Showing papers on "Docking (molecular) published in 1994"

Flexibases: a way to enhance the use of molecular docking methods.

Abstract: Specially expanded databases containing three-dimensional structures are created to enhance the utility of docking methods to find new leads, i.e., active compounds of pharmacological interest. The expansion is based on the automatic generation of a set of maximally dissimilar conformations. The ligand receptor system of methotrexate and dihydrofolate reductase is used to demonstrate the feasibility of creating flexibases and their utility in docking studies.

Prediction of the binding sites of huperzine A in acetylcholinesterase by docking studies

Abstract: We have performed docking studies with the SYSDOC program on acetylcholinesterase (AChE) to predict the binding sites in AChE of huperzine A (HA), which is a potent and selective, reversible inhibitor of AChE. The unique aspects of our docking studies include the following: (i) Molecular flexibility of the guest and the host is taken into account, which permits both to change their conformations upon binding. (ii) The binding energy is evaluated by a sum of energies of steric, electrostatic and hydrogen bonding interactions. In the energy calculation no grid approximation is used, and all hydrogen atoms of the system are treated explicitly. (iii) The energy of cation-π interactions between the guest and the host, which is important in the binding of AChE, is included in the calculated binding energy. (iv) Docking is performed in all regions of the host's binding cavity. Based on our docking studies and the pharmacological results reported for HA and its analogs, we predict that HA binds to the bottom of the binding cavity of AChE (the gorge) with its ammonium group interacting with Trp84, Phe330, Glu199 and Asp72 (catalytic site). At the the opening of the gorge with its ammonium group partially interacting with Trp279 (peripheral site). At the catalytic site, three partially overlapping subsites of HA were identified which might provide a dynamic view of binding of HA to the catalytic site.

A Novel Nonpeptide HIV-1 Protease Inhibitor: Elucidation of the Binding Mode and Its Application in the Design of Related Analogs

Abstract: HIV-1 protease has been identified as a significant target enzyme in AIDS research. While numerous peptide-derived inhibitors have been described, the identification of a nonpeptide inhibitor remains an important goal. Using an HIV-1 protease mass screening technique, 4-hydroxy-3-(3-phenoxypropyl)-2H-1-benzopyran-2-one (1) was identified as a nonpeptide competitive inhibitor of the enzyme. Employing a Monte Carlo-based docking procedure, the coumarin was docked in the active site of the enzyme, revealing a binding mode that was later confirmed by the X-ray crystal analysis. Several analogs were prepared to test the binding interactions and improve the overall binding affinity. The most active compound in the study was 4,7-dihydroxy-3-[4-(2-methoxyphenyl)butyl]-2H-1-benzopyran-2-one (31).

A proposed model of bradykinin bound to the rat B2 receptor and its utility for drug design.

Abstract: A putative model of bradykinin bound to the rat B2 receptor was generated using a combination of homology modeling (from the known transmembrane structure of bacteriorhodopsin), energy minimization, molecular dynamics, and a two-stage conformational search as a docking simulation. Overall, the proposed bound ligand adopts a twisted "S" shape, wherein a C-terminal beta-turn is buried in the receptor just below the extracellular boundary of the cell membrane and the N-terminus is interacting with negatively charged residues in extracellular loop 3 of the receptor (most notably Asp268 and Asp286). Mutagenesis experiments describing mutations which result in both a loss of bradykinin affinity as well as those which have no effect on bradykinin affinity are in good agreement with the proposed structure. In short, the mutagenesis results and the computational simulations each point to the same region of the receptor as likely to bind bradykinin. A double mutation, predicted as being likely to have a dramatic effect on bradykinin binding affinity, was confirmed experimentally, adding some validation to the proposed complex. Moreover, a new pseudopeptide bradykinin receptor antagonist (D-Arg0-Arg1-[12-aminododecanoyl]2- Ser3-D-Tic4-Oic5-Arg6) was designed on the basis of the model, and found to have good receptor affinity. Speculation regarding other possible sites for mutagenesis are also described.

A genetic algorithm based method for docking flexible molecules

Abstract: We describe a computational method for docking flexible molecules into protein binding sites. The method uses a genetic algorithm (GA) to search the combined conformation/orientation space of the molecule to find low energy conformations. Several techniques are described that increase the efficiency of the basic search method. These include the use of several interacting GA subpopulations or niches; the use of a “growing” algorithm that initially docks only a small part of the molecule, and the use of gradient minimization during the search. To illustrate the method, we dock Cbz-GlyP-Leu-Leu (ZGLL) into thermolysin. This system was chosen because a well refined crystal structure is available and because another docking method had previously been tested on this system. Our method is able to find conformations that lie physically close to and in some cases lower in energy than the crystal conformation in reasonable periods of time on readily available hardware.

A shape- and chemistry-based docking method and its use in the design of HIV-1 protease inhibitors

Abstract: The program DOCK [1,2] has been used successfully to identify molecules which will bind to a specified receptor [3]. The original method ranks molecules based on their shape complementarity to the receptor site and relies on the chemist to bring the appropriate electrostatic or hydrogen bond properties into the molecular skeletons obtained in the search. This is useful when screening a small database of compounds, where it is not likely that molecules with both the correct shape and electrostatic properties will be found. As large databases are more likely to have redundant molecular shapes with a variety of functionality (e.g., members of a congeneric series), it would be useful to have a method which identifies molecules with both the correct shape and functionality. To this end we have modified the DOCK 1.0 method to target user-specified atom types to selected positions in the receptor site. The target sites can be chosen based on structural evidence, calculation or inspection. Targeted-DOCK improves the ability of the DOCK method to find the crystallographically determined binding mode of a ligand. Additionally, targeted-DOCK searches a database of small molecules at 100–1000 times the rate of DOCK 1.0, allowing more molecules to be screened and more sophisticated scoring schemes to be employed. Targeted-DOCK has been used successfully in the design of a novel non-peptide inhibitor of HIV-1 protease.

Prediction of the binding site of 1-benzyl-4-[(5,6-dimethoxy-1-indanon-2-yl)methyl]piperidine in acetylcholinesterase by docking studies with the SYSDOC program

Abstract: In the preceding paper we reported on a docking study with the SYSDOC program for predicting the binding sites of huperzine A in acetylcholinesterase (AChE) [Pang, Y.-P. and Kozikowski, A.P., J. Comput.-Aided Mol. Design, 8 (1994) 669]. Here we present a prediction of the binding sites of 1-benzyl-4-[(5,6-dimethoxy-1-indanon-2-yl)methyl]piperidine (E2020) in AChE by the same method. E2020 is one of the most potent and selective reversible inhibitors of AChE, and this molecule has puzzled researchers, partly due to its flexible structure, in understanding how it binds to AChE. Based on the results of docking 1320 different conformers of E2020 into 69 different conformers of AChE and on the pharmacological data reported for E2020 and its analogs, we predict that both the R- and the S-isomer of E2020 span the whole binding cavity of AChE, with the ammonium group interacting mainly with Trp84, Phe330 and Asp72, the phenyl group interacting mainly with Trp84 and Phe330, and the indanone moiety interacting mainly with Tyr70 and Trp279. The topography of the calculated E2020 binding sites provides insights into understanding the high potency of E2020 in the inhibition of AChE and provides hints as to possible structural modifications for identifying improved AChE inhibitors as potential therapeutics for the palliative treatment of Alzheimer's disease.

Predicting molecular interactions and inducible complementarity: Fragment docking of fab‐peptide complexes

Abstract: Antibody-antigen interactions are representative of a broad class of receptor-ligand interactions involving both specificity and potential inducible complementarity. To test possible mechanisms of antigenantibody recognition and specificity computationally, we have used a Metropolis Monte Carlo algorithm to dock fragments of the epitope Glu-Val-Val-Pro-His-Lys-Lys to the X-ray structures of both the free and the complexed Fab of the antibody B13I2 (raised against the C-helix of myohemerythri). The fragments Pro-His and Val-Pro-His, which contain residues experimentally identified as important for binding, docked correctly to both structures, but all tetrapeptide and larger fragments docked correctly only to the complexed Fab, even when torsional flexibility was added to the ligand. However, only tetrapeptide and larger fragments showed significantly more favorable energies when docked to the complexed Fab coordinates than when docked to either the free Fab or a non-specific site remote from the combining site. Comparison of the free and complexed B13I2 structures revealed that atoms within 5 A of Val-Pro-His showed little movement upon peptide binding, but atoms within 5 A of the other four epitope residues showed greater movements. These results computationally distinguish recognition and binding processes with practical implications for drug design strategies. Overall, this new fragment docking approach establishes distinct roles for the “lock-and-key” (recognition) and the “handshake” (binding) paradigms in antibody-antigen interaction, suggests an incremental approach to incorporating flexibility in computational docking, and identifies critical regions within receptor binding sites for ligand recognition. © 1994 Wiley-Liss, Inc.

GREEN: A program package for docking studies in rational drug design

Abstract: A program package, GREEN, has been developed that enables docking studies between ligand molecules and a protein molecule. Based on the structure of the protein molecule, the physical and chemical environment of the ligand-binding site is expressed as three-dimensional grid-point data. The grid-point data are used for the real-time evaluation of the protein-ligand interaction energy, as well as for the graphical representation of the binding-site environment. The interactive docking operation is facilitated by various built-in functions, such as energy minimization, energy contribution analysis and logging of the manipulation trajectory. Interactive modeling functions are incorporated for designing new ligand molecules while considering the binding-site environment and the protein-ligand interaction. As an example of the application of GREEN, a docking study is presented on the complex between trypsin and a synthetic trypsin inhibitor. The program package will be useful for rational drug design, based on the 3D structure of the target protein.

An energy-minimized casein submicelle working model.

Abstract: To develop a molecular basis for structure-function relationships of the complex milk protein system, an energy-minimized, three-dimensional model of a casein submicelle was constructed consisting of kappa-casein, four alpha s1-casein, and four beta-casein molecules. The models for the individual caseins were from previously reported energy-minimized, three-dimensional structures. Docking of one kappa-casein and four alpha s1-casein molecules produced a framework structure through the interaction of two hydrophobic antiparallel sheets of kappa-casein with two small hydrophobic antiparallel sheets (residue 163-174) of two preformed alpha s1-casein dimers. The resulting structure is approximately spherically symmetric, with a loose packing density; its external portion is composed of the hydrophilic domains of the four alpha s1-caseins, while the central portion contains two hydrophbic cavities on either side of the kappa-casein central structure. Symmetric and asymmetric preformed dimers of beta-casein formed from the interactions of C-terminal beta-spiral regions as a hinge point could easily be docked into each of the two central cavities of the alpha-kappa framework. This yielded two plausible energy-minimized, three-dimensional structures for submicellar casein, one with two symmetric beta-casein dimers and one with two asymmetric dimers. These refined submicellar structures are in good agreement with biochemical, chemical, and solution structural information available for submicellar casein.

Rigid‐body docking with mutant constraints of influenza hemagglutinin with antibody HC19

Abstract: An automatic docking algorithm has been applied to the modeling of the complex between hemagglutinin from influenza virus and the Fab fragment of a monoclonal antibody raised against this antigen. We have introduced here the use of biochemical information provided by mutants of hemagglutinin. The docking procedure finds a small number of candidate solutions where three sites of escape mutations are buried and form hydrogen bonds in the interface. The localization of the epitope is improved by additional biochemical data about mutants that do not affect antibody binding. Five candidate solutions with low energy, reasonably well-packed interfaces, and six to ten hydrogen bonds are compatible with mutant information. One of the five stands out as generally better than the others from these points of views.

Docking analysis of a series of benzylamino acetylcholinesterase inhibitors with a phthalimide, benzoyl, or indanone moiety.

Abstract: The enzyme-binding mode of a series of acetylcholinesterase inhibitors has been analyzed on the basis of the crystal structure of the Torpedo enzyme using docking programs DOCK and directed-DOCK. The inhibitors have a benzyl group connected to tertiary ammonium nitrogen at one end and a phthalimide, benzoyl, or indanone moiety at the other. Our modeling results have indicated that the benzyl group interacts with Trp 84, which is located near the bottom of the binding pocket and is postulated to be the quaternary ammonium binding site for acetylcholine. The other aromatic ring has been found to interact with Trp 279 at the peripheral hydrophobic site. In addition, the hydrogen-bonding interaction between a carbonyl group of the inhibitor and Tyr 121 OH seems to play an important role. Our active-orientation model is, at least qualitatively, consistent with structure-activity data for more than 50 compounds and should be useful for the design of more potent inhibitors.

A model of the serotonin 5-HT1A receptor: agonist and antagonist binding sites.

Abstract: We built a model for the 5-HT1A receptor, using the 3D-structure of bacteriorhodopsin as a structural template. With the use of site-directed mutagenesis data, several potent 5-HT1A agonists, belonging to five different structural classes, and an aryloxypropanolamine antagonist, were docked into the receptor model. After docking, the surrounding of the ligands appeared to be in full agreement with previously reported SAR-data of 5-HT1A ligands. In this study, for the first time, an explanation for 5-HT SAR results is given in terms of interactions between ligands and amino acid residues. Also the selectivity of 8-OH-DPAT for the 5-HT1A receptor is accounted for. In our model the agonists and the antagonist interact with different residues on several helices. They all interact with the essential aspartic acid on helix III, that is known to bind all amines to receptors for biogenic amines. This partial overlap of the binding sites accounts for the antagonism of the class of aryloxypropanolamines and for the deviating SAR of this class of compounds when compared to agonists.

Molecular modeling of the interaction of polyproline-based peptides with the Abl-SH3 domain: rational modification of the interaction

Abstract: A molecular model of the interaction of polyproline-rich peptides with the Abl-SH3 domain is proposed, based on docking calculations with the DOCK program coupled with molecular dynamics simulations. Two distinct binding modes of the peptide to the same aromatic-rich region (Tyr10, Phe12, Trp39, Trp50, Tyr55) of the domain were obtained. It is proposed that these two models could represent different binding modes of proline-rich peptides to Src homology region 3 domains. Several peptide mutants were designed to determine whether the two orientations were possible. Analysis of the Kd values and fluorescence emission of these peptides indicate that one of the orientations is more plausible and that residues at position 4 of the peptide interact with the RT loop, being important in modulating the peptide affinity for the Abl-SH3 domain.

Bioreactor compositions with enhanced cell binding

Abstract: Compositions of the invention include packing materials having compounds thereon with enhanced cell binding with respect to collagen. These packing materials are useful for in vitro uses such as for cell culture in bioreactors. Suitable compounds with enhanced cell binding include synthetic peptides that mimic the conformation necessary for recognition and docking of collagen binding species (such as cell surface receptors for collagen and fibronectin) and have the amino acid residues -Ile-Ala- folded in a β-bend.

Molecular Docking: A Tool for Ligand Discovery and Design

Abstract: The ability to propose reasonable ligand-receptor binding geometries is crucial to the success of structure-based drug design. One approach is to “dock” molecules together in many ways and then “score” or evaluate each orientation; in a database of compounds, those which score well should be more likely to bind to the target macromolecule. A method that combines a rapid, geometric docking algorithm with the evaluation of molecular mechanics interaction energies is presented. The “force field score” is successful in identifying the experimental binding mode in four systems, and represents an improvement over the other scoring methods tested. The degree of orientational sampling required to reproduce and identify the known geometries, with and without energy-minimization, is also investigated. Both scoring and sampling issues are of paramount importance to the usefulness of molecular docking in real-life applications.

A comparison of GA and RSNR docking

Abstract: Molecular docking calculations with genetic algorithms (GA) are compared with results calculated by a numeric random sampling Newton-Raphson (RSNR) method. The intermolecular interaction energy minimum is searched for using both a genetic algorithm approach and a numeric one for the docking process. Intermolecular interactions of a larger molecular complex of an anticancer drug have been investigated. The performance of GAs on molecular docking calculations is discussed and compared with the numerical method. The results of implementation indicate that the GA approach is superior to conventional methods used in energy minimization when there exist many local minima as well as a global minimum. The GA method, which is computationally more practical for applications to large biological systems, provides a rational approach to drug discovery and novel molecular structure design. >

Conformation Analysis of Sialyl LeX by Molecular Mechanics

Abstract: The conformation of a tetrasaccharide Sialyl LeX was investigated by molecular mechanics calculations. The initial models were constructed by docking X-ray structures of the component monosaccharides through glycosidic bonds and they were optimized by molecular mechanics. Two different docking modes were applied. It was shown that the docking mode influence the resultant stable conformations significantly, but the most stable conformation was independent of the mode.