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Results for “Molecular Docking Simulation”

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PubMedDate not supplied

The influence of variations of ligand protonation and tautomerism on protein-ligand recognition and binding energy landscape.

We investigate the influence of variations of ligand protonation and tautomeric states on the protein-ligand binding energy landscape by applying the concept of structural consensus. In docking simulations, allowing full flexibility of the ligand, we explore whether the native binding mode could be successfully recovered using a non-native ligand protonation state. Here, we consider three proteins, dihydrofolate reductase, transketolase, and alpha-trichosanthin, complexed with ligands having multiple tautomeric forms. We find that for the majority of protonation and tautomeric states the native binding mode can be recovered without a great loss of accuracy.

Crystallography, X-Ray↗

PubMed1999

Molecular scaffold-based design and comparison of combinatorial libraries focused on the ATP-binding site of protein kinases.

Compound libraries were designed to target specifically the ATP cofactor-binding site in protein kinases by combining knowledge- and diversity-based design elements. A key aspect of the approach is the identification of molecular building blocks or scaffolds that are compatible with the binding site and therefore capture some aspects of target specificity. Scaffolds were selected on the basis of docking calculations and analysis of known inhibitors. We have generated 75 molecular scaffolds and applied different strategies to compute diverse compounds from scaffolds or, alternatively, to screen compound databases for molecules containing these scaffolds. The resulting libraries had a similar degree of molecular diversity, with at most 12% of the compounds being identical. However, their scaffold distributions differed significantly and a small number of scaffolds dominated the majority of compounds in each library.

Adenosine Triphosphate↗

PubMed2005

Analysis of structure-activity relationships for MT2 selective antagonists by melatonin MT1 and MT2 receptor models.

Three-dimensional homology models of human MT(1) and MT(2) melatonin receptors were built with the aim to investigate the structure-activity relationships (SARs) of MT(2) selective antagonists. A common interaction pattern was proposed for a series of structurally different MT(2) selective antagonists, which were positioned within the binding site by docking and simulated annealing. The proposed antagonist binding mode to the MT(2) receptor is characterized by the accommodation of the out-of-plane substituents in a hydrophobic pocket, which resulted as being fundamental for the explanation of the antagonist behavior and the MT(2) receptor selectivity. Moreover, to assess the ability of the MT(2) receptor model to reproduce the SARs of MT(2) antagonists, three new derivatives of the MT(2) selective antagonist N-[1-(4-chloro-benzyl)-4-methoxy-1H-indol-2-ylmethyl]-propionamide (7) were synthesized and tested for their receptor affinity and intrinsic activity. These compounds were docked into the MT(2) receptor model and were submitted to molecular dynamics studies, providing results in qualitative agreement with the experimental data. These results confirm the importance of the out-of-plane group in receptor binding and selectivity and provide a partial validation of the proposed G protein-coupled receptor model.

Amino Acid Sequence↗

PubMedDate not supplied

Prediction of IgE(Lb4)-ligand complex structures by automated docking.

A mouse monoclonal anti-2,4,6-trinitrophenyl IgE (clone Lb4) was screened with a random set of over 2000 compounds, and several ligands were found to bind with affinities comparable to that of the immunizing hapten (KD in the microM range). An automated docking algorithm was used for the prediction of complex structures formed by 2,4-dinitrophenyl (DNP) and non-DNP ligands in the fragment variable region of IgE(Lb4). All ligands were found to dock in an L-shaped cavity of 15 x 16 x 10 A, surrounded by complementary-determining regions L1, L3, H2 and H3. The ligands were found to occupy the same binding site in different orientations. For rigid ligands the most stable orientation could be predicted with high probability, based on the calculated energy of binding and the occurrence frequencies of identical complexes obtained by repeated simulations. The localization of a flexible ligand (cycrimine-R) was more ambiguous, but it still docked in the same site. The results support a model for heteroligating antibody (Ab) binding sites, where different ligands utilize the total set of available contacts in different combinations. It is suggested that although pseudoenergies calculated by the docking algorithm do not correlate with experimentally measured binding energies, the screening-and-docking procedure can be useful for the mapping of Ab and other receptor binding sites ligating small molecules.

2,4-Dinitrophenol↗

PubMed2005

Progress in protein-protein docking: atomic resolution predictions in the CAPRI experiment using RosettaDock with an improved treatment of side-chain flexibility.

RosettaDock uses real-space Monte Carlo minimization (MCM) on both rigid-body and side-chain degrees of freedom to identify the lowest free energy docked arrangement of 2 protein structures. An improved version of the method that uses gradient-based minimization for off-rotamer side-chain optimization and includes information from unbound structures was used to create predictions for Rounds 4 and 5 of CAPRI. First, large numbers of independent MCM trajectories were carried out and the lowest free energy docked configurations identified. Second, new trajectories were started from these lowest energy structures to thoroughly sample the surrounding conformation space, and the lowest energy configurations were submitted as predictions. For all cases in which there were no significant backbone conformational changes, a small number of very low-energy configurations were identified in the first, global search and subsequently found to be close to the center of the basin of attraction in the free energy landscape in the second, local search. Following the release of the experimental coordinates, it was found that the centers of these free energy minima were remarkably close to the native structures in not only the rigid-body orientation but also the detailed conformations of the side-chains. Out of 8 targets, the lowest energy models had interface root-mean-square deviations (RMSDs) less than 1.1 A from the correct structures for 6 targets, and interface RMSDs less than 0.4 A for 3 targets. The predictions were top submissions to CAPRI for Targets 11, 12, 14, 15, and 19. The close correspondence of the lowest free energy structures found in our searches to the experimental structures suggests that our free energy function is a reasonable representation of the physical chemistry, and that the real space search with full side-chain flexibility to some extent solves the protein-protein docking problem in the absence of significant backbone conformational changes. On the other hand, the approach fails when there are significant backbone conformational changes as the steric complementarity of the 2 proteins cannot be modeled without incorporating backbone flexibility, and this is the major goal of our current work.

Algorithms↗

PubMed1995

A computer modeling postulated mechanism for angiotensin II receptor activation.

The angiotensin II receptor of the AT1-type has been modeled starting from the experimentally determined three-dimensional structure of bacteriorhodopsin as the template. Intermediate 3D structures of rhodopsin and beta 2-adrenergic receptors were built because no direct sequence alignment is possible between the AT1 receptor and bacteriorhodopsin. Docking calculations were carried out on the complex of the modeled receptor with AII, and the results were used to analyze the binding possibilities of DuP753-type antagonistic non-peptide ligands. We confirm that the positively charged Lys199 on helix 5 is crucial for ligand binding, as in our model; the charged side chain of this amino acid interacts strongly with the C-terminal carboxyl group of peptide agonists or with the acidic group at the 2'-position of the biphenyl moiety of DuP753-type antagonists. Several other receptor residues which are implicated in the binding of ligands and the activation of receptor by agonists are identified, and their functional role is discussed. Therefore, a plausible mechanism of receptor activation is proposed. The three-dimensional docking model integrates most of the available experimental observations and helps to plan pertinent site-directed mutagenesis experiments which in turn may validate or modify the present model and the proposed mechanism of receptor activation.

Amino Acid Sequence↗

PubMed2006

Anticancer thiopyrano[2,3-d][1,3]thiazol-2-ones with norbornane moiety. Synthesis, cytotoxicity, physico-chemical properties, and computational studies.

A series of novel 9-substituted-3,7-dithia-5-azatetracyclo[9.2.1.0(2,10).0(4,8)]tetradecen-4(8)-ones-6 have been synthesized by a stereoselective hetero-Diels-Alder reaction of 5-ylidene-4-thioxo-2-thiazolidone derivatives with norbornene-2. All the compounds have been evaluated for antitumor activity in in vitro human tumor cell lines, and 10 of them possessed significant and selective cytotoxicity (MGM logGI50 approximately -4.17 to -4.98, for individual cell lines logGI50 up to -8). COMPARE analyses of differential growth inhibition patterns of compounds at the GI50 level showed high correlations with some of the antitubulin agents. The lipophilicity of the compounds was studied by RP-TLC and found to correlate well with calculated logP values. Docking and structure-activity relationship studies produced seven QSAR models with 2 or 3 variables, with correlation coefficients r2>0.9 and leave-one-out cross-validation correlation coefficients, q2>0.8.

Antineoplastic Agents↗

PubMed2005

A new potential cyclooxygenase-2 inhibitor, pyridinic analogue of nimesulide.

In this paper, the binding mode of original pyridinic compounds structurally related to nimesulide, a preferential cyclooxygenase (COX)-2 inhibitor, is analyzed by docking simulations in order to understand structure-activity relationships of this family. Structural modifications are proposed to reverse the selectivity of the more active inhibitor of the series characterized by a preferential activity on COX-1. On the basis of these modifications, a new compound with a bromo substituent was designed and showed a COX-2 selective inhibition.

Crystallography, X-Ray↗

PubMed2003

Novel, highly potent aldose reductase inhibitors: cyano(2-oxo-2,3-dihydroindol-3-yl)acetic acid derivatives.

Cyano(2-oxo-2,3-dihydroindol-3-yl)acetic acid derivatives were synthesized and tested as a novel class of aldose reductase (ALR2) inhibitors. Each compound was evaluated as a diastereomeric mixture, due to tautomeric equilibria in solution. The parent compound 39 exhibited a good inhibitory activity with an IC(50) value of 0.85 microM, similar to that of the well-known ARI sorbinil (IC(50) 0.50 microM). The concurrent introduction of a halogen and a lipophilic group in the 5- and in the 1-positions, respectively, of the indole nucleus of 39, gave compound 55, cyano[5-fluoro-1-(4-methylbenzyl)-2-oxo-2,3-dihydroindol-3-yl]acetic acid, which displayed the highest activity (IC(50) 0.075 microM, very close to that of tolrestat IC(50) 0.046 microM), with a good selectivity toward ALR2 compared with aldehyde reductase (ALR1) (16.4-fold), and no appreciable inhibitory properties against sorbitol dehydrogenase (SD), or glutathione reductase (GR). The isopropyl ester 59, a prodrug of 55, was found to be almost as effective as tolrestat in preventing cataract development in severely galactosemic rats when administered as an eye drop solution. Docking simulation of 55 into a three-dimensional model of human ALR2 made it possible to formulate the hypothesis that the 2-hydroxy tautomer was the active species binding into the catalytic site of the enzyme. This was fully consistent with the structure-activity relationships within this series of cyanooxoindolylacetic acid derivatives.

Acetates↗

PubMed1997

Structural consensus in ligand-protein docking identifies recognition peptide motifs that bind streptavidin.

Computational structure prediction of streptavidin-peptide complexes for known recognition sequences and a number of random di-, tri-, and tetrapeptides has been conducted, and mechanisms of peptide recognition with streptavidin have been investigated by a new computational protocol. The structural consensus criterion, which is computed from multiple docking simulations and measures the accessibility of the dominant binding mode, identifies recognition motifs from a set of random peptide sequences, whereas energetic analysis is less discriminatory. The predicted conformations of recognition tripeptide and tetrapeptide sequences are also in structural harmony and composed of peptide fragments that are individually unfrustrated in their bound conformation, resulting in a minimally frustrated energy landscape for recognition peptides.

Amino Acid Sequence↗

PubMed2002

Computational simulation of the docking of Prochlorothrix hollandica plastocyanin to potosystem I: modeling the electron transfer complex.

We have used several docking algorithms (GRAMM, FTDOCK, DOT, AUTODOCK) to examine protein-protein interactions between plastocyanin (Pc)/photosystem I (PSI) in the electron transfer reaction. Because of the large size and complexity of this system, it is faster and easier to use computer simulations than conduct x-ray crystallography or nuclear magnetic resonance experiments. The main criterion for complex selection was the distance between the copper ion of Pc and the P700 chlorophyll special pair. Additionally, the unique tyrosine residue (Tyr(12)) of the hydrophobic docking surface of Prochlorothrix hollandica Pc yields a specific interaction with the lumenal surface of PSI, thus providing the second constraint for the complex. The structure that corresponded best to our criteria was obtained by the GRAMM algorithm. In this structure, the solvent-exposed histidine that coordinates copper in Pc is at the van der Waals distance from the pair of stacked tryptophans that separate the chlorophylls from the solvent, yielding the shortest possible metal-to-metal distance. The unique tyrosine on the surface of the Prochlorothrix Pc hydrophobic patch also participates in a hydrogen bond with the conserved Asn(633) of the PSI PsaB polypeptide (numbering from the Synechococcus elongatus crystal structure). Free energy calculations for complex formation with wild-type Pc, as well as the hydrophobic patch Tyr(12)Gly and Pro(14)Leu Pc mutants, were carried out using a molecular mechanics Poisson-Boltzman, surface area approach (MM/PBSA). The results are in reasonable agreement with our experimental studies, suggesting that the obtained structure can serve as an adequate model for P. hollandica Pc-PSI complex that can be extended for the study of other cyanobacterial Pc/PSI reaction pairs.

Algorithms↗

PubMed1994

Computer modeling analysis for enediyne chromophore-apoprotein complex of macromolecular antitumor antibiotic C-1027.

On the basis of the van der Waals and electrostatic potential energy calculations and energy minimization (EM), a model for the apoprotein-chromophore complex of C-1027 has been constructed by docking the apoprotein (Apo-C1027) and the chromophore (C1027-Chr). The model of the apoprotein-chromophore complex also suggests the most probable stereochemistry of the chromophore (8R,9S,13R,17R), specific interactions between Apo-C1027 and C1027-Chr, and the origin of the stabilization of the chromophore by the apoprotein. The acetylenic bond of C1027-Chr appears to be stabilized by (1) hydrophobic interactions with the bottom of the pocket of Apo-C1027, (2) orbital interaction with Cys36-Cys45 disulfide bond, (3) van der Waals contact with Pro76, and (4) pi-pi stacking with the benzene moiety of the chromophore. In this model, molecular dynamics (MD) simulation of the chromophore indicates that the acetylene bond distance (C2-C7) of the apoprotein-bound chromophore is longer than that of the unbound chromophore.

Amino Acid Sequence↗

PubMed2000

Structural study of the sodium channel inactivation gate peptide including an isoleucine-phenylalanine-methionine motif and its analogous peptide (phenylalanine/glutamine) in trifluoroethanol solutions and SDS micelles.

In order to gain insight into the gating mechanisms of Na+ channels, in particular their inactivation mechanisms, we studied the structures of the Na+ channel inactivation gate related peptide which includes the IFM (Ile-Phe-Met) motif (Ac-KKKFGGQDIFMTEEQKK-NH2; K1480-K1496 in rat brain type-IIA Na+ channels, MP-3A) and its F/Q(Gln) substituted one (MP-4A) in trifluoroethanol (TFE) solutions and sodium dodecyl sulfate (SDS) micelles using circular dichroism (CD) and 1H-NMR spectroscopies. Based on observed nuclear Overhauser effect constraints, three-dimensional structures of MP-3A and MP-4A were determined using simulated annealing molecular dynamics/ energy minimization calculations. In TFE solutions, no appreciable differences in the structure were observed using either CD or NMR spectra. In SDS micelles, however, the two peptides exhibited definitely different structures from each other. It was found that in MP-3A, residues 11488 and T1491 were spatially proximate with each other owing to hydrogen bonding between the amide proton of 11488 and the hydroxyl oxygen atom of T1491, whereas in MP-4A, F/Q substitution separated them owing to conformational changes. The solvent-accessible surfaces calculated for the structures of MP-3A and MP-4A showed that the former has a smoother interaction surface to the hydrophobic docking site than the latter. In conclusion, the conformational changes, as well as decreased hydrophobicity around the IFM motif owing to the F/Q mutation, may be one reason why F1489Q mutated channels cannot inactivate almost completely.

Amino Acid Motifs↗

PubMed1996

Comparative molecular field analysis of haptens docked to the multispecific antibody IgE(Lb4)

Using comparative molecular field analysis (CoMFA), three-dimensional quantitative structure-activity relationships were developed for 27 haptens which bind to the monoclonal antibody IgE(Lb4). In order to obtain an alignment for these structurally very diverse antigens, the compounds were docked to a previously modeled receptor structure using the automated docking program AUTODOCK (Goodsell, D.S.; Olson, A.J. Proteins: Struct., Funct., Genet. 1990, 8, 195-202). Remarkably, this alignment method yielded highly consistent QSAR models, as indicated by the corresponding cross-validated r2 values (0.809 for a model with carbon as probe atom, 0.773 for a model with hydrogen as probe atom). Conventional alignment failed in providing a basis for self-consistent CoMFAs. Amino acids Tyr H 50, Tyr H 52, and Trp H 95 of the receptor appeared to be of crucial importance for binding of various antigens. These findings are consistent with earlier considerations of aromatic residues being responsible for the multispecificity of certain immunoglobulins.

Antibodies, Monoclonal↗

PubMed2001

Computational characterization of substrate binding and catalysis in S-adenosylhomocysteine hydrolase.

S-Adenosylhomocysteine (AdoHcy) hydrolase catalyzes the reversible hydrolysis of AdoHcy to adenosine (Ado) and homocysteine (Hcy), playing an essential role in modulating the cellular Hcy levels and regulating activities of a host of methyltransferases in eukaryotic cells. This enzyme exists in an open conformation (active site unoccupied) and a closed conformation (active site occupied with substrate or inhibitor) [Turner, M. A., Yang, X., Yin, D., Kuczera, K., Borchardt, R. T., and Howell, P. L. (2000) Cell Biochem. Biophys. 33, 101-125]. To investigate the binding of natural substrates during catalysis, the computational docking program AutoDock (with confirming calculations using CHARMM) was used to predict the binding modes of various substrates or inhibitors with the closed and open forms of AdoHcy hydrolase. The results have revealed that the interaction between a substrate and the open form of the enzyme is nonspecific, whereas the binding of the substrate in the closed form is highly specific with the adenine moiety of a substrate as the main recognition factor. Residues Thr57, Glu59, Glu156, Gln181, Lys186, Asp190, Met351, and His35 are involved in substrate binding, which is consistent with the crystal structure. His55 in the docked model appears to participate in the elimination of water from Ado through the interaction with the 5'-OH group of Ado. In the same reaction, Asp131 removes a proton from the 4' position of the substrate after the oxidation-reduction reaction in the enzyme. To identify the residues that bind the Hcy moiety, AdoHcy was docked to the closed form of AdoHcy hydrolase. The Hcy tail is predicted to interact with His55, Cys79, Asn80, Asp131, Asp134, and Leu344 in a strained conformation, which may lower the reaction barrier and enhance the catalysis rate.

Adenosine↗

PubMedDate not supplied

Chemical proteomic tool for ligand mapping of CYP antitargets: an NMR-compatible 3D QSAR descriptor in the Heme-Based Coordinate System.

Chemical proteomic strategies strive to probe and understand protein-ligand interactions across gene families. One gene family of particular interest in drug and xenobiotic metabolism are the cytochromes P450 (CYPs), the topic of this article. Although numerous tools exist to probe affinity of CYP-ligand interactions, fewer exist for the rapid experimental characterization of the structural nature of these interactions. As a complement to recent advances in X-ray crystallography, NMR methods are being developed that allow for fairly high throughput characterization of protein-ligand interactions. One especially promising NMR approach involves the use of paramagnetic induced relaxation effects to measure distances of ligand atoms from the heme iron in CYP enzymes. Distances obtained from these T(1) relaxation measurements can be used as a direct source of 1-dimensional structural information or to restrain a ligand docking to generate a 3-dimensional data set. To facilitate such studies, we introduce the concept of the Heme-Based Coordinate System and present how it can be used in combination with NMR T(1) relaxation data to derive 3D QSAR descriptors directly or in combination with in silico docking. These descriptors should have application in defining the binding preferences of CYP binding sites using 3D QSAR models. They are especially well-suited for the biasing of fragment assembly and combinatorial chemistry drug design strategies, to avoid fragment or reagent combinations with enhanced affinity for CYP antitargets.

Computer Simulation↗

PubMed2002

Flexsim-R: a virtual affinity fingerprint descriptor to calculate similarities of functional groups.

Methods to describe the similarity of fragments occurring in drug-like molecules are of fundamental importance in computational drug design. In the early phase of lead discovery, they can help to select diverse building blocks for combinatorial compound libraries intended for broad screening. In lead optimization, such methods can guide bioisosteric replacements of one functional group by another or serve as descriptors for QSAR calculations. In this paper, we outline the development of a novel 3D descriptor, termed Flexsim-R, which is a further extension of our virtual affinity fingerprint idea. Descriptors are calculated based on docking of small fragments such as building blocks for combinatorial chemistry or functional groups of drug-like molecules into a reference panel of protein binding sites. The method is validated by examining the neighborhood behavior of the affinity fingerprints and by deriving predictive QSAR models for a couple of literature peptide data sets.

Algorithms↗

PubMedDate not supplied

CoMFA and docking study of novel estrogen receptor subtype selective ligands.

We present the results from a Comparative Molecular Field Analysis (CoMFA) and docking study of a diverse set of 36 estrogen receptor ligands whose relative binding affinities (RBA) with respect to 17beta-Estradiol were available in both isoforms of the nuclear estrogen receptors (ER alpha, ER beta). Initial CoMFA models exhibited a correlation between the experimental relative binding affinities and the molecular steric and electrostatic fields; ER alpha: r2 = 0.79, q2 = 0.44 ER beta: r2 = 0.93, q2 = 0.63. Addition of the solvation energy of the isolated ligand improved the predictive nature of the ER beta model initially; r2 = 0.96, q2 = 0.70 but upon rescrambling of the data-set and reselecting the training set at random, inclusion of the ligand solvation energy was found to have little effect on the predictive nature of the CoMFA models. The ligands were then docked inside the ligand binding domain (LBD) of both ER alpha and ER beta utilizing the docking program Gold, after-which the program CScore was used to rank the resulting poses. Inclusion of both the Gold and CScore scoring parameters failed to improve the predictive ability of the original CoMFA models. The subtype selectivity expressed as RBA(ER alpha/ER beta) of the test sets was predicted using the most predictive CoMFA models, as illustrated by the cross-validated r2. In each case the most selective ligands were ranked correctly illustrating the utility of this method as a prescreening tool in the development of novel estrogen receptor subtype selective ligands.

Binding Sites↗