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PubMedDate not supplied

Modeling the structural basis of human CCR5 chemokine receptor function: from homology model building and molecular dynamics validation to agonist and antagonist docking.

This article describes the construction and validation of a three-dimensional model of the human CCR5 receptor using a homology-based approach starting from the X-ray structure of the bovine rhodopsin receptor. The reliability of the model is assessed through molecular dynamics and docking simulations using both natural agonists and a synthetic antagonist. Some important structural and functional features of the receptor cavity and the extracellular loops are identified, in agreement with data available from site-directed mutagenesis. The results of this study help to explain the structural basis for the recognition, activation, and inhibition processes of CCR5 and may provide fresh insights for the design of HIV-1 entry blockers.

CCR5 Receptor Antagonists↗
PubMedDate not supplied

GFscore: a general nonlinear consensus scoring function for high-throughput docking.

Most of the recent published works in the field of docking and scoring protein/ligand complexes have focused on ranking true positives resulting from a Virtual Library Screening (VLS) through the use of a specified or consensus linear scoring function. In this work, we present a methodology to speed up the High Throughput Screening (HTS) process, by allowing focused screens or for hitlist triaging when a prohibitively large number of hits is identified in the primary screen, where we have extended the principle of consensus scoring in a nonlinear neural network manner. This led us to introduce a nonlinear Generalist scoring Function, GFscore, which was trained to discriminate true positives from false positives in a data set of diverse chemical compounds. This original Generalist scoring Function is a combination of the five scoring functions found in the CScore package from Tripos Inc. GFscore eliminates up to 75% of molecules, with a confidence rate of 90%. The final result is a Hit Enrichment in the list of molecules to investigate during a research campaign for biological active compounds where the remaining 25% of molecules would be sent to in vitro screening experiments. GFscore is therefore a powerful tool for the biologist, saving both time and money.

Molecular Structure↗
PubMed2000

Graph-theoretic techniques for macromolecular docking

We propose a solution to the problem of docking two macromolecules. We represent each of two proteins as a set of potential hydrogen bond donors and acceptors and use a clique-detection algorithm to find maximally complementary sets of donor/acceptor pairs. Preliminary results are presented which demonstrate the feasibility of the method.

Journal Article↗
PubMed2002

Structures of protein-protein complexes are docked using only NMR restraints from residual dipolar coupling and chemical shift perturbations.

NMR structures of protein-protein and protein-ligand complexes rely heavily on intermolecular NOEs. Recent work has shown that if no significant conformational changes occur upon complex formation residual dipolar coupling can replace most of the NOE restraints in protein-protein complexes, while restraints derived from chemical shift perturbations can largely replace intermolecular NOEs in protein-ligand structures. By combining restraints from chemical shift perturbations with orientation restraints derived from measurements of residual dipolar couplings, we show that the structure of the EIN-HPr complex can be calculated without NOE restraints. The final structure, built from the crystal structures of EIN and HPr in their uncomplexed form and docked only with NMR restraints, places HPr within 2.5 A of the position determined from the mean NMR structure of the complex.

Bacterial Proteins↗
PubMed2003

Docking of protein-protein complexes on the basis of highly ambiguous intermolecular distance restraints derived from 1H/15N chemical shift mapping and backbone 15N-1H residual dipolar couplings using conjoined rigid body/torsion angle dynamics.

A simple and reliable method for docking protein-protein complexes using (1)H(N)/(15)N chemical shift mapping and backbone (15)N-(1)H residual dipolar couplings is presented and illustrated with three complexes (EIN-HPr, IIA(Glc)-HPr, and IIA(Mtl)-HPr) of known structure. The (1)H(N)/(15)N chemical shift mapping data are transformed into a set of highly ambiguous, intermolecular distance restraints (comprising between 400 and 3000 individual distances) with translational and some degree of orientational information content, while the dipolar couplings provide information on relative protein-protein orientation. The optimization protocol employs conjoined rigid body/torsion angle dynamics in simulated annealing calculations. The target function also comprises three nonbonded interactions terms: a van der Waals repulsion term to prevent atomic overlap, a radius of gyration term (E(rgyr)) to avoid expansion at the protein-protein interface, and a torsion angle database potential of mean force to bias interfacial side chain conformations toward physically allowed rotamers. For the EIN-HPr and IIA(Glc)-HPr complexes, all structures satisfying the experimental restraints (i.e., both the ambiguous intermolecular distance restraints and the dipolar couplings) converge to a single cluster with mean backbone coordinate accuracies of 0.7-1.5 A. For the IIA(Mtl)-HPr complex, twofold degeneracy remains, and the structures cluster into two distinct solutions differing by a 180 degrees rotation about the z axis of the alignment tensor. The correct and incorrect solutions which have mean backbone coordinate accuracies of approximately 0.5 and approximately 10.5 A, respectively, can readily be distinguished using a variety of criteria: (a) examination of the overall (1)H(N)/(15)N chemical shift perturbation map (because the incorrect cluster predicts the presence of residues at the interface that experience only minimal chemical shift perturbations; this information is readily incorporated into the calculations in the form of ambiguous intermolecular repulsion restraints); (b) back-calculation of dipolar couplings on the basis of molecular shape; or (c) the E(rgyr) distribution which, because of its global nature, directly reflects the interfacial packing quality. This methodology should be particularly useful for high throughput, NMR-based, structural proteomics.

Bacterial Proteins↗
PubMed2005

Crystal structure of BRL 42715, C6-(N1-methyl-1,2,3-triazolylmethylene)penem, in complex with Enterobacter cloacae 908R beta-lactamase: evidence for a stereoselective mechanism from docking studies.

BRL 42715, C6-(N1-methyl-1,2,3-triazolylmethylene)penem, is an active-site-directed inactivator of bacterial beta-lactamases. The crystal structure of Enterobacter cloacae 908R class C beta-lactamase in complex with BRL 42715, docking, and energy minimization studies explain stereoselectivity of the binding of C6-(heterocyclic methylene)penems against class C beta-lactamase.

Crystallography, X-Ray↗
PubMed2005

Docking, triggering, and biological activity of dynemicin A in DNA: a computational study.

The triggering and biological activity of the naturally occurring enediyne dynemicin A (1) was investigated, both inside and outside the minor groove of the duplex 10-mer B-DNA sequence d(CTACTACTGG).d(CCAGTAGTAG), using density functional theory (B3LYP with the 3-21G and 6-31G(d) basis set), BD(T)/cc-pVDZ (Brueckner doubles with a perturbative treatment of triple excitations), and the ONIOM approach. Enediyne 1 is triggered by NADPH in a strongly exothermic reaction (-88 kcal/mol), which involves a number of intermediate steps. Untriggered 1 has a high barrier for the Bergman cyclization (52 kcal/mol) that is lowered after triggering to 16.7 kcal/mol due to an epoxide opening and the accompanying strain relief. The Bergman reaction of triggered 1 is slightly exothermic by 2.8 kcal/mol. The singlet biradical formed in this reaction is kinetically stable (activation enthalpies of 19.5 and 21.8 kcal/mol for retro-Bergman reactions) and is as reactive as para-benzyne. The activity-relevant docking mode is an edge-on insertion into the minor groove, whereas the intercalation between base pairs, although leading to larger binding energies, excludes a triggering of 1 and the development of its biological activity. Therefore, an insertion-intercalation model is developed, which can explain all known experimental observations made for 1. On the basis of the insertion-intercalation model it is explained why large intercalation energies suppress the biological activity of dynemicin and why double-strand scission can be achieved only in a two-step mechanism that involves two enediyne molecules, explaining thus the high ratio of single-strand to double-strand scission observed for 1.

Algorithms↗
PubMed2006

Effects of solvent viscosity on ligand interconversion dynamics in the primary docking site of heme proteins.

Interconversion dynamics of the ligand in the primary docking site of myoglobin (Mb) and hemoglobin (Hb) in trehalose and glycerol/D2O mixtures at 283 K was investigated by probing time-resolved vibrational spectra of CO photolyzed from these proteins. The interconversion dynamics in viscous media are similar to those in aqueous solution, indicating that it is minimally coupled to the solvent-coupled large-scale protein motion. Interconversion rates in the heme pocket of Hb in water solution are slower than those of Mb in trehalose glass, suggesting that the interconversion barrier in Hb is intrinsically higher than that in Mb and is not modified by the solvent viscosity.

Binding Sites↗
PubMed1994

Homology modeling of the dopamine D2 receptor and its testing by docking of agonists and tricyclic antagonists.

We present the first model of dopamine D2 receptor transmembrane helices constructed directly from the bacteriorhodopsin (bR) coordinates derived from two-dimensional electron diffraction experiments. We have tested this model by its ability to accommodate rigid agonist and semirigid antagonist molecules which were docked into the putative binding pocket with stabilizing interactions. The model is consistent with structure-activity relationships of agonists and antagonists that interact with the receptor. It also illuminates data on a Na+ site for regulation of receptor function. The plausibility of the model is increased by its consistency with many mutagenesis studies on G protein-coupled receptors. Further, this model provides a basis to suggest testable molecular mechanisms for changes in the D2 conformational states for high- and low-affinity binding and signal transduction. Changes in the conformational state of the receptor are hypothesized to be due partly to movement of helix 7. In contrast to the model presented here, other published models were built using ideal helical structures or following the sense of the bacteriorhodopsin structure rather than the actual available coordinates. The presented model for the dopamine G protein-coupled receptor can be reconciled with the recent rhodopsin projection structure (Schertler, G. F. X.; Villa, C.; Henderson, R. Projection Structure of Rhodopsin.

Allosteric Regulation↗
PubMed1986

Docking flexible ligands to macromolecular receptors by molecular shape.

We present a method to explore the interaction of flexible ligands with receptors of known geometry on the basis of molecular shape. This method is an extension of that described by Kuntz et al. (J. Mol. Biol. 1982, 161, 269). The shape of a binding site on a macromolecular receptor is represented as a set of overlapping spheres. Each ligand is divided into a small set of large rigid fragments that are docked separately into the binding site and then rejoined later in the calculation. The division of ligands into separate fragments allows a degree of flexibility at the position that joins them. The rejoined fragments are then energy minimized in the receptor site. We illustrate the method with two test cases: dihydrofolate reductase/methotrexate and prealbumin/thyroxine. For each test case, the method finds binding geometries for the ligand near that observed crystallographically as well as others that provide good steric fit with the receptor.

Binding Sites↗
PubMed2001

Metabolism of sirolimus and its derivative everolimus by cytochrome P450 3A4: insights from docking, molecular dynamics, and quantum chemical calculations.

A combination of quantum chemical calculations and molecular simulations (DOCKing and molecular dynamics) is used to investigate the metabolism of sirolimus (rapamycin) and its derivative everolimus (SDZ-RAD) by cytochrome P450 3A4. Both molecules are drugs with high immunosuppressive activity. Our calculations yield qualitative predictions of the regiospecificities of the hydroxylations and O-dealkylations occurring in these two substrates which are in good agreement with recent experimental results. An analysis of the modeled enzyme-substrate interactions allows us to rationalize the reduced metabolic activity of the larger substrate everolimus compared to sirolimus. Moreover, our simulations suggest that hydrogen donor functionalities close to the metabolic site are important for anchoring the substrate at the active center of the enzyme. In particular, we predict that replacing one hydroxyl group by a fluorine atom should considerably suppress the major metabolic reaction in sirolimus, 39-O-demethylation.

Algorithms↗
PubMed2001

Acyclic and cyclopropyl analogues of adenosine bisphosphate antagonists of the P2Y1 receptor: structure-activity relationships and receptor docking.

The activation of P2Y1 receptors in platelets contributes to platelet aggregation, and selective antagonists are sought as potential antithrombotic agents. We reported (Kim et al. J. Med. Chem. 2000, 43, 746-755) that acyclic analogues of adenine nucleotides, containing two phosphate groups on a symmetrically branched aliphatic chain, attached at the 9-position of adenine, are moderately potent P2Y1 receptor antagonists. In this study we have varied the chain structure, to include asymmetric substitution, olefinic, and cyclopropyl groups. These antagonists inhibited the stimulation of phospholipase C in turkey erythrocyte membranes induced by 30 nM 2-MeS-ADP in the micromolar range. In the series of symmetrically branched aliphatic groups substituted with two phosphate groups, the optimal antagonist potency occurred with the 2-methylpropyl group. A 2-chloro-N(6)-methyladenine derivative, 2-[2-(2-chloro-6-methylaminopurin-9-yl)methyl]propane-1,3-bisoxy(diammoniumphosphate) (7), was a full antagonist at the P2Y1 receptor with an IC(50) value of 0.48 microM. Esterification of one of the phosphate groups or substitution with O-acetyl greatly reduced the antagonist potency at the P2Y1 receptor. Removal of a methylene group of 7 or inclusion of an olefinic or cyclopropyl group also reduced potency. A pair of enantiomeric glycerol derivatives demonstrated a 5-fold stereoselectivity for the S-isomer. Stereoisomerically defined analogues of 7 containing a cyclopropyl group in place of the branched carbon were less potent than 7 as antagonists, with IC(50) values of 2-3 microM. No agonist activity was observed for these analogues. A new rhodopsin-based molecular model of the P2Y1 receptor indicated that the optimal docked orientation of the two monophosphate moieties relative to the adenine N(6) (compared to a rigid, bicyclic analogue) was consistent with the dependence of antagonist potency on chain length. The 3'-phosphate was predicted to occupy a restricted space, deeper in the binding cleft than the 5'-phosphate location. In summary, modification of the flexible spacer chain linking bisphosphate groups to the adenine moiety provided many moderately potent antagonists.

Adenosine Diphosphate↗
PubMed2002

Angiotensin II vs its type I antagonists: conformational requirements for receptor binding assessed from NMR spectroscopic and receptor docking experiments.

The conformations of three angiotensin II (AII) peptide antagonists ([Sar1]-AII(1-7)-NH(2), [Sar1,Val5,Ala8]-AII and the AII antipeptide, [Glu1,Gly2,Val5,Val8]-AII) were assessed in a lipid medium. A common backbone turn was identified through modeling and spectroscopic studies. The His6 residue acted as a pivoting point beyond which each peptide adopted two distinct conformations. One principle conformer resembled that previously determined for AII while the other was designated as an AII antagonist like conformer. A computational overlay between the nonpeptide antagonist, Losartan, and both the AII and the AII like conformation of [Sar1,Val5,Ala8]-AII revealed common pharmacophoric points with RMS deviations between 1 and 1.5 A. Both the AII conformer and the AII antagonist like conformer of [Sar1,Val5,Ala8]-AII were docked into a model of the AT(1) receptor. Receptor residue Phe289 and Asp281 provided good contact points for both peptides. Some differences were also noted. The terminal carboxyl of AII contacted Lys199 of the receptor while that of [Sar1,Val5,Ala8]-AII bridged Arg23 at the top of helix 1. The Asp1 side chain of AII interacted with His183 of the receptor.

Angiotensin I↗
PubMed2002

2-Ethyl and 2-ethylidene analogues of 1alpha,25-dihydroxy-19-norvitamin D(3): synthesis, conformational analysis, biological activities, and docking to the modeled rVDR ligand binding domain.

Novel 19-nor analogues of 1alpha,25-dihydroxyvitamin D(3) were prepared and substituted at C-2 with an ethylidene group. The synthetic pathway was via Wittig-Horner coupling of the corresponding A-ring phosphine oxides with the protected 25-hydroxy Grundmann's ketones. Selective catalytic hydrogenation of 2-ethylidene analogues provided the 2alpha- and 2beta-ethyl compounds. The 2-ethylidene-19-nor compounds with a methyl group from the ethylidene moiety in a trans relationship to the C(6)-C(7) bond (E-isomers) were more potent than the corresponding Z-isomers and the natural hormone in binding to the vitamin D receptor. Both geometrical isomers (E and Z) of (20S)-2-ethylidene-19-norvitamin D(3) and both 2alpha-ethyl-19-norvitamins (in the 20R- and 20S-series) have much higher HL-60 differentiation activity than does 1alpha,25-(OH)(2)D(3). Both E-isomers (20R and 20S) of 2-ethylidene vitamins are characterized by very high calcemic activity in rats. The three-dimensional structure model of the rat vitamin D receptor and the computational docking of four synthesized (20R)-19-norvitamin D(3) analogues into its binding pocket are also reported.

Animals↗
PubMed2002

Inhibitory mode of 1,5-diarylpyrazole derivatives against cyclooxygenase-2 and cyclooxygenase-1: molecular docking and 3D QSAR analyses.

The Lamarckian genetic algorithm of AutoDock 3.0 has been employed to dock 40 1,5-diarylpyrazole class compounds into the active sites of cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1). The binding models were demonstrated in the aspects of inhibitor's conformation, subsite interaction, and hydrogen bonding. The data of geometrical parameters and RMSD values compared with the known inhibitor, SC-558 (43), show that these inhibitors interact respectively with COX-2 and COX-1 in a very similar way. The r(2) values of 0.648 for COX-2 and 0.752 for COX-1 indicate that the calculated binding free energies correlate well with the inhibitory activities. The structural and energetic differences in inhibitory potencies of 1,5-diarylpyrazoles were reasonably explored, and the COX-2/COX-1 selectivity was demonstrated by the three-dimensional (3D) interaction models of inhibitors complexing with these two enzymes. Using the binding conformations of 1,5-diarylpyrazoles, consistent and highly predictive 3D quantitative structure-activity relationship (QSAR) models were developed by performing comparative molecular field analyses (CoMFA) and comparative molecular similarity analyses (CoMSIA). The q(2) values are 0.635 and 0.641 for CoMFA and CoMSIA models, respectively. The predictive ability of these models was validated by SC-558 (43) and a set of 10 other compounds that were not included in the training set. Mapping these models back to the topology of the active site of COX-2 leads to a better understanding of vital diarylpyrazole compounds and COX-2 interactions. Structure-based investigations and the final 3D QSAR results provided possible guidelines and accurate activity predictions for novel inhibitor design.

Algorithms↗
PubMed2004

HierVLS hierarchical docking protocol for virtual ligand screening of large-molecule databases.

To provide practical means for rapidly scanning the extensive experimental combinatorial chemistry libraries now available for high-throughput screening (HTS), it is essential to establish computational virtual ligand screening (VLS) techniques to rapidly identify out of a large library all active compounds against a particular protein target. Toward this goal we developed HierVLS, a fast hierarchical docking approach that starts with a coarse grain conformational search over a large number of configurations filtered with a fast but crude energy function, followed by a succession of finer grain levels, using successively more accurate but more expensive descriptions of the ligand-protein-solvent interactions to filter successively fewer cases. The final step of this procedure optimizes one configuration of the ligand in the protein site using our most accurate energy expression and description of the solvent, which would be impractical for all conformations and sites sampled in the coarse level. HierVLS is based on the HierDock approach, but rather than allowing an hour or more to determine the best binding site and energy for each ligands (as in HierDock), we have adapted our procedure so that it can lead to reliable results while using only 4 min (866 MHz Pentium III processor) per ligand. To validate the accuracy for HierVLS to predict the experimentally observed binding conformation, we considered 37 cocrystal structures comprising 11 target proteins. We find that HierVLS identifies the correct binding mode for all 37 cocrystals. In addition, the calculated binding energies correlate well with available experimental binding constants. To validate how well HierVLS can identify the correct ligand in an extensive library of decoys, we considered a library of over 10 000 molecules. HierVLS identifies 26 out of the 37 cases in the top 2% ranked by binding affinity among the 10 037 molecules. The failures result from either metal-containing sites on the protein or water-mediated ligand-protein interactions, which we anticipate can be solved within the constraints of practical VLS. We then applied HierVLS to screen a 55000-compound virtual library against the target protein-tyrosine phosphatase 1B (ptp1b). The top 250 compounds by binding affinity included all six ptp1b cocrystal ligands added to the library plus three other experimentally confirmed binders. The best (top 1) binder is an experimentally confirmed positive. We conclude that HierVLS is useful for selecting leads for a particular target out of large combinatorial databases.

Carbonic Anhydrase II↗
PubMed2004

Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening.

Glide's ability to identify active compounds in a database screen is characterized by applying Glide to a diverse set of nine protein receptors. In many cases, two, or even three, protein sites are employed to probe the sensitivity of the results to the site geometry. To make the database screens as realistic as possible, the screens use sets of "druglike" decoy ligands that have been selected to be representative of what we believe is likely to be found in the compound collection of a pharmaceutical or biotechnology company. Results are presented for releases 1.8, 2.0, and 2.5 of Glide. The comparisons show that average measures for both "early" and "global" enrichment for Glide 2.5 are 3 times higher than for Glide 1.8 and more than 2 times higher than for Glide 2.0 because of better results for the least well-handled screens. This improvement in enrichment stems largely from the better balance of the more widely parametrized GlideScore 2.5 function and the inclusion of terms that penalize ligand-protein interactions that violate established principles of physical chemistry, particularly as it concerns the exposure to solvent of charged protein and ligand groups. Comparisons to results for the thymidine kinase and estrogen receptors published by Rognan and co-workers (J. Med. Chem. 2000, 43, 4759-4767) show that Glide 2.5 performs better than GOLD 1.1, FlexX 1.8, or DOCK 4.01.

Binding Sites↗
PubMed2005

A combination of docking, QM/MM methods, and MD simulation for binding affinity estimation of metalloprotein ligands.

To alleviate the problems in the receptor-based design of metalloprotein ligands due to inadequacies in the force-field description of coordination bonds, a four-tier approach was devised. Representative ligand-metalloprotein interaction energies are obtained by subsequent application of (1) docking with metal-binding-guided selection of modes, (2) optimization of the ligand-metalloprotein complex geometry by combined quantum mechanics and molecular mechanics (QM/MM) methods, (3) conformational sampling of the complex with constrained metal bonds by force-field-based molecular dynamics (MD), and (4) a single point QM/MM energy calculation for the time-averaged structures. The QM/MM interaction energies are, in a linear combination with the desolvation-characterizing changes in the solvent-accessible surface areas, correlated with experimental data. The approach was applied to structural correlation of published binding free energies of a diverse set of 28 hydroxamate inhibitors to zinc-dependent matrix metalloproteinase 9 (MMP-9). Inclusion of steps 3 and 4 significantly improved both correlation and prediction. The two descriptors explained 90% of variance in inhibition constants of all 28 inhibitors, ranging from 0.08 to 349 nM, with the average unassigned error of 0.318 log units. The structural and energetic information obtained from the time-averaged MD simulation results helped understand the differences in binding modes of related compounds.

Binding Sites↗