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Results for “Molecular Docking Simulation”

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PubMed2003

Molecular recognition between 4a S/R-galanthamine diastereoisomers and alpha-cyclodextrin.

Molecular recognition between 4a S/R-galanthamine diastereoisomers (1: 4a S-galanthamine;2: 4a R-galanthamine) and alpha-cyclodextrin (alpha-CD) were studied by use of docking and molecular dynamics (MD) simulation approaches. The binding energy of constructed 2...alpha-CD complexes is approximately 17 kcal mol(-1) lower than that of 1...alpha-CD, implying a stronger binding ability of 2 with alpha-CD than that of1. The theoretical modeling result is consistent with our previous CZE result, which demonstrated that alpha-CD is an efficient chiral additive for separating 1 and 2. The modeling result also indicates that both hydrophobic interaction and H-bond force may work as major factors for molecular recognition between the galanthamine diastereoisomers and alpha-CD.

Computer Simulation↗

PubMed2006

Computational studies of H5N1 hemagglutinin binding with SA-alpha-2, 3-Gal and SA-alpha-2, 6-Gal.

For influenza H5N1 hemagglutinin, a switch from SA-alpha-2, 3-Gal to SA-alpha-2, 6-Gal receptor specificity is a critical step leading to the conversion from avian-to-human to human-to-human infection. Therefore, the understanding of the binding modes of SA-alpha-2, 3-Gal and SA-alpha-2, 6-Gal to H5N1 hemagglutinin will be very important for the examination of possible mutations needed for going from an avian to a human flu virus. Based on the available H5N1 hemagglutinin crystal structure, the binding profiles between H5N1 hemagglutinin and two saccharide ligands, SA-alpha-2, 3-Gal and SA-alpha-2, 6-Gal, were investigated by ab initio quantum mechanics, molecular docking, molecular mechanics, and molecular dynamics simulations. It was found that SA-alpha-2, 3-Gal has strong multiple hydrophobic and hydrogen bond interactions in its trans conformation with H5N1 hemagglutinin, whereas the SA-alpha-2, 6-Gal only shows weak interactions in a different conformation (cis type).

Computational Biology↗

PubMed2003

Identifying inhibitors of the SARS coronavirus proteinase.

The Severe Acute Respiratory Syndrome (SARS) is a serious respiratory illness that has recently been reported in parts of Asia and Canada. In this study, we use molecular dynamics (MD) simulations and docking techniques to screen 29 approved and experimental drugs against the theoretical model of the SARS CoV proteinase as well as the experimental structure of the transmissible gastroenteritis virus (TGEV) proteinase. Our predictions indicate that existing HIV-1 protease inhibitors, L-700,417 for instance, have high binding affinities and may provide good starting points for designing SARS CoV proteinase inhibitors.

Antiviral Agents↗

PubMed2005

Exploring blocker binding to a homology model of the open hERG K+ channel using docking and molecular dynamics methods.

Binding of blockers to the human voltage-gated hERG potassium channel is studied using a combination of homology modelling, automated docking calculations and molecular dynamics simulations, where binding affinities are evaluated using the linear interaction energy method. A homology model was constructed based on the available crystal structure of the bacterial KvAP channel and the affinities of a series of sertindole analogues predicted using this model. The calculations reproduce the relative binding affinities of these compounds very well and indicate that both polar interactions near the intracellular opening of the selectivity filter as well as hydrophobic complementarity in the region around F656 are important for blocker binding. These results are consistent with recent alanine scanning mutation experiments on the blocking of the hERG channel by other compounds.

Amino Acid Sequence↗

PubMed2001

Mechanisms of tetraethylammonium ion block in the KcsA potassium channel.

We report results from automated docking and microscopic molecular dynamics simulations of the tetraethylammonium (TEA) complexes with KcsA. Binding modes and energies for TEA binding at the external and internal sides of the channel pore are examined utilising the linear interaction energy method. Effects of the channel ion occupancy (based on our previous results for the ion permeation mechanisms) on the binding energies are considered. Calculations show that TEA forms stable complexes at both the external and internal entrances of the selectivity filter. Furthermore, the effects of the Y82V mutation are evaluated and the results show, in agreement with experimental data, that the mutant has a significantly reduced binding affinity for TEA at the external binding site, which is attributed to stabilising hydrophobic interactions between the ligand and the tyrosines.

Bacterial Proteins↗

PubMed2004

Cyclohexylcarbamic acid 3'- or 4'-substituted biphenyl-3-yl esters as fatty acid amide hydrolase inhibitors: synthesis, quantitative structure-activity relationships, and molecular modeling studies.

Fatty acid amide hydrolase (FAAH) is a promising target for modulating endocannabinoid and fatty acid ethanolamide signaling, which may have important therapeutic potential. We recently described a new class of O-arylcarbamate inhibitors of FAAH, including the cyclohexylcarbamic acid biphenyl-3-yl ester URB524 (half-maximal inhibitory concentration, IC(50) = 63 nM), which have significant anxiolytic-like properties in rats. In the present study, by introducing a selected group of substituents at the meta and para positions of the distal phenyl ring of URB524, we have characterized structure-activity profiles for this series of compounds and shown that introduction of small polar groups in the meta position greatly improves inhibitory potency. Most potent in the series was the m-carbamoyl derivative URB597 (4i, IC(50) = 4.6 nM). Furthermore, quantitative structure-activity relationship (QSAR) analysis of an extended set of meta-substituted derivatives revealed a negative correlation between potency and lipophilicity and suggested that small-sized substituents may undertake polar interactions with the binding pocket of the enzyme. Docking studies and molecular dynamics simulations, using the crystal structure of FAAH, indicated that the O-biphenyl scaffold of the carbamate inhibitors can be accommodated within a lipophilic region of the substrate-binding site, where their folded shape mimics the initial 10-12 carbon atoms of the arachidonyl moiety of anandamide (a natural FAAH substrate) and methyl arachidonyl fluorophosphonate (a nonselective FAAH inhibitor). Moreover, substituents at the meta position of the distal phenyl ring can form hydrogen bonds with atoms located on the polar section of a narrow channel pointing toward the membrane-associated side of the enzyme. The structure-activity characterization reported here should help optimize the pharmacodynamic and pharmacokinetic properties of this class of compounds.

Amidohydrolases↗

PubMed2006

Comparative study of ortho- and meta-nitrated inhibitors of catechol-O-methyltransferase: interactions with the active site and regioselectivity of O-methylation.

In this work, we present a comparative case study of "ortho-" and "meta-nitrated" catecholic inhibitors of catechol-O-methyltransferase (COMT), with regard to their interaction with the catalytic site of the enzyme and the in vitro regioselective formation of their mono-O-methyl ether metabolites. In particular, the effects of altering the attachment position of the inhibitors' side-chain substituent, within the classic nitrocatechol pharmacophore, were investigated. For this purpose, we compared two simple regioisomeric nitrocatechol-type inhibitors of COMT, BIA 3-228 and BIA 8-176, which contain the benzoyl substituent attached at the meta and ortho positions, respectively, relative to the nitro group. The two compounds were slowly O-methylated by COMT in vitro, but the particular substitution pattern of each compound was shown to have a profound impact on the regioselectivity of their O-methylation. To provide a plausible interpretation of these results, a comprehensive analysis of the protein-inhibitor interactions and of the relative chemical susceptibility to O-methylation of the catechol hydroxyl groups was performed by means of docking simulations and ab initio molecular orbital calculations. The major structural and chemical factors that determine the enzyme regioselectivity of O-methylation were identified, and the X-ray structure of the complex of COMT with S-adenosyl-l-methionine and BIA 8-176 is herein disclosed. This is the first reported structure of the soluble form of COMT complexed with a nitrocatecholic inhibitor having a bulky substituent group in adjacent position (ortho) to the nitro group. Structural and dynamic aspects of this complex are analyzed and discussed, in the context of the present study.

Animals↗

PubMed2026

Genome-Wide Analysis of Triticum aestivum Root Meristem Growth Factor (RGF) Gene Family Highlights TaRGF5 as a Putative Component of Root-Associated Signaling.

Wheat (Triticum aestivum), a key global crop, faces rising drought stress that limits root growth and water uptake. Root meristem growth factors (RGFs) are small peptides that regulate root stem cell maintenance, meristem activity, and lateral root formation in model plants, yet the RGF gene family remains unexplored in wheat. Here, we performed a comprehensive genome-wide analysis of the TaRGF gene family, identifying 15 genes distributed across the A, B, and D subgenomes and classified into five homeologous groups (TaRGF1-TaRGF5), predominantly located on chromosomes 2 and 6. All TaRGFs contained a characteristic RGF motif, with dibasic cleavage sites and Asp-Tyr motifs indicating conserved maturation mechanisms. Based on the phylogenetic analysis, the TaRGF5 homeologs showed the highest similarity to Arabidopsis thaliana RGF5. Tested RNA-seq data revealed predominantly root-enriched expression for all TaRGF genes, with TaRGF5 exhibiting the most root-preferential and downregulation under drought stress. Quantitative real-time PCR (qRT-PCR) confirmed that drought stress suppressed the expression of TaRGF5A, TaRGF5B, and TaRGF5D in roots of wheat cultivar Sids-13 across all time points, unlike the higher accumulation seen in controls. Promoter analysis predicted a unique BES1 transcription factor binding site exclusively in TaRGF5B, linking brassinosteroid signaling to peptide-mediated root regulation. Structural modeling and molecular docking predicted an interaction between wheat TaRGF5 homeologs and root growth factor-insensitive receptor kinase (TaRGI3), characterized by conserved sulfotyrosine-mediated binding and favorable interaction energetics. Based on this characterization of the wheat RGF gene family, particularly the potential role of TaRGF5 in root development and drought-adaptation signaling, we propose targeting this gene for functional analysis to improve wheat resilience under water-limited conditions.

Triticum↗

PubMed2005

Molecular insight into pseudolysin inhibition using the MM-PBSA and LIE methods.

Pseudolysin, the extracellullar elastase of Pseudomonas aeruginosa (EC: 3.4.24.26) plays an important role in the pathogenesis of P. aeruginosa infections. In the present study, molecular dynamics simulations and theoretical affinity predictions were used to gain molecular insight into pseudolysin inhibition. Four low molecular weight inhibitors were docked at their putative binding sites and molecular dynamics (MD) simulations were performed for 5.0 ns, and the free energy of binding was calculated by the linear interaction energy method. The number and the contact surface area of stabilizing hydrophobic, aromatic, and hydrogen bonding interactions appears to reflect the affinity differences between the inhibitors. The proteinaceous inhibitor, Streptomyces metalloproteinase inhibitor (SMPI) was docked in three different binding positions and MD simulations were performed for 3.0 ns. The MD trajectories were used for molecular mechanics-Poisson-Boltzmann surface area analysis of the three binding positions. Computational alanine scanning of the average pseudolysin-SMPI complexes after MD revealed residues at the pseudolysin-SMPI interface giving the main contribution to the free energy of binding. The calculations indicated that SMPI interacts with pseudolysin via the rigid active site loop, but that also contact sites outside this loop contribute significantly to the free energy of association.

Amino Acid Sequence↗

PubMed1997

A comparison of heuristic search algorithms for molecular docking.

This paper describes the implementation and comparison of four heuristic search algorithms (genetic algorithm, evolutionary programming, simulated annealing and tabu search) and a random search procedure for flexible molecular docking. To our knowledge, this is the first application of the tabu search algorithm in this area. The algorithms are compared using a recently described fast molecular recognition potential function and a diverse set of five protein-ligand systems. Statistical analysis of the results indicates that overall the genetic algorithm performs best in terms of the median energy of the solutions located. However, tabu search shows a better performance in terms of locating solutions close to the crystallographic ligand conformation. These results suggest that a hybrid search algorithm may give superior results to any of the algorithms alone.

Algorithms↗

PubMed1990

Molecular modelling study of antigen binding to oxazolone-specific antibodies: the Ox1 idiotypic IgG and its mature variant with increased affinity to 2-phenyloxazolone.

Structural models of the variable domains of the murine anti-2-phenyloxazolone IgG (Ox1 idiotype) and its somatic variant, which has higher affinity to the hapten 2-phenyloxazolone, were constructed by computer-aided model building using known structures of highly homologous immunoglobulins as templates. Molecular dynamics simulations were used to dock the hapten between the VL and VH domains. The hapten is predicted to bind to slightly different sites in the two models. Hypotheses concerning the role of a number of preferred mutations in anti-oxazolone variants are presented. These can be tested by mutagenesis and crystallography. In particular, the higher binding affinities of the different antibody variants are shown to correlate with better complementarity of electrostatics. The molecular dynamic simulations also suggest that two mobile tryptophans at the mouth of the pocket may play an important role in the binding of hapten.

Amino Acid Sequence↗

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↗

PubMed2004

Classical force field parameters for the heme prosthetic group of cytochrome c.

Accurate force fields are essential for describing biological systems in a molecular dynamics simulation. To analyze the docking of the small redox protein cytochrome c (cyt c) requires simulation parameters for the heme in both the reduced and oxidized states. This work presents parameters for the partial charges and geometries for the heme in both redox states with ligands appropriate to cyt c. The parameters are based on both protein X-ray structures and ab initio density functional theory (DFT) geometry optimizations at the B3LYP/6-31G* level. The simulations with the new parameter set reproduce the geometries of the X-ray structures and the interaction energies between water and heme prosthetic group obtained from B3LYP/6-31G* calculations. The parameter set developed here will provide new insights into docking processes of heme containing redox proteins.

Algorithms↗

PubMed2000

Influence of mRNA self-structure on hybridization: computational tools for antisense sequence selection.

Antisense targeting, an innovative technology based on preventing biosynthesis through sequence-specific hybridization of mRNA to synthetic oligodeoxynucleotides (ODNs), is used to selectively and transiently downregulate the expression of any gene product. Its potential applications are both investigative (neurobiology and related disciplines) and therapeutic (oncology, virology, genetic diseases), and several antisense-based drugs are currently undergoing clinical trials. However, the reported efficiencies vary and there is still a lack of clarity in the underlying mechanisms of action. A critical factor of antisense efficiency is the issue of target site selection, as both mRNA and ODN molecules exhibit a significant amount of highly heterogeneous self-structure and the region selected for targeting may well be sterically or energetically inaccessible. Because of the prohibitively large chain length, mRNA structural information is not accessible by X-ray crystallography or NMR, making a modeling approach indispensable. I outline how the latest molecular modeling techniques can be employed to establish the secondary (2D) and tertiary (3D) structures into which a given mRNA folds during and after transcription. The aim should be to integrate 2D prediction results achieved by (a) free-energy minimization, (b) kinetic folding simulations, (c) iterative population breeding by genetic algorithms, and (d) phylogenetic comparison techniques. These results can form the input of a 3D structure prediction paradigm based on constraint-satisfying programming, governed by experimental molecular mechanical constraints, and refined by molecular dynamics simulations. Finally, the automated docking (by simulated annealing) of ODN molecules to the mRNA structure can provide information about the accessibility of target mRNA regions for hybridization. To date, the great majority of studies that employ antisense as a tool select their target sequences more or less randomly. Although the wealth of molecular interactions that take place within a cell makes complete predictability unrealistic, the kind of information that can be extracted from such techniques is of relevance to every application of antisense technology, both investigative and therapeutic.

Algorithms↗

PubMed1996

Positioning hydrogen atoms by optimizing hydrogen-bond networks in protein structures.

A method is presented that positions polar hydrogen atoms in protein structures by optimizing the total hydrogen bond energy. For this goal, an empirical hydrogen bond force field was derived from small molecule crystal structures. Bifurcated hydrogen bonds are taken into account. The procedure also predicts ionization states of His, Asp, and Glu residues. During optimization, side-chain conformations of His, Gln, and Asn residues are allowed to change their last chi angle by 180 degrees to compensate for crystallographic misassignments. Crystal structure symmetry is taken into account where appropriate. The results can have significant implications for molecular dynamics simulations, protein engineering, and docking studies. The largest impact, however, is in protein structure verification: over 85% of protein structures tested can be improved by using our procedure.

Amino Acids↗

PubMed2006

Molecular basis of substrate recognition in D-3-hydroxybutyrate dehydrogenase from Pseudomonas putida.

D-3-Hydroxybutyrate dehydrogenase from Pseudomonas putida (EC 1.1.1.30) belongs to the family of short-chain dehydrogenases/reductases (SDRs). It catalyzes the reversible and stereospecific oxidation of D-3-hydroxybutyrate (D-3-HB) to acetoacetate with the aid of NAD(+) as coenzyme. This study contributes to understanding the mechanism and the high specificity of this enzyme towards its negatively charged and hydrophilic substrate. Sequence comparison of 44 bacterial HBDHs shows the residues Gln91, His141, Lys149, Lys192, and Gln193 to be strictly conserved. Site-directed mutagenesis of these amino acids to alanine and subsequent kinetic characterization of the mutated enzymes provides insight into the importance of these residues for substrate recognition and catalysis. Docking studies and molecular-dynamics simulations based on a three-dimensional structure model of a complex between P. putida HBDH and its coenzyme obtained by comparative molecular modeling were performed and provided deeper insight into the binding of the ligands at the molecular level. They show the residues Gln91, His141, Gln193, and, in particular, Lys149 to be involved in a hydrogen-bonding network with the carboxylate group of the substrate.

3-Hydroxybutyric Acid↗

PubMed2002

Analysis of ice-binding sites in fish type II antifreeze protein by quantum mechanics.

Many organisms living in cold environments can survive subzero temperatures by producing antifreeze proteins (AFPs) or antifreeze glycoproteins. In this paper we investigate the ice-binding surface of type II AFP by quantum mechanical methods, which, to the best of our knowledge, represents the first time that molecular orbital computational approaches have been applied to AFPs. Molecular mechanical approaches, including molecular docking, energy minimization, and molecular dynamics simulation, were used to obtain optimal systems for subsequent quantum mechanical analysis. We selected 17 surface patches covering the entire surface of the type II AFP and evaluated the interaction energy between each of these patches and two different ice planes using semi-empirical quantum mechanical methods. We have demonstrated the weak orbital overlay phenomenon and the change of bond orders in ice. These results consistently indicate that a surface patch containing 19 residues (K37, L38, Y20, E22, Y21, I19, L57, T56, F53, M127, T128, F129, R17, C7, N6, P5, G10, Q1, and W11) is the most favorable ice-binding site for both a regular ice plane and an ice plane where water O atoms are randomly positioned. Furthermore, for the first time the computation results provide new insights into the weakening of the ice lattice upon AFP binding, which may well be a primary factor leading to AFP-induced ice growth inhibition.

Animals↗

PubMed1999

Ice-binding surface of fish type III antifreeze.

We employed computational techniques, including molecular docking, energy minimization, and molecular dynamics simulation, to investigate the ice-binding surface of fish type III antifreeze protein (AFP). The putative ice-binding site was previously identified by mutagenesis, structural analysis, and flatness evaluation. Using a high-resolution x-ray structure of fish type III AFP as a model, we calculated the ice-binding interaction energy of 11 surface patches chosen to cover the entire surface of the protein. These various surface patches exhibit small but significantly different ice-binding interaction energies. For both the prism ice plane and an "ice" plane in which water O atoms are randomly positioned, our calculations show that a surface patch containing 14 residues (L19, V20, T18, S42, V41, Q9, P12, A16, M21, T15, Q44, I13, N14, K61) has the most favorable interaction energy and corresponds to the previously identified ice-binding site of type III AFP. Although in general agreement with the earlier studies, our results also suggest that the ice-binding site may be larger than the previously identified "core" cluster that includes mostly hydrophilic residues. The enlargement mainly results from the inclusion of peripheral hydrophobic residues and K61.

Amino Acid Sequence↗