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 235 records · Page 13Linked to original sources

PubMed2004

Modelling and simulation: a computational perspective in anticancer drug discovery.

The availability of high-quality molecular graphics tools in the public domain is changing the way macromolecular structure is perceived by researchers, educators and students alike. Computational methods have become increasingly important in a number of areas such as comparative or homology modelling, functional site location, characterization of ligand-binding sites in proteins, docking of small molecules into protein binding sites, protein-protein docking, and molecular dynamics simulations. The results obtained yield information that sometimes is beyond current experimental possibilities and can be used to guide and improve a vast array of experiments. On the basis of our improved level of understanding of molecular recognition and the widespread availability of target structures, it is reasonable to assume that computational methods will continue aiding not only in the design and interpretation of hypothesis-driven experiments in the field of cancer research but also in the rapid generation of new hypotheses.

Amino Acid Sequence↗

PubMed2004

Development of the force field parameters for phosphoimidazole and phosphohistidine.

Phosphorylation of histidine-containing proteins is a key step in the mechanism of many phosphate transfer enzymes (kinases, phosphatases) and is the first stage in a wide variety of signal transduction cascades in bacteria, yeast, higher plants, and mammals. Studies of structural and dynamical aspects of such enzymes in the phosphorylated intermediate states are important for understanding the intimate molecular mechanisms of their functioning. Such information may be obtained via molecular dynamics and/or docking simulations, but in this case appropriate force field parameters for phosphohistidine should be explicitly defined. In the present article we describe development of the GROMOS96 force field parameters for phosphoimidazole molecule--a realistic model of the phosphohistidine side chain. The parameterization is based on the results of ab initio quantum chemical calculations with subsequent refinement and testing using molecular mechanics and molecular dynamics simulations. The set of force constants and equilibrium geometry is employed to derive force field for the phosphohistidine moiety. Resulting parameters and topology are incorporated into the molecular modeling package GROMACS and used in molecular dynamics simulations of a phosphohistidine-containing protein in explicit solvent.

Algorithms↗

PubMed1999

Catechol(amine)s as probes of lactoperoxidase catalytic site structure: spectroscopic and modeling studies.

Binding affinities to lactoperoxidase (LPO) of a homologous series of substituted catechol(amine)s [such as catechol, 4-methylcatechol, 3,4-dihydroxybenzoic acid, 3,4-dihydroxyphenylacetic acid, 3-(3,4-dihydroxyphenyl)propionic acid; dopamine, noradrenaline, adrenaline; L-3,4-dihydroxyphenylalanine] were studied by UV-visible spectroscopy and docking simulations. Dissociation constant (Kd) values were calculated by direct fitting of the experimental data and fall in a range of 3-95 mM. Thermodynamic parameters are comparable with those reported for the interaction of LPO with p-substituted phenols, suggesting a similar general mode of binding. Furthermore, the relative contributions to binding energy, described by the unimolecular constant Ku, show that interaction between protein and ligands originates from a relatively large number of groups. Docking and molecular dynamics simulations, in agreement with experimental evidence, predict that the substrate is localized into the access channel in the vicinity of heme distal pocket. This channel is characterized by a hydrophobic patch (six Phe residues) and by a charged contribution (two Glu and one His residues). All of the substrates, except caffeic acid, may approach the protein active site. Positively charged Arg372 acts as a gate above the heme distal pocket and seems to address substrate orientation in relation to the side-chain terminal group.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2003

Adenosine A2A-dopamine D2 receptor-receptor heteromerization: qualitative and quantitative assessment by fluorescence and bioluminescence energy transfer.

There is evidence for strong functional antagonistic interactions between adenosine A2A receptors (A2ARs) and dopamine D2 receptors (D2Rs). Although a close physical interaction between both receptors has recently been shown using co-immunoprecipitation and co-localization assays, the existence of a A2AR-D2R protein-protein interaction still had to be demonstrated in intact living cells. In the present work, fluorescence resonance energy transfer (FRET) and bioluminescence resonance energy transfer (BRET) techniques were used to confirm the occurrence of A2AR-D2R interactions in co-transfected cells. The degree of A2AR-D2R heteromerization, measured by BRET, did not vary after receptor activation with selective agonists, alone or in combination. BRET competition experiments were performed using a chimeric D2R-D1R in which helices 5 and 6, the third intracellular loop (I3), and the third extracellular loop (E3) of the D2R were replaced by those of the dopamine D1 receptor (D1R). Although the wild type D2R was able to decrease the BRET signal, the chimera failed to achieve any effect. This suggests that the helix 5-I3-helix 6-E3 portion of D2R holds the site(s) for interaction with A2AR. Modeling of A2AR and D2R using a modified rhodopsin template followed by molecular dynamics and docking simulations gave essentially two different possible modes of interaction between D2R and A2AR. In the most probable one, helix 5 and/or helix 6 and the N-terminal portion of I3 from D2R approached helix 4 and the C-terminal portion of the C-tail from the A2AR, respectively.

Binding Sites↗

PubMed2004

Severe acute respiratory syndrome coronavirus 3C-like proteinase N terminus is indispensable for proteolytic activity but not for enzyme dimerization. Biochemical and thermodynamic investigation in conjunction with molecular dynamics simulations.

Severe acute respiratory syndrome (SARS) coronavirus is a novel human coronavirus and is responsible for SARS infection. SARS coronavirus 3C-like proteinase (SARS 3CL(pro)) plays key roles in viral replication and transcription and is an attractive target for anti-SARS drug discovery. In this report, we quantitatively characterized the dimerization features of the full-length and N-terminal residues 1-7 deleted SARS 3CL(pro)s by using glutaraldehyde cross-linking SDS-PAGE, size-exclusion chromatography, and isothermal titration calorimeter techniques. Glutaraldehyde cross-linking SDS-PAGE and size-exclusion chromatography results show that, similar to the full-length SARS 3CL(pro), the N-terminal deleted SARS 3CL(pro) still remains a dimer/monomer mixture within a wide range of protein concentrations. Isothermal titration calorimeter determinations indicate that the equilibrium dissociation constant (K(d)) of the N-terminal deleted proteinase dimer (262 microm) is very similar to that of the full-length proteinase dimer (227 microm). Enzymatic activity assay using the fluorescence resonance energy transfer method reveals that N-terminal deletion results in almost complete loss of enzymatic activity for SARS 3CL(pro). Molecular dynamics and docking simulations demonstrate the N-terminal deleted proteinase dimer adopts a state different from that of the full-length proteinase dimer, which increases the angle between the two protomers and reduces the binding pocket that is not beneficial to the substrate binding. This conclusion is verified by the surface plasmon resonance biosensor determination, indicating that the model substrate cannot bind to the N-terminal deleted proteinase. These results suggest the N terminus is not indispensable for the proteinase dimerization but may fix the dimer at the active state and is therefore vital to enzymatic activity.

Binding Sites↗

PubMed2006

Experimental/theoretical electrostatic properties of a styrylquinoline-type HIV-1 integrase inhibitor and its progenitors.

We have established that polyhydroxylated styrylquinolines are potent inhibitors of HIV-1 integrase (IN). Among them, we have identified (E)-8-hydroxy-2-[2-(4,5-dihydroxy-3-methoxyphenyl)-ethenyl]-7-quinolinecarboxylic acid (1) as a promising lead. Previous molecular dynamics simulations and docking procedures have shown that the inhibitory activity involves one or two metal cations (Mg2+), which are present in the vicinity of the active center of the enzyme. However, such methods are generally based on a force-field approach and still remain not as reliable as ab initio calculations with extended basis sets on the whole system. To go further in this area, the aim of the present study was to evaluate the predictive ability of the electron density and electrostatic properties in the structure-activity relationships of this class of HIV-1 antiviral drugs. The electron properties of the two chemical progenitors of 1 were derived from both high-resolution X-ray diffraction experiments and ab initio calculations. The twinning phenomenon and solvent disorder were observed during the crystal structure determination of 1. Molecule 1 exhibits a planar s-trans conformation, and a zwitterionic form in the crystalline state is obtained. This geometry was used for ab initio calculations, which were performed to characterize the electronic properties of 1. The electron densities, electrostatic potentials, and atomic charges of 1 and its progenitors are here compared and analyzed. The experimental and theoretical deformation density bond peaks are very comparable for the two progenitors. However, the experimental electrostatic potential is strongly affected by the crystal field and cannot straightforwardly be used as a predictive index. The weak difference in the theoretical electron densities between 1 and its progenitors reveals that each component of 1 conserves its intrinsic properties, an assumption reinforced by a 13C NMR study. This is also shown through an excellent correlation of the atomic charges for the common fragments. The electrostatic potential minima in zwitterionic and nonzwitterionic forms of 1 are discussed in relation with the localization of possible metal chelation sites.

Carbon Isotopes↗

PubMed2000

Shape complementarity, binding-site dynamics, and transition state stabilization: a theoretical study of Diels-Alder catalysis by antibody 1E9.

Antibody 1E9 is a protein catalyst for the Diels-Alder reaction between tetrachlorothiophene dioxide and N-ethylmaleimide. Quantum mechanical calculations have been employed to study the 1E9-catalyzed Diels-Alder reaction in the gas phase. The transition states and intermediates were all determined at the B3LYP/6-31G*//HF/6-31G* level. The cycloaddition step is predicted to be rate-determining, and the endo reaction pathway is strongly favored. Binding of the reactants and the transition states to antibody 1E9 was investigated by docking and molecular dynamics simulations. The linear interaction energy (LIE) method was adopted to estimate the free energy barrier of the 1E9-catalyzed Diels-Alder reaction. The catalytic efficiency of antibody 1E9 is achieved by enthalpic stabilization of the transition state, near-perfect shape complementarity of the hydrophobic binding site for the transition state, and a strategically placed hydrogen-bonding interaction.

Antibodies, Catalytic↗

PubMed2003

(9Z)- and (11Z)-8-methylretinals for artificial visual pigment studies: stereoselective synthesis, structure, and binding models.

Artificial visual pigment formation was studied by using 8-methyl-substituted retinals in an effort to understand the effect that alkyl substitution of the chromophore side chain has on the visual cycle. The stereoselective synthesis of the 9-cis and 11-cis isomers of 8-methylretinal, as well as the 5-demethylated analogues is also described. The key bond formations consist of a thallium-accelerated Suzuki cross-coupling reaction between cyclohexenylboronic acids and dienyliodides (C6-C7), and a highly stereocontrolled Horner-Wadsworth-Emmons or Wittig condensation (C11-C12). The cyclohexenylboronic acid was prepared by trapping the precursor cyclohexenyllithium species with B(OiPr)(3) or B(OMe)(3). The cyclohexenyllithium species is itself obtained by nBuLi-induced elimination of a trisylhydrazone (Shapiro reaction), or depending upon the steric hindrance of the ring, by iodine-metal exchange. In binding experiments with the apoprotein opsin, only 9-cis-5-demethyl-8-methylretinal yielded an artificial pigment; 9-cis-8-methylretinal simply provided residual binding, while evidence of artificial pigment formation was not found for the 11-cis analogues. Molecular-mechanics-based docking simulations with the crystal structure of rhodopsin have allowed us to rationalize the lack of binding displayed by the 11-cis analogues. Our results indicate that these isomers are highly strained, especially when bound, due to steric clashes with the receptor, and that these interactions are undoubtedly alleviated when 9-cis-5-demethyl-8-methylretinal binds opsin.

Binding Sites↗

PubMed2002

Novel computer program for fast exact calculation of accessible and molecular surface areas and average surface curvature.

New computer programs, SurfRace and FastSurf, perform fast calculations of the solvent accessible and molecular (solvent excluded) surface areas of macromolecules. Program SurfRace also calculates the areas of cavities inaccessible from the outside. We introduce the definition of average curvature of molecular surface and calculate average molecular surface curvatures for each atom in a structure. All surface area and curvature calculations are analytic and therefore yield exact values of these quantities. High calculation speed of this software is achieved primarily by avoiding computationally expensive mathematical procedures wherever possible and by efficient handling of surface data structures. The programs are written initially in the language C for PCs running Windows 2000/98/NT, but their code is portable to other platforms with only minor changes in input-output procedures. The algorithm is robust and does not ignore either multiplicity or degeneracy of atomic overlaps. Fast, memory-efficient and robust execution make this software attractive for applications both in computationally expensive energy minimization algorithms, such as docking or molecular dynamics simulations, and in stand-alone surface area and curvature calculations.

Algorithms↗

PubMed2004

Novel approaches for modeling of the A1 adenosine receptor and its agonist binding site.

The present work describes the building of a human A(1) adenosine receptor (hA(1)AR) model, based on the X-ray crystal structure of bovine rhodopsin, and its use as a basis for the investigation of some important structural characteristics of the receptor. One of the issues investigated was the protonation position of two histidine residues known to influence ligand binding, with protonation of His251 (6.52) in epsilon position and His278 (7.43) in delta position showing the best agreement with experimental evidence. The model was also used to study the position and structural role of water molecules present in the helical bundle. Finally, the binding site location and the ligand docking were investigated using an objective strategy. A suitable site for the binding of the ribose moiety of adenosine was first postulated and further confirmed by means of a novel chemometric strategy based on GRIND descriptors. Using this position as an anchor point, the binding of adenosine was studied by docking and molecular dynamics simulations obtaining two putative binding positions in good agreement with experimental data.

Adenosine↗

PubMed2026

Cross-tissue Mendelian randomization prioritizes RAB27B as a brain-derived candidate protein for postpartum depression.

OBJECTIVE: Postpartum depression (PPD) is one of the most common and debilitating complications of childbirth, yet the candidate proteins linking genetic risk to disease remain poorly defined. Building on recent genome-wide association studies (GWAS), we sought to integrate cross-tissue proteogenomic data to identify candidate proteins for PPD and explore therapeutic opportunities. METHODS: We conducted two-sample Mendelian randomization (MR) using genome-wide significant cis-protein QTLs from brain (n = 608 proteins), cerebrospinal fluid (CSF; n = 214), and plasma (n = 612). PPD summary statistics were obtained from FinnGen R8 (13,657 cases, 236,178 controls) and replicated in an independent GWAS. Phenome-wide association (PheWAS) was used to assess pleiotropy. Potential therapeutic targets were evaluated through DSigDB drug repurposing, molecular docking, and molecular dynamics simulations. RESULTS: Among all proteins tested, RAB27B was the only brain-derived protein surpassing Bonferroni correction (OR = 1.60; 95% CI: 1.30-1.96; P = 6.6 × 10⁻⁶), whereas no significant proteins were identified in CSF or plasma. This association was replicated in an independent GWAS (OR = 1.27; 95% CI: 1.02-1.58; P = 0.037). PheWAS identified no pleiotropic associations at genome-wide significance. In silico drug repurposing identified pregnenolone as a candidate ligand with computationally predicted stable binding to RAB27B, providing a starting point for future experimental validation. CONCLUSION: This study provides the first cross-tissue proteogenomic evidence that RAB27B is a brain-derived, reproducible candidate protein genetically associated with PPD. By extending GWAS signals to functional protein-level mechanisms and therapeutic inference, our findings nominate RAB27B and pregnenolone as promising directions for postpartum psychiatric research.

Humans↗

PubMed2003

Structural and functional characterization of the human CCR5 receptor in complex with HIV gp120 envelope glycoprotein and CD4 receptor by molecular modeling studies.

The entry of human immunodeficiency virus (HIV) into cells depends on a sequential interaction of the gp120 envelope glycoprotein with the cellular receptors CD4 and members of the chemokine receptor family. The CC chemokine receptor CCR5 is such a receptor for several chemokines and a major coreceptor for the entry of R5 HIV type-1 (HIV-1) into cells. Although many studies focus on the interaction of CCR5 with HIV-1, the corresponding interaction sites in CCR5 and gp120 have not been matched. Here we used an approach combining protein structure modeling, docking and molecular dynamics simulation to build a series of structural models of the CCR5 in complexes with gp120 and CD4. Interactions such as hydrogen bonds, salt bridges and van der Waals contacts between CCR5 and gp120 were investigated. Three snapshots of CCR5-gp120-CD4 models revealed that the initial interactions of CCR5 with gp120 are involved in the negatively charged N-terminus (Nt) region of CCR5 and positively charged bridging sheet region of gp120. Further interactions occurred between extracellular loop2 (ECL2) of CCR5 and the base of V3 loop regions of gp120. These interactions may induce the conformational changes in gp120 and lead to the final entry of HIV into the cell. These results not only strongly support the two-step gp120-CCR5 binding mechanism, but also rationalize extensive biological data about the role of CCR5 in HIV-1 gp120 binding and entry, and may guide efforts to design novel inhibitors.

CD4 Antigens↗

PubMed2005

Computational studies and drug design for HIV-1 reverse transcriptase inhibitors of 3',4'-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) analogs.

Molecular docking and molecular dynamics simulation were applied to study the binding mode of 3',4'-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) analogs anti-HIV inhibitors with HIV-1 RT. The results suggest that there is a strong hydrogen bond between DCK O16 and NH of Lys101, and that DCK analogues might act similarly as other types of HIV-1 RT inhibitors. The investigation about drug resistance for DCK shows no remarkable influence on the most frequently observed mutation K103N of HIV-1 RT. Based on the proposed mechanism, some new structures were designed and predicted by a SVM model. All compounds exhibited potent inhibitory activities against HIV replication in H9 lymphocytes with EC50 values lower than 1.95 microM. The rationality of the method was validated by experimental results.

Camphor↗

PubMed2005

Modelling the interaction of catecholamines with the alpha 1A adrenoceptor towards a ligand-induced receptor structure.

Adrenoceptors are members of the important G protein coupled receptor family for which the detailed mechanism of activation remains unclear. In this study, we have combined docking and molecular dynamics simulations to model the ligand induced effect on an homology derived human alpha1A adrenoceptor. Analysis of agonist/alpha1A adrenoceptor complex interactions focused on the role of the charged amine group, the aromatic ring, the N-methyl group of adrenaline, the beta hydroxyl group and the catechol meta and para hydroxyl groups of the catecholamines. The most critical interactions for the binding of the agonists are consistent with many earlier reports and our study suggests new residues possibly involved in the agonist-binding site, namely Thr-174 and Cys-176. We further observe a number of structural changes that occur upon agonist binding including a movement of TM-V away from TM-III and a change in the interactions of Asp-123 of the conserved DRY motif. This may cause Arg-124 to move out of the TM helical bundle and change the orientation of residues in IC-II and IC-III, allowing for increased affinity of coupling to the G-protein.

Adrenergic alpha-1 Receptor Agonists↗

PubMed2005

Macrocyclic inhibitors of the malarial aspartic proteases plasmepsin I, II, and IV.

The first macrocyclic inhibitor of the Plasmodium falciparum aspartic proteases plasmepsin I, II, and IV with considerable selectivity over the human aspartic protease cathepsin D has been identified. A series of macrocyclic compounds were designed and synthesized. Cyclizations were accomplished using ring-closing metathesis with the second generation Grubbs catalyst. These compounds contain either a 13-membered or a 16-membered macrocycle and incorporate a 1,2-dihydroxyethylene as transition state mimicking unit. The binding mode of this new class of compounds was predicted with automated docking and molecular dynamics simulations, with an estimation of the binding affinities through the linear interaction energy (LIE) method.

Animals↗

PubMed2005

Structural basis for the GSK-3beta binding affinity and selectivity against CDK-2 of 1-(4-aminofurazan-3yl)-5-dialkylaminomethyl-1H-[1,2,3] triazole-4-carboxylic acid derivatives.

A novel structural class of glycogen synthase kinase-3beta inhibitors is modeled using quantum mechanics, automated docking, and molecular dynamics simulations. The proposed binding modes identify important hydrogen bonds and salt-bridges with the ATP-binding pocket of the kinase. The modeled complexes justify the observed structure-activity relationships and provide a structural basis for the high selectivity of these inhibitors against cyclin dependent kinase-2.

Adenosine Triphosphate↗

PubMed2005

Structural insight into the interactions of SoxV, SoxW and SoxS in the process of transport of reductants during sulfur oxidation by the novel global sulfur oxidation reaction cycle.

Microbial redox reactions involving inorganic sulfur compounds, mainly the sulfur anions, are one of the vital reactions responsible for the environmental sulfur balance. These reactions are mediated by phylogenetically diverse prokaryotes, some of which also take part in the extraction of metal ions from their sulfur containing ores. These sulfur oxidizers oxidize inorganic sulfur compounds like sulfide, thiosulfate etc. to produce reductants that are used for carbon dioxide fixation or in respiratory electron transfer chains. The sulfur oxidizing gene cluster (sox) of alpha-Proteobacteria comprises of at least 15 genes, forming two transcriptional units, viz., soxSR and soxVWXYZABCDEFGH. SoxV is known to be a CcdA homolog involved in the transport of reductants from cytoplasm to periplasm. SoxW and SoxS are periplasmic thioredoxins, which (SoxW) interact with SoxV and thereby help in the redox reactions. We have employed homology modeling to construct the three-dimensional structures of the SoxV, SoxW and SoxS proteins from Rhodovulum sulfidophilum. With the help of docking and molecular dynamics simulations we have identified the amino acid residues of these proteins involved in the interaction. The probable biochemical mechanism of the transport of reductants through the interactions of these proteins has also been investigated. Our study provides a rational basis to interpret the molecular mechanism of the biochemistry of sulfur anion oxidation reactions by these ecologically important organisms.

Alphaproteobacteria↗

PubMed2002

Nitrophenyl derivatives as aldose reductase inhibitors.

Nitrophenyl derivatives were recently discovered as a new class of ALR2 inhibitors by means of docking and database screening of the National Cancer Institute database of organic molecules. The nitro group was predicted to bind to the Tyr48 and His110 active site residues of the enzyme, the site where acidic ALR2 inhibitors such as carboxylic acids bind in their anionic form. Given the novelty of these compounds, we decided to expand their structure-activity relationships by synthesizing and testing a series of derivatives and the corresponding compounds having a carboxylic group instead of the nitro moiety; the results obtained were rationalized by means of docking and molecular dynamics simulations. On the whole there is an agreement between inhibitory data and the results of molecular modeling experiments, supporting the hypothesized binding mode of these compounds.

Aldehyde Reductase↗