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At least 73 records · Page 4Linked to original sources
PubMed1998

Surface solid angle-based site points for molecular docking.

We are developing a new site descriptor for the DOCK molecular modeling program suite. Sphgen, the current site description program for the DOCK suite, describes the pockets of a macromolecule by filling a volume with intersecting spheres. DOCK then identifies possible ligand orientations in the pocket by overlapping the atoms of proposed ligands with the sphere centers. Sphgen limits use of the DOCK program to concave binding regions, but macromolecular binding regions can be solvent-exposed rather than buried pockets. We present a more general site descriptor, based on the surface solid angle, which generates site points by determining the solid angle of exposure for points on the surface of the molecule, then identifying patches of surface with similar solid angle values which are then built into site points. We find possible ligand orientations by matching shape-based site points on the ligand and protein and demanding complementary solid angle values. Orientations are evaluated using the DOCK's force field-based score, which evaluates the Coulombic and van der Waals energy. The surface solid angle descriptor displays the complementary characteristics of the interfaces of our test systems: trypsin/trypsin inhibitor, chymotrypsin/turkey ovomucoid third domain, and subtilisin/chymotrypsin inhibitor. The solid angle site points can be used by DOCK to generate orientations within 1.5 A r.m.s.d. of the crystal structure orientation.

Algorithms↗
PubMed1998

Flexible docking allowing induced fit in proteins: insights from an open to closed conformational isomers.

Here we dock a ligand onto a receptor surface allowing hinge-bending domain/substructural movements. Our approach mimics and manifests induced fit in molecular recognition. All angular rotations are allowed on the one hand, while a conformational space search is avoided on the other. Rather than dock each of the molecular parts separately with subsequent reconstruction of the consistently docked molecules, all parts are docked simultaneously while still utilizing the position of the hinge from the start. Like pliers closing on a screw, the receptor automatically closes on its ligand in the best surface-matching way. Movements are allowed either in the ligand or in the larger receptor, hence reproducing induced molecular fit. Hinge bending movements are frequently observed when molecules associate. There are numerous examples of open versus closed conformations taking place upon binding. Such movements are observed when the substrate binds to its respective enzyme. In particular, such movements are of interest in allosteric enzymes. The movements can involve entire domains, subdomains, loops, (other) secondary structure elements, or between any groups of atoms connected by flexible joints. We have implemented the hinges at points and at bonds. By allowing 3-dimensional (3-D) rotation at the hinge, several rotations about (consecutive or nearby) bonds are implicitly taken into account. Alternatively, if required, the point rotation can be restricted to bond rotation. Here we illustrate this hinge-bending docking approach and the insight into flexibility it provides on a complex of the calmodulin with its M13 ligand, positioning the hinges either in the ligand or in the larger receptor. This automated and efficient method is adapted from computer vision and robotics. It enables utilizing entire molecular surfaces rather than focusing a priori on active sites. Hence, allows attaining the overall optimally matching surfaces, the extent and type of motions which are involved. Here we do not treat the conformational flexibility of side-chains or of very small pieces of the molecules. Therefore, currently available methods addressing these issues and the method presented here, are complementary to each other, expanding the repertoire of computational docking tools foreseen to aid in studies of recognition, conformational flexibility and drug design.

Algorithms↗
PubMed1998

Flexible docking using Tabu search and an empirical estimate of binding affinity.

This article describes the implementation of a new docking approach. The method uses a Tabu search methodology to dock flexibly ligand molecules into rigid receptor structures. It uses an empirical objective function with a small number of physically based terms derived from fitting experimental binding affinities for crystallographic complexes. This means that docking energies produced by the searching algorithm provide direct estimates of the binding affinities of the ligands. The method has been tested on 50 ligand-receptor complexes for which the experimental binding affinity and binding geometry are known. All water molecules are removed from the structures and ligand molecules are minimized in vacuo before docking. The lowest energy geometry produced by the docking protocol is within 1.5 A root-mean square of the experimental binding mode for 86% of the complexes. The lowest energies produced by the docking are in fair agreement with the known free energies of binding for the ligands.

Algorithms↗
PubMed1997

Critical evaluation of the research docking program for the CASP2 challenge.

The binding positions of six small-molecule ligands in their complexes with target proteins were predicted using our Research docking program for the CASP2 challenge. Research uses a Monte Carlo procedure with pairwise energies and allows for the conformational searching of ligand torsional space. We were able to predict 2 of the 5 noncovalent complexes within 2 A root-mean-square (RMS) of the experimental structures as ranked by interaction energy or by a score calculated using our interaction evaluation program, Out-rank. In addition, for 4 of the 5 noncovalent structures we found a docking within 2 A RMS of the experimental structure within the top 20 dockings as ranked by energy. The main limitation in our approach is in the ability of the energy function and Outrank to discriminate among the lowest energy dockings. On the other hand, our success in exploring the multi-dimensional docking space of position, orientation and conformation is encouraging.

Arabinose↗
PubMed1999

Efficacy and selectivity in flexible database docking.

Flexible database docking with DOCK 4.0 has been evaluated for its ability to retrieve biologically active molecules from a database of approximately 1,000 compounds with known activities against thrombin and the progesterone receptor. The retrieval of known actives and chemically similar but inactive molecules was monitored as a function of conformational and orientational sampling. The largest enrichment of actives among the 10% highest ranking molecules is obtained when only five conformations are used to seed the next round of ligand reconstruction and limited sampling is applied to place the base fragment in the binding site. The performance of energy and chemical scoring, as implemented in DOCK 4.0, was found to depend on the protein used for docking. For the progesterone receptor, energy scoring yields the largest enrichments (64%) in terms of actives retrieved among the 10% top scoring molecules, while chemical scoring performs best for thrombin (94%). With the exception of the application of energy scoring to the progesterone receptor, both energy-based scoring schemes applied in this study do not discriminate well between true actives and chemically similar but inactive compounds. In conclusion, flexible docking is able to effectively prioritize high-throughput screening databases, using less conformational sampling than normally required for appropriate reconstruction of protein-ligand complexes. The more subtle discrimination between chemically similar classes of active and inactive compounds remains, however, problematic.

Algorithms↗
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↗
PubMed1998

Flexible ligand docking using conformational ensembles.

Molecular docking algorithms suggest possible structures for molecular complexes. They are used to model biological function and to discover potential ligands. A present challenge for docking algorithms is the treatment of molecular flexibility. Here, the rigid body program, DOCK, is modified to allow it to rapidly fit multiple conformations of ligands. Conformations of a given molecule are pre-calculated in the same frame of reference, so that each conformer shares a common rigid fragment with all other conformations. The ligand conformers are then docked together, as an ensemble, into a receptor binding site. This takes advantage of the redundancy present in differing conformers of the same molecule. The algorithm was tested using three organic ligand protein systems and two protein-protein systems. Both the bound and unbound conformations of the receptors were used. The ligand ensemble method found conformations that resembled those determined in X-ray crystal structures (RMS values typically less than 1.5 A). To test the method's usefulness for inhibitor discovery, multi-compound and multi-conformer databases were screened for compounds known to bind to dihydrofolate reductase and compounds known to bind to thymidylate synthase. In both cases, known inhibitors and substrates were identified in conformations resembling those observed experimentally. The ligand ensemble method was 100-fold faster than docking a single conformation at a time and was able to screen a database of over 34 million conformations from 117,000 molecules in one to four CPU days on a workstation.

Algorithms↗
PubMed1992

New algorithm to model protein-protein recognition based on surface complementarity. Applications to antibody-antigen docking.

A novel algorithm is presented which models protein-protein interactions using surface complementarity. The method is applied to antibody-antigen docking. A steric scoring scheme, based upon a soft potential, is used to assess complementarity, and a simple electrostatic model is then used to remove infeasible interactions. The soft potential allows for structural changes that occur during docking. Biochemical knowledge is necessary to reduce the number of docking orientations produced by the method to a manageable size. The information used includes the known epitope residues and a single loose distance constraint. The method is applied to all three crystallographically determined antibody-lysozyme complexes, HyHEL-10, D1.3 and HyHEL-5. For the first time, a predicted antibody structure (that of D1.3) is used as a docking target. In the four systems modelled, the method identifies between 15 and 40 possible docking orientations. The root-mean-square (r.m.s.) deviation between these orientations and the relevant crystallographic complex is measured in the interface region. For all four complexes an orientation is found with r.m.s. deviation in the range 1.9 A and 4.8 A. The algorithm is implemented on a single instruction/multiple datastream (SI/MD) architecture computer. The use of a parallel architecture computer ensures detailed coverage of the search space, whilst still maintaining a search time of two days.

Algorithms↗
PubMed1996

c-Jun can recruit JNK to phosphorylate dimerization partners via specific docking interactions.

Structurally related serine/threonine kinases recognize similar phosphoacceptor peptides in vitro yet in vivo, they phosphorylate distinct substrates. To understand the basis for this specificity, we studied the interaction between the Jun kinases (JNKs) and Jun proteins. JNKs phosphorylate c-Jun very efficiently, JunD less efficiently, but they do not phosphorylate JunB. Effective JNK substrates require a separate docking site and specificity-conferring residues flanking the phosphoacceptor. The docking site increases the efficiency and specificity of the phosphorylation reaction. JunB has a functional JNK docking site but lacks specificity-conferring residues. Insertion of such residues brings JunB under JNK control. JunD, by contrast, lacks a JNK docking site, but its phosphoacceptor peptide is identical to that of c-Jun. Substrates such as JunD can be phosphorylated by JNK through heterodimerization with docking competent partners. Therefore, heterodimerization can affect the recognition of transcription factors by signal-regulated protein kinases.

Amino Acid Sequence↗
PubMed1999

Molecular docking studies on interaction of diverse retinol structures with human alcohol dehydrogenases predict a broad role in retinoid ligand synthesis.

Some members of the human alcohol dehydrogenase (ADH) family possess retinol dehydrogenase activity and may thus function in production of the active nuclear receptor ligand retinoic acid. Many diverse natural forms of retinol exist including all-trans-retinol (vitamin A(1)), 9-cis-retinol, 3,4-didehydroretinol (vitamin A(2)), 4-oxo-retinol, and 4-hydroxy-retinol as well as their respective carboxylic acid derivatives which are active ligands for retinoid receptors. This raises the question of whether ADHs can accommodate all these different retinols and thus participate in the activation of several retinoid ligands. The crystal structures of human ADH1B and ADH4 provide the opportunity to examine their active sites for potential binding to many diverse retinol structures using molecular docking algorithms. The criteria used to score successful docking included achievement of distances of 1.9-2.4 A between the catalytic zinc and the hydroxyl oxygen of retinol and 3.2-3.6 A between C-4 of the coenzyme NAD and C-15 of retinol. These distances are sufficient to enable hydride transfer during the oxidation of an alcohol to an aldehyde. By these criteria, all-trans-retinol, 4-oxo-retinol, and 4-hydroxy-retinol were successfully docked to both ADH1B and ADH4. However, 9-cis-retinol and 3,4-didehydroretinol, which have more restrictive conformations, were successfully docked to only ADH4 which possesses a wider active site than ADH1B and more easily accommodates the C-19 methyl group. Furthermore, docking of all retinols was more favorable in the active site of ADH4 rather than ADH1B as measured by force field and contact scores. These findings suggest that ADH1B has a limited capacity to metabolize retinols, but that ADH4 is well suited to function in the metabolism of many diverse retinols and is predicted to participate in the synthesis of the active ligands all-trans-retinoic acid, 9-cis-retinoic acid, 3, 4-didehydroretinoic acid, 4-oxo-retinoic acid, and 4-hydroxy-retinoic acid.

Alcohol Dehydrogenase↗
PubMed1999

The SH2/SH3 adaptor protein dock interacts with the Ste20-like kinase misshapen in controlling growth cone motility.

Recent studies suggest that the SH2/SH3 adaptor Dock/Nck transduces tyrosine phosphorylation signals to the actin cytoskeleton in regulating growth cone motility. The signaling cascade linking the action of Dock/Nck to the reorganization of cytoskeleton is poorly understood. We now demonstrate that Dock interacts with the Ste20-like kinase Misshapen (Msn) in the Drosophila photoreceptor (R cell) growth cones. Loss of msn causes a failure of growth cones to stop at the target, a phenotype similar to loss of dock, whereas overexpression of msn induces pretarget growth cone termination. Physical and genetic interactions between Msn and Dock indicate a role for Msn in the Dock signaling pathway. We propose that Msn functions as a key controller of growth cone cytoskeleton in response to Dock-mediated signals.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Evaluation of docking strategies for virtual screening of compound databases: cAMP-dependent serine/threonine kinase as an example.

In an effort to establish efficient docking routines for computational screening of compound databases on protein structures, cAMP-dependent protein kinase has been selected as a test case and a variety of docking options and scoring functions were compared. These included rigid-body and flexible docking and scoring based on surface complementarity and/or force field energy. Inhibitors were removed from complex crystal structures and added to compound libraries in their binding conformations and, in addition, deliberately modified conformations. Rigid-body docking and contact scoring well reproduced two of three experimental enzyme-inhibitor complexes. Ligand docking with flexible torsional angles failed to do so but anchored search of some inhibitors converged near to experimental structures, however, only when energy scoring was applied.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1995

Thermodynamic and activation parameters for binding of a pyrene-labeled substrate by the Tetrahymena ribozyme: docking is not diffusion-controlled and is driven by a favorable entropy change.

Association and dissociation rates for the pyrene-(pyr)-labeled oligoribonucleotide substrate pyrCUCU binding to the L-21 ScaI group I ribozyme are reported as a function of temperature. Combined with thermodynamic parameters for binding of pyrCUCU to rGGAGAA, the results allow calculation of the activation and thermodynamic parameters for docking of pyrCUCU into the catalytic core of the ribozyme. The activation enthalpy for docking is 22 kcal/mol, much larger than the approximately 4 kcal/mol expected for a diffusion-controlled process. Thus, docking is not diffusion-controlled. The activation and equilibrium entropies for docking are favorable at 21 and 37 eu, respectively. The results suggest the rate-limiting step and the driving force for docking may involve desolvation of RNA functional groups or of Mg2+ ions.

Animals↗
PubMed1996

Mutations in the Tetrahymena ribozyme internal guide sequence: effects on docking of the P1 helix into the catalytic core and correlation with catalytic activity.

Binding of substrate by the ribozyme derived from the self-splicing intron of Tetrahymena thermophila involves at least two steps. In the first step, base pairing between the ribozyme internal guide sequence (IGS) and the substrate forms a helical duplex (P1). Through specific tertiary interactions between P1 and the ribozyme core, P1 is then docked into the ribozyme active site. We have investigated the effects of compensatory mutations in positions 2-6 of the P1 helix on docking of P1 into the ribozyme core. Equilibrium binding of matching oligonucleotides by catalytically active IGS mutant ribozymes was evaluated by gel-shift analysis. While the strength of base pairing changed with base composition as expected, the strength of tertiary interactions between P1 and the ribozyme core was not affected by the P1 mutations. These results support a model in which efficient docking of P1 is determined by P1 structure and the presence of a conserved G-U pair. Determination of the rate of dissociation of matching oligonucleotides from each ribozyme revealed that mutations in the IGS change the tightness of binding by increasing or decreasing the dissociation rate. Surprisingly, dissociation rates determined in this fashion were 20-900-fold less than the values of the multiple-turnover rate constant for these ribozymes, initially suggesting that turnover did not require product dissociation. A more detailed analysis for the wild-type ribozyme defined two distinct product dissociation rates. The slower rate equaled that determined under the conditions used for the equilibrium binding studies. The weighted average of the two dissociation rates equaled the multiple-turnover rate constant. These results are explained by a model in which ribozyme preparations consist of two ribozyme conformers: one with tight docking of P1 and another with weaker docking of P1.

Animals↗
PubMed2000

New approach to molecular docking and its application to virtual screening of chemical databases

This paper describes the validation of a molecular docking method and its application to virtual database screening. The code flexibly docks ligand molecules into rigid receptor structures using a tabu search methodology driven by an empirically derived function for estimating the binding affinity of a protein-ligand complex. The docking method has been tested on 70 ligand-receptor complexes for which the experimental binding affinity and binding geometry are known. The lowest energy geometry produced by the docking protocol is within 2.0 A root mean square of the experimental binding mode for 79% of the complexes. The method has been applied to the problem of virtual database screening to identify known ligands for thrombin, factor Xa, and the estrogen receptor. A database of 10,000 randomly chosen "druglike" molecules has been docked into the three receptor structures. In each case known receptor ligands were included in the study. The results showed good separation between the predicted binding affinities of the known ligand set and the database subset.

Journal Article↗
PubMed1997

Multiple automatic base selection: protein-ligand docking based on incremental construction without manual intervention.

A possible way of tackling the molecular docking problem arising in computer-aided drug design is the use of the incremental construction method. This method consists of three steps: the selection of a part of a molecule, a so-called base fragment, the placement of the base fragment into the active site of a protein, and the subsequent reconstruction of the complete drug molecule. Assuming that a part of a drug molecule is known, which is specific enough to be a good base fragment, the method is proven to be successful for a large set of docking examples. In addition, it leads to the fastest algorithms for flexible docking published so far. In most real-world applications of docking, large sets of ligands have to be tested for affinity to a given protein. Thus, manual selection of a base fragment is not practical. On the other hand, the selection of a base fragment is critical in that only few selections lead to a low-energy structure. We overcome this limitation by selecting a representative set of base fragments instead of a single one. In this paper, we present a set of rules and algorithms to automate this selection. In addition, we extend the incremental construction method to deal with multiple fragmentations of the drug molecule. Our results show that with multiple automated base selection, the quality of the docking predictions is almost as good as with one manually preselected base fragment. In addition, the set of solutions is more diverse and alternative binding modes with low scores are found. Although the run time of the overall algorithm increases, the method remains fast enough to search through large ligand data sets.

Automation↗
PubMed1999

MCDOCK: a Monte Carlo simulation approach to the molecular docking problem.

Prediction of the binding mode of a ligand (a drug molecule) to its macromolecular receptor, or molecular docking, is an important problem in rational drug design. We have developed a new docking method in which a non-conventional Monte Carlo (MC) simulation technique is employed. A computer program, MCDOCK, was developed to carry out the molecular docking operation automatically. The current version of the MCDOCK program (version 1.0) allows for the full flexibility of ligands in the docking calculations. The scoring function used in MCDOCK is the sum of the interaction energy between the ligand and its receptor, and the conformational energy of the ligand. To validate the MCDOCK method, 19 small ligands, the binding modes of which had been determined experimentally using X-ray diffraction, were docked into their receptor binding sites. To produce statistically significant results, 20 MCDOCK runs were performed for each protein-ligand complex. It was found that a significant percentage of these MCDOCK runs converge to the experimentally observed binding mode. The root-mean-square (rms) of all non-hydrogen atoms of the ligand between the predicted and experimental binding modes ranges from 0.25 to 1.84 A for these 19 cases. The computational time for each run on an SGI Indigo2/R10000 varies from less than 1 min to 15 min, depending upon the size and the flexibility of the ligands. Thus MCDOCK may be used to predict the precise binding mode of ligands in lead optimization and to discover novel lead compounds through structure-based database searching.

Binding Sites↗
PubMed1999

DREAM++: flexible docking program for virtual combinatorial libraries.

We present a set of programs, DREAM+2 (Docking and Reaction programs using Efficient seArch Methods written in C++), for docking computationally generated ligands into macromolecular binding sites. DREAM++ is composed of three programs: ORIENT++, REACT++ and SEARCH++. The program ORIENT++ positions molecules in a binding site with the DOCK algorithm. Its output can be used as input to REACT++ and SEARCH+2. The program REACT++ performs user-specific chemical reactions on a docked molecule, so that reaction products can be evaluated for three dimensional complementarity with the macromolecular site. The program SEARCH++ performs an efficient conformation search on the reaction products using a hybrid backtrack and incremental construction algorithm. We have applied the programs to HIV protease-inhibitor complexes as test systems. We found that we can differentiate high-affinity ligands based on several measures: interaction energies, occupancy of protein subsites and the number of successfully docked conformations for each product. Encouraged by the results in the test case, we applied the programs to propose novel inhibitors of HIV protease. These inhibitors can be generated by organic reactions using commercially available reagents. They are alternatives to the inhibitors synthesized by Glaxo.

Algorithms↗