automated ligand docking program that uses a genetic algorithm to explore the full range of ligand conformational flexibility with partial flexibility of the protein, and satisfies the fundamental requirement that the ligand must displace loosely bound water on binding. Numerous enhancements and modifications have been applied to the original technique resulting in a substantial increase in the reliability and the applicability of the algorithm. The advanced algorithm has been tested on a dataset of 100 complexes extracted from the Brookhaven Protein DataBank. When used to dock the ligand back into the binding site, GOLD achieved a 71% success rate in identifying the experimental binding mode.

Algorithms↗

PubMed2006

The energetic network of hotspot residues between Cdc25B phosphatase and its protein substrate.

We have investigated the functional network of hotspot residues at the remote docking site of two cell cycle regulators, namely Cdc25B phosphatase and its native protein substrate Cdk2-pTpY/CycA. Specifically, we have studied the roles of energetically important residues (Arg488, Arg492, Tyr497 on Cdc25B and Asp206 and Asp210 on Cdk2-pTpY/CycA) by generating a diverse set of substitutions and performing double and triple mutant cycle analyses. This transient protein-protein interaction is particularly well-suited for this mutagenic approach because various control experiments ensure that the effect of each mutation is limited to the interaction of interest. We find binary coupling energies for ion pairs and hydrogen bonds ranging from 0.7 kcal/mol to 3.9 kcal/mol and ternary coupling energies of 1.9 kcal/mol and 2.8 kcal/mol. Overall our biochemical analyses are in good agreement with the docked structure of the complex and suggest the following roles for the individual hotspot residues on Cdc25B. The most important contributor, Arg492, forms a specific and tight bidentate interaction with Asp206 and a weaker interaction with Asp210 that cannot be replaced by a Lys. Although Tyr497 does not directly participate in this ionic network, it is important for buttressing Arg492 using both its hydrophobic (aromatic ring) and hydrophilic characteristics (hydrogen bonding). Arg488 participates less specifically in the electrostatic network with Asp206 and Asp210 of the protein substrate as it can partially be replaced by Lys. Our data provide insight how a cluster of residues in a docking site remote from the site of the chemical reaction can bring about efficient and specific substrate recognition.

Amino Acid Sequence↗

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↗

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↗

PubMed2005

Spatial orientation of the antagonist granisetron in the ligand-binding site of the 5-HT3 receptor.

The serotonin type 3 receptor (5-HT(3)R) is a member of the cys-loop ligand-gated ion channel (LGIC) superfamily. Like almost all membrane proteins, high-resolution structural data are unavailable for this class of receptors. We have taken advantage of the high degree of homology between LGICs and the acetylcholine binding protein (AChBP) from the freshwater snail Lymnea stagnalis, for which high-resolution structural data are available, to create a structural model for the extracellular (i.e., ligand-binding) domain of the 5-HT(3)R and to perform a series of ligand docking experiments to delineate the architecture of the ligand-binding site. Structural models were created using homology modeling with the AChBP as a template. Docking of the antagonist granisetron was carried out using a Lamarckian genetic algorithm to produce models of ligand-receptor complexes. Two energetically similar conformations of granisetron in the binding site were obtained from the docking simulations. In one model, the indazole ring of granisetron is near Trp90 and the tropane ring is near Arg92; in the other, the orientation is reversed. We used double-mutant cycle analysis to determine which of the two orientations is consistent with experimental data and found that the data are consistent with the model in which the indazole ring of granisetron interacts with Arg92 and the tropane ring interacts with Trp90. The combination of molecular modeling with double-mutant cycle analysis offers a powerful approach for the delineation of the architecture of the ligand-binding site.

Animals↗

PubMed2003

Rat polymerase beta gapped DNA interactions: antagonistic effects of the 5' terminal PO4 - group and magnesium on the enzyme binding to the gapped DNAs with different ssDNA gaps.

The role of the 5' terminal phosphate group downstream from the primer and magnesium cations in the energetics and dynamics of the gapped DNA recognition by rat polymerase beta have been examined, using the fluorescence titration and stopped-flow techniques. The analyses have been performed with the entire series of gapped DNA substrates differing in the size of the ssDNA gap. The 5' terminal phosphate group and magnesium cations exert antagonistic effect on enzyme binding to gapped DNA that depends on the length of the ssDNA gap. The PO4 - group amplifies the differences between the substrates with different ssDNA gaps, while in the presence of magnesium, affinities and structural changes induced in the DNA are very similar among examined DNA substrates. Both, the phosphate group and Mg+2 differ dramatically in affecting the thermodynamic response of the gapped DNA-rat pol beta system to the salt concentration. The data indicate that these distinct effects result from affecting the structure of the DNA, in the case of the phosphate group, and from direct magnesium binding to the protein. The mechanism of rat enzyme binding depends on the length of the ssDNA gap and the presence of the 5' terminal phosphate group. Complex formation with DNAs having three, four, and five residues in the gap occurs by a minimum three-step sequential mechanism. Depending on the presence of the 5' terminal phosphate group and/or magnesium, binding of the enzyme to a DNA containing two residues in the ssDNA gap is described by the same three-step or by a simpler two-step mechanism. With the DNA containing only one residue in the gap, binding is always described by only a two-step mechanism. The PO4 - group and magnesium cations have opposite effects on internal stability of the complexes with different length of the ssDNA gap. While the PO4 - group increases the stability of internal intermediates with the increasing length of the gap, Mg+2 decreases the stability of the intermediates with longer ssDNA gap. As a result, the combined favorable orientation effect of the phosphate group and the unfavorable Mg+2 effect lead to the optimal docking of the ssDNA gaps with three and four residues by the enzyme.

Animals↗

PubMed2002

Development of biologically active compounds by combining 3D QSAR and structure-based design methods.

One of the major challenges in computational approaches to drug design is the accurate prediction of the binding affinity of novel biomolecules. In the present study an automated procedure which combines docking and 3D-QSAR methods was applied to several drug targets. The developed receptor-based 3D-QSAR methodology was tested on several sets of ligands for which the three-dimensional structure of the target protein has been solved--namely estrogen receptor, acetylcholine esterase and protein-tyrosine-phosphatase 1B. The molecular alignments of the studied ligands were determined using the docking program AutoDock and were compared with the X-ray structures of the corresponding protein-ligand complexes. The automatically generated protein-based ligand alignment obtained was subsequently taken as basis for a comparative field analysis applying the GRID/GOLPE approach. Using GRID interaction fields and applying variable selection procedures, highly predictive models were obtained. It is expected that concepts from receptor-based 3D QSAR will be valuable tools for the analysis of high-throughput screening as well as virtual screening data.

Binding Sites↗