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At least 865 records · Page 48Linked to original sources
PubMed2006

Docking and three-dimensional quantitative structure-activity relationship (3D QSAR) analyses of nonsteroidal progesterone receptor ligands.

We report a docking and comparative molecular similarity indices analysis (CoMSIA) study of progesterone receptor (PR) ligands with an emphasis on nonsteroids including tanaproget. The ligand alignment generation, a critical part of model building, comprised two stages. First, thorough conformational sampling of docking poses within the PR binding pocket was made with the program GOLD. Second, a strategy to select representative poses for CoMSIA was developed utilizing the FlexX scoring function. After manual replacement of five poses where this approach had problems, a significant correlation (r(2) = 0.878) between the experimental affinities and electrostatic, hydrophobic, and hydrogen bond donor properties of the aligned ligands was found. Extensive model validation was made using random-group cross-validations, external test set predictions (r(pred)(2) = 0.833), and consistency check between the CoMSIA model and the PR binding site structure. Robustness, predictive ability, and automated alignment generation make the model a potential tool for virtual screening.

Binding Sites↗
PubMed2006

Proposal of a new binding orientation for non-peptide AT1 antagonists: homology modeling, docking and three-dimensional quantitative structure-activity relationship analysis.

A three-dimensional model of the AT1 receptor was constructed by means of a homology modeling procedure, using the X-ray structure of bovine rhodopsin as the initial template and taking into account the available site-directed mutagenesis data. The docking of losartan and its active metabolite EXP3174, followed by 1 ns of molecular dynamics (MD) simulation inserted into the phospholipid bilayer, suggested a different binding orientation for these antagonists from those previously proposed. Furthermore, the docking of several non-peptide antagonists was used as an alignment tool for the development of a three-dimensional quantitative structure-activity relationship (3D-QSAR) model, and the good results confirmed our binding hypothesis and the reliability of the model.

Amino Acid Sequence↗
PubMed1996

Molecular similarity based on DOCK-generated fingerprints.

An alternative method for defining molecular similarity is presented. By using the docking program DOCK and a reference panel of protein binding sites, fingerprints for a set of molecules have been generated, based on calculated interaction energies. These binding patterns allowed us to calculate matrices of similarity coefficients which subsequently were used for nearest-neighbor searches within the database. Our results indicate that the method is suitable for finding significant similarities of compounds of the same biological activity. Although the overall performance of a traditional 2D similarity method is better in the test systems investigated, our 3D approach can be regarded as complementary since it is able to detect similarities independent of the covalent structure of the compounds. Thus it should be a useful 3D database-searching tool for rational lead discovery.

Amino Acid Sequence↗
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↗
PubMed1999

Consensus scoring: A method for obtaining improved hit rates from docking databases of three-dimensional structures into proteins.

We present the results of an extensive computational study in which we show that combining scoring functions in an intersection-based consensus approach results in an enhancement in the ability to discriminate between active and inactive enzyme inhibitors. This is illustrated in the context of docking collections of three-dimensional structures into three different enzymes of pharmaceutical interest: p38 MAP kinase, inosine monophosphate dehydrogenase, and HIV protease. An analysis of two different docking methods and thirteen scoring functions provides insights into which functions perform well, both singly and in combination. Our data shows that consensus scoring further provides a dramatic reduction in the number of false positives identified by individual scoring functions, thus leading to a significant enhancement in hit-rates.

Algorithms↗
PubMed1999

Two-stage method for protein-ligand docking.

A two-stage method for the computational prediction of the structure of protein-ligand complexes is proposed. Given an experimentally determined structure of the protein, in the first stage a large number of plausible ligand conformations is generated using the fast docking algorithm FlexX. In the second stage these conformations are minimized and reranked using a method based on a classical force field. The two-stage method is tested for 10 different protein-ligand complexes. For 9 of them experimentally determined structures are known. It turns out that the two-stage method strongly improves the predictive power as compared to that of the fast docking stage alone. The tenth case is a bona fide prediction of a complex of thrombin with a new inhibitor for which no experimentally determined structure is available so far.

Algorithms↗
PubMed2000

Modeling of kappa-opioid receptor/agonists interactions using pharmacophore-based and docking simulations.

The interaction of the kappa-opioid receptor with arylacetamide and benzomorphan derivatives acting as agonists was modeled through pharmacophore-based and docking calculations. Potentially bioactive conformations of representative ligands (U-50,488 and its benzo-fused analogues 4 and 6 for arylacetamides and MPCB for benzomorphans) were identified by systematic conformational analysis and docked into a 3D model of the kappa-receptor. The obtained complexes, refined by energy-minimization and molecular dynamics, were evaluated for their consistency with structure-activity relationships and site-directed mutagenesis data. The following interactions are hypothesized to govern the ligand-receptor recognition process: (i) a salt bridge between the Asp138 carboxylate and the protonated nitrogen of the bound agonist; (ii) a hydrogen bond donated by the Tyr312 hydroxyl to the carbonyl oxygen of arylacetamides and MPCB; (iii) hydrophobic interactions established by the dichlorophenyl moiety of arylacetamides and the pendant phenyl ring of MPCB with the surrounding side chains of Tyr312, Leu224, Leu295, and Ala298; (iv) a pi-stacking contact between the Tyr312 side chain and the phenyl ring of arylacetamides; (v) a hydrogen bond linking the His291 imidazole ring to the phenolic hydroxy group featured by typical benzomorphans and the arylacetamides 4 and 6.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed2005

Electrical docking of microtubules for kinesin-driven motility in nanostructures.

We demonstrate localized electrical control of the docking of microtubules onto engineered kinesin-coated structures. After applying a voltage to a gold electrode, we observe an enhanced transport of microtubules from solution toward the surface and a subsequent increase of the amount of moving microtubule shuttles. Switching off the voltage leads to a partial detachment of microtubules from the surface. The surface coverage of microtubules, during both the docking and undocking events, follows an exponential time dependence. We provide a simple kinetic model, incorporating the equilibrium between free and surface-bound microtubules, that explains these data.

Binding Sites↗
PubMed1998

Identification and energetic ranking of possible docking sites for pterin on dihydrofolate reductase.

The reliability of new methodology for detecting sites for ligand binding on the surfaces of proteins has been tested using a range of dihydrofolate reductase (DHFR) crystal structures. Docking of the pterin molecule to ten such DHFR structures has been examined. Initial docking sites were selected using the VDW-FFT method we have developed recently. This procedure was followed by rigid geometry optimization and solvation energy calculations using our parametrized reaction field multipoles (PRFM) method and the finite difference solution of the Poisson equation (FDPB) method. Two different sets of MM parameters, from the OPLS and Amber94 force fields, have been used. In eight cases the energy of the complexes with pterin bound at the active site was the lowest with the recent Amber94 parameters. In one case the spurious first-ranked site was only 1.8 kcal/mol lower in energy compared with the active site. The other 'failure' of the method may, in fact, represent a valid initial binding site. The calculations with the old OPLS parameters gave slightly worse results.

Binding Sites↗
PubMed2001

Ligand-receptor docking with the Mining Minima optimizer.

The optimizer developed for the Mining Minima algorithm, which uses ideas from Genetic Algorithms, the Global Underestimator Method, and Poling, has been adapted for use in ligand-receptor docking. The present study describes the resulting methodology and evaluates its accuracy and speed for 27 test systems. The performance of the new docking algorithm appears to be competitive with that of previously published methods. The energy model, an empirical force field with a distance-dependent dielectric treatment of solvation, is adequate for a number of test cases, although incorrect low-energy conformations begin to compete with the correct conformation for larger sampling volumes and for highly solvent-exposed binding sites that impose little steric constraint on the ligand.

Algorithms↗
PubMed2000

Statistical relationships among docking scores for different protein binding sites.

This report describes the existence of statistical relationships among scores computed with the DOCK program for a library of small molecules and a panel of protein binding sites. Multivariate relationships are observed in docking scores computed for a constant set of ligands in different binding sites of proteins that are dissimilar in structure and function. The structural basis for the correlations found among scores is analyzed in terms of size, shape and charge characteristics of the binding sites considered. Interestingly, these results parallel a growing body of evidence demonstrating the promiscuous behavior of small molecules in their interactions with macromolecules that could have an impact in future efforts in drug design.

Binding Sites↗
PubMed2001

A comparative docking study and the design of potentially selective MMP inhibitors.

As part of a program aimed at the design and synthesis of constrained MMP inhibitors, a survey of the reported X-ray and NMR structures of MMP/inhibitor complexes was performed, revealing mutations of key amino acids at different subsites between MMPs. A comparative study of fully automated docking programs AutoDock and DOCK in closely approximating the X-ray crystal structures of ten selected MMP inhibitors was performed. AutoDock proved to be highly reliable, efficient and predictive for a set of inhibitors with less than six atom types.

Binding Sites↗
PubMedDate not supplied

Comparative binding energy analysis of haloalkane dehalogenase substrates: modelling of enzyme-substrate complexes by molecular docking and quantum mechanical calculations.

We evaluate the applicability of automated molecular docking techniques and quantum mechanical calculations to the construction of a set of structures of enzyme-substrate complexes for use in Comparative binding energy (COMBINE) analysis to obtain 3D structure-activity relationships. The data set studied consists of the complexes of eighteen substrates docked within the active site of haloalkane dehalogenase (DhlA) from Xanthobacter autotrophicus GJ10. The results of the COMBINE analysis are compared with previously reported data obtained for the same dataset from modelled complexes that were based on an experimentally determined structure of the DhlA-dichloroethane complex. The quality of fit and the internal predictive power of the two COMBINE models are comparable, but better external predictions are obtained with the new approach. Both models show a similar composition of the principal components. Small differences in the relative contributions that are assigned to important residues for explaining binding affinity differences can be directly linked to structural differences in the modelled enzyme-substrate complexes: (i) rotation of all substrates in the active site about their longitudinal axis, (ii) repositioning of the ring of epihalohydrines and the halogen substituents of 1,2-dihalopropanes, and (iii) altered conformation of the long-chain molecules (halobutanes and halohexanes). For external validation, both a novel substrate not included in the training series and two different mutant proteins were used. The results obtained can be useful in the future to guide the rational engineering of substrate specificity in DhlA and other related enzymes.

Binding Sites↗
PubMed2003

3D-QSAR and docking studies on 4-anilinoquinazoline and 4-anilinoquinoline epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors.

The overexpression and/or mutation of the epidermal growth factor receptor (EGFR) tyrosine kinase has been observed in many human solid tumors, and is under intense investigation as a novel anticancer molecular target. Comparative 3D-QSAR analyses using different alignments were undertaken employing comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA) for 122 anilinoquinazoline and 50 anilinoquinoline inhibitors of EGFR kinase. The SYBYL multifit alignment rule was applied to three different conformational templates, two obtained from a MacroModel Monte Carlo conformational search, and one from the bound conformation of erlotinib in complex with EGFR in the X-ray crystal structure. In addition, a flexible ligand docking alignment obtained with the GOLD docking program, and a novel flexible receptor-guided consensus dynamics alignment obtained with the DISCOVER program in the INSIGHTII modeling package were also investigated. 3D-QSAR models with q2 values up to 0.70 and r2 values up to 0.97 were obtained. Among the 4-anilinoquinazoline set, the q2 values were similar, but the ability of the different conformational models to predict the activities of an external test set varied considerably. In this regard, the model derived using the X-ray crystallographically determined bioactive conformation of erlotinib afforded the best predictive model. Electrostatic, hydrophobic and H-bond donor descriptors contributed the most to the QSAR models of the 4-anilinoquinazolines, whereas electrostatic, hydrophobic and H-bond acceptor descriptors contributed the most to the 4-anilinoquinoline QSAR, particularly the H-bond acceptor descriptor. A novel receptor-guided consensus dynamics alignment has also been introduced for 3D-QSAR studies. This new alignment method may incorporate to some extent ligand-receptor induced fit effects into 3D-QSAR models.

Aniline Compounds↗
PubMed2004

Validation of an empirical RNA-ligand scoring function for fast flexible docking using Ribodock.

We report the design and validation of a fast empirical function for scoring RNA-ligand interactions, and describe its implementation within RiboDock, a virtual screening system for automated flexible docking. Building on well-known protein-ligand scoring function foundations, features were added to describe the interactions of common RNA-binding functional groups that were not handled adequately by conventional terms, to disfavour non-complementary polar contacts, and to control non-specific charged interactions. The results of validation experiments against known structures of RNA-ligand complexes compare favourably with previously reported methods. Binding modes were well predicted in most cases and good discrimination was achieved between native and non-native ligands for each binding site, and between native and non-native binding sites for each ligand. Further evidence of the ability of the method to identify true RNA binders is provided by compound selection ('enrichment factor') experiments based around a series of HIV-1 TAR RNA-binding ligands. Significant enrichment in true binders was achieved amongst high scoring docking hits, even when selection was from a library of structurally related, positively charged molecules. Coupled with a semi-automated cavity detection algorithm for identification of putative ligand binding sites, also described here, the method is suitable for the screening of very large databases of molecules against RNA and RNA-protein interfaces, such as those presented by the bacterial ribosome.

Fluorescence Resonance Energy Transfer↗
PubMed2004

Docking-based CoMFA and CoMSIA studies of non-nucleoside reverse transcriptase inhibitors of the pyridinone derivative type.

Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on a set of pyridinone derivatives. A molecular alignment obtained by docking of compounds into the non-nucleoside reverse transcriptase inhibitor binding site of HIV-1 was used. Good correlations between the calculated binding free energies and experimental inhibitory activities suggest that the binding conformations of these inhibitors are reasonable. Robust and predictive 3D-QSAR models were obtained with q2 values of 0.706 and 0.723 for CoMFA and CoMSIA, respectively. The models were validated by an external test set obtaining r2 pred values of 0.720 and 0.750 for CoMFA and CoMSIA, respectively. The CoMFA, CoMSIA and docking results help to understand the type of interactions that occur between pyridinone derivatives with the non-nucleoside reverse transcriptase inhibitor binding pocket, and explain the viral resistance to pyridinone derivatives upon mutation of amino acids Tyr181 and Tyr188. The results obtained provide information for a better understanding of the drug resistant mechanisms. The 3D-QSAR models derived will be used to guide the design of pyridinone derivatives active against mutant strains of reverse transcriptase.

Computer Simulation↗
PubMed2003

Defects in synaptic vesicle docking in unc-18 mutants.

Sec1-related proteins function in most, if not all, membrane trafficking pathways in eukaryotic cells. The Sec1-related protein required in neurons for synaptic vesicle exocytosis is UNC-18. Several models for UNC-18 function during vesicle exocytosis are under consideration. We have tested these models by characterizing unc-18 mutants of the nematode Caenorhabditis elegans. In the absence of UNC-18, the size of the readily releasable pool is severely reduced. Our results show that the near absence of fusion-competent vesicles is not caused by a reduction in syntaxin levels, by a mislocalization of syntaxin, by a defect in fusion or by a failure to open syntaxin during priming. Rather, we found a reduction of docked vesicles at the active zone in unc-18 mutants, suggesting that UNC-18 functions, directly or indirectly, as a facilitator of vesicle docking.

Animals↗
PubMed2004

Docking and scoring in virtual screening for drug discovery: methods and applications.

Computational approaches that 'dock' small molecules into the structures of macromolecular targets and 'score' their potential complementarity to binding sites are widely used in hit identification and lead optimization. Indeed, there are now a number of drugs whose development was heavily influenced by or based on structure-based design and screening strategies, such as HIV protease inhibitors. Nevertheless, there remain significant challenges in the application of these approaches, in particular in relation to current scoring schemes. Here, we review key concepts and specific features of small-molecule-protein docking methods, highlight selected applications and discuss recent advances that aim to address the acknowledged limitations of established approaches.

Binding Sites↗