Showing papers on "Docking (molecular) published in 1998"
TL;DR: A new docking approach using a Tabu search methodology to dock flexibly ligand molecules into rigid receptor structures using an empirical objective function with a small number of physically based terms derived from fitting experimental binding affinities for crystallographic complexes.
Abstract: 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.
371 citations
TL;DR: 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.
Abstract: 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.
264 citations
TL;DR: It is shown that simple modification of fullerenes can result in high-affinity ligands of the HIV protease, for which they are highly complementary in structure and chemical nature.
Abstract: We have developed and applied a computational strategy to increase the affinity of fullerene-based inhibitors of the HIV protease. The result is a approximately 50-fold increase in affinity from previously tested fullerene compounds. The strategy is based on the design of derivatives which may potentially increase hydrophobic desolvation upon complex formation, followed by the docking of the hypothetical derivatives into the HIV protease active site and assessment of the model complexes so formed. The model complexes are generated by the program DOCK and then analyzed for desolvated hydrophobic surface. The amount of hydrophobic surface desolvated was compared with a previously tested compound, and if this amount was significantly greater, it was selected as a target. Using this approach, two targets were identified and synthesized, using two different synthetic approaches: a diphenyl C60 alcohol (5) based on a cyclopropyl derivative of Bingel (Chem.Ber. 1993, 126, 1957-1959) and a diisopropyl cyclohexyl C60 alcohol (4a) as synthesized by Ganapathi et al. (J. Org.Chem. 1995, 60, 2954-2955). Both showed tighter binding than the originally tested compound (diphenethylaminosuccinate methano-C60, Ki = 5 microM) with Ki values of 103 and 150 nM, respectively. In addition to demonstrating the utility of this approach, it shows that simple modification of fullerenes can result in high-affinity ligands of the HIV protease, for which they are highly complementary in structure and chemical nature.
174 citations
TL;DR: It is demonstrated directly that mutations and modifications which inhibit a step following substrate binding are not necessarily involved in catalysis, including specific structural transitions of the catalytic cycle.
Abstract: The complex formed by the hairpin ribozyme and its substrate consists of two independently folding domains which interact to form a catalytic structure. Fluorescence resonance energy transfer methods permit us to study reversible transitions of the complex between open and closed forms. Results indicate that docking of the domains is required for both the cleavage and ligation reactions. Docking is rate-limiting for ligation (2 min-1) but not for cleavage, where docking (0.5 min-1) precedes a rate-limiting conformational transition or slow-reaction chemistry. Strikingly, most modifications to the RNA (such as a G+1A mutation in the substrate) or reaction conditions (such as omission of divalent metal ion cofactors) which inhibit catalysis do so by preventing docking. This demonstrates directly that mutations and modifications which inhibit a step following substrate binding are not necessarily involved in catalysis. An improved kinetic description of the catalytic cycle is derived, including specific structural transitions.
163 citations
TL;DR: The solution structure of the tumor suppressor p16INK4A has been determined by NMR, and important recognition regions of both cdk4 and p16ink4A have been identified.
133 citations
TL;DR: The three key challenges addressed in the development of SPECITOPE, a tool for screening large structural databases for potential ligands to a protein, are to eliminate infeasible candidates early in the search, incorporate ligand and protein side‐chain flexibility upon docking, and provide an appropriate rank for potential new ligands.
Abstract: The three key challenges addressed in our development of SPECITOPE, a tool for screening large structural databases for potential ligands to a protein, are to eliminate infeasible candidates early in the search, incorporate ligand and protein side-chain flexibility upon docking, and provide an appropriate rank for potential new ligands. The protein ligand-binding site is modeled by a shell of surface atoms and by hydrogen-bonding template points for the ligand to match, conferring specificity to the interaction. SPECITOPE combinatorially matches all hydrogen-bond donors and acceptors of the screened molecules to the template points. By eliminating molecules that cannot match distance or hydrogen-bond constraints, the transformation of potential docking candidates into the ligand-binding site and the shape and hydrophobic complementarity evaluations are only required for a small subset of the database. SPECITOPE screens 140,000 peptide fragments in about an hour and has identified and docked known inhibitors and potential new ligands to the free structures of four distinct targets: a serine protease, a DNA repair enzyme, an aspartic proteinase, and a glycosyltransferase. For all four, protein side-chain rotations were critical for successful docking, emphasizing the importance of inducible complementarity for accurately modeling ligand interactions. SPECITOPE has a range of potential applications for understanding and engineering protein recognition, from inhibitor and linker design to protein docking and macromolecular assembly.
120 citations
TL;DR: It is shown that the method is very accurate and can model induced fit in the ligand and the binding site and that any attempt to model binding must take protein rearrangements into account.
Abstract: A novel procedure for docking ligands in a flexible binding site is presented. It relies on conjugate gradient minimization, during which nonbonded interactions are gradually switched on. Short Monte Carlo minimization runs are performed on the most promising candidates. Solvation is implicitly taken into account in the evaluation of structures with a continuum model. It is shown that the method is very accurate and can model induced fit in the ligand and the binding site. The docking procedure has been successfully applied to three systems. The first two are the binding of progesterone and 5b-androstane-3,17-dione to the antigen binding fragment of a steroid binding antibody. A comparison of the crystal structures of the free and the two complexed forms reveals that any attempt to model binding must take protein rearrangements into account. Furthermore, the two ligands bind in two different orientations, posing an additional challenge. The third test case is the docking of a . N- 2-naphthyl-sulfonyl-glycyl -D-para-amidino-phenyl-alanyl-piperidine .NAPAP to human a-thrombin. In contrast to steroids, NAPAP is a very flexible ligand, and no information of its conformation in the binding site is used. All docking calculations are started from X-ray conformations of proteins with the uncomplexed binding site. For all three systems the best minima in terms of free energy have a root mean square deviation from the X-ray structure ˚ smaller than 1.5 A for the ligand atoms. Q 1998 John Wiley & Sons, Inc. J Comput Chem 19 :2 1 )37, 1998
120 citations
TL;DR: The result of two blind trials of protein docking are encouraging--for complexes that are not too large and do not undergo sizeable conformational change upon association, the algorithms are now able to suggest reasonably accurate models.
118 citations
TL;DR: An extensive characterization of the stable dimerization domain at the N terminus of RIalpha was carried out, showing striking similarities yet subtle differences not only in their secondary structure but also in the distribution of residues important for both docking andDimerization functions.
113 citations
TL;DR: The models presented here are consistent with the SAR seen for the inhibition of a number of isolated enzymes and provide a structural basis to explain their specificity and have been used successfully to design new highly potent protein kinase inhibitors.
Abstract: Previously, our laboratories have reported on a new class of highly potent tyrosine kinase inhibitors based on the pyrido[2,3-d]pyrimidine core template. To understand the structural basis for the potency and specificity, a model for the binding mode of this class of inhibitors to the tyrosine kinase domains of c-Src, PDGFr, FGFr, and EGFr tyrosine kinases was developed from structural information (principally utilizing the catalytic domain of c-AMP-dependent protein kinase as template) and structure−activity relationship (SAR) information. In the resulting docking mode, the pyrido[2,3-d]pyrimidine template shows a hydrogen-bonding pattern identical to that of olomoucine. The 6-aryl substituent of the heterocycle is located deep in the binding cleft in a pocket not used by ATP, which helps to confer high-affinity binding as well as specificity. The 2-anilino and 2-(dialkylamino)alkylamino substituents as well as the 7-urea substituent of inhibitors within this class are located at the entrance of the bind...
110 citations
TL;DR: Results define the consensus sequence XXPXKPX which is recognized by the CasSH3 domain, which shows structural characteristics of a docking molecule and may serve to bring C3G to specific compartments within the cell.
TL;DR: A series of novel phenethylthiazolylthiourea (PETT) derivatives targeting the nonnucleoside inhibitor (NNI) binding site of HIV reverse transcriptase (RT) have been designed based on the structure of the NNI binding pocket and showed potent anti-HIV activity.
TL;DR: Distortion of the IRE helix by the internal loop/bulge near a conserved unpaired C required for IRP binding and adjacent to an IRP cross-linking site suggests a role for the pocket in ferritin IRE/IRP interactions.
Abstract: The ferritin IRE, a highly conserved (96−99% in vertebrates) mRNA translation regulatory element in animal mRNA, was studied by molecular modeling (using MC-SYM and DOCKING) and by NMR spectroscopy...
TL;DR: Results indicate that the membrane-docking surface of the C2 domain is localized to the same surface that cooperatively binds a pair of Ca2+ ions, and that the three Ca2-binding loops themselves provide most or all of the membrane contacts.
Abstract: Docking of C2 domains to target membranes is initiated by the binding of multiple Ca2+ ions to a conserved array of residues imbedded within three otherwise variable Ca2+-binding loops. We have loc...
TL;DR: A computational approach for predicting structures of ligand‐protein complexes and analyzing binding energy landscapes that combines Monte Carlo simulated annealing technique to determine the ligand bound conformation with the dead‐end elimination algorithm for side‐chain optimization of the protein active site residues is presented.
Abstract: We present a computational approach for predicting structures of ligand-protein complexes and analyzing binding energy landscapes that combines Monte Carlo simulated annealing technique to determine the ligand bound conformation with the dead-end elimination algorithm for side-chain optimization of the protein active site residues Flexible ligand docking and optimization of mobile protein side-chains have been performed to predict structural effects in the V32I/I47V/V82I HIV-1 protease mutant bound with the SB203386 ligand and in the V82A HIV-1 protease mutant bound with the A77003 ligand The computational structure predictions are consistent with the crystal structures of these ligand-protein complexes The emerging relationships between ligand docking and side-chain optimization of the active site residues are rationalized based on the analysis of the ligand-protein binding energy landscape
TL;DR: The molecular models generated from the CYP102 crystal structure template are consistent with experimental information from site-directed mutagenesis studies, steroidal substrate specificity and active site inhibitor studies, and point to potential determinants of substrate specificity within these related enzymes.
01 Jan 1998
TL;DR: This article examines some aspects related to conformational energy modeling and reviews a variety of global optimization approaches developed for the protein folding and peptide docking problems.
Abstract: The recent advances in genetic engineering, high powered computing and global optimization continue to stimulate interest in the area of molecular modeling and protein structure prediction. The goal of these eeorts is the ability to correctly predict native protein conformations and the binding interactions of macromolecules. These two problems currently dominate the eld of computational chemistry and, through the use of detailed molecular models, they have also greatly innuenced research in the area of global optimization. This article examines some aspects related to conformational energy modeling and reviews a variety of global optimization approaches developed for the protein folding and peptide docking problems.
TL;DR: An algorithm developed to handle biomolecular structural recognition problems, based on an extension and generalization of the Hough transform and the Geometric Hashing paradigms for rigid object recognition, which allows hinge induced motions to exist in either the receptor or the ligand molecules of diverse sizes.
Abstract: In this work, we present an algorithm developed to handle biomolecular structural recognition problems, as part of an interdisciplinary research endeavor of the Computer Vision and Molecular Biology fields. A key problem in rational drug design and in biomolecular structural recognition is the generation of binding modes between two molecules, also known as molecular docking. Geometrical fitness is a necessary condition for molecular interaction. Hence, docking a ligand (e.g., a drug molecule or a protein molecule), to a protein receptor (e.g., enzyme), involves recognition of molecular surfaces. Conformational transitions by "hinge-bending" involves rotational movements of relatively rigid parts with respect to each other. The generation of docked binding modes between two associating molecules depends on their three dimensional structures (3-D) and their conformational flexibility. In comparison to the particular case of rigid-body docking, the computational difficulty grows considerably when t...
TL;DR: A computationally efficient scheme that uses filter functions that are applied to all docked conformations to remove structures with certain energetically unfavorable properties and significantly improves the accuracy of the structure predictions.
Abstract: Current docking methods can generate bound conformations of a ligand close to the experimentally observed structure of a protein–ligand complex. However, the scoring functions used to evaluate the potential solutions are not yet reliable enough at giving the highest ranks to the best structure predictions. One approach to this problem is the use of filter functions that are applied to all docked conformations to remove structures with certain energetically unfavorable properties. We present a computationally efficient scheme for such a postprocessing of docking results. For each of the conformations generated for a given protein–ligand complex, four properties are calculated: the fraction of the ligand volume buried inside the binding pocket, the size of lipophilic cavities along the protein–ligand interface, the solvent-accessible surface (SAS) of nonpolar parts of the ligand, and the number of close contacts between non-hydrogen-bonded polar atoms of the ligand and the protein. These four terms were used to filter out the majority of the calculated solutions and to rescore the remaining ones. On a test set of 32 protein–ligand complexes, this protocol significantly improves the accuracy of the structure predictions.
TL;DR: A new method for the fully automated and rapid flexible docking of inhibitors covalently bound to serine proteases is described, which combines an energy function specifically tuned for molecular docking and an evolutionary programming search engine and takes advantage of the constained geometry about the site of covalent attachment to dramatically limit the search space and increase search efficiency.
Abstract: Viral serine proteases have become increasingly attractive targets for rational drug design. Many known inhibitors of serine proteases form a covalent bond to the activated serine oxygen, an interaction not taken into account by available docking software used for database mining. We describe a new method for the fully automated and rapid flexible docking of inhibitors covalently bound to serine proteases. The method combines an energy function specifically tuned for molecular docking and an evolutionary programming search engine, and takes advantage of the constained geometry about the site of covalent attachment to dramatically limit the search space and increase search efficiency. Results for several test systems are presented, including a database search which yielded a known inhibitor as a highranking compound.
Journal Article•
TL;DR: Developments in computer-aided drug design are automated approaches for the flexible alignment of molecules, the flexible docking of ligands to their binding sites, and the stepwise assembly of synthetically easily accessible ligands from combinatorial libraries of fragments.
Abstract: The increasing number of protein 3D structures and the success of structure-based approaches has led to the development of several experimental and theoretical techniques for the rational design of protein ligands. Combinatorial chemistry significantly speeds up the synthesis of potential new drug candidates. Diversity considerations, as well as the use of 3D structural information of the biological targets, reduce the size of huge libraries to a reasonable number of rationally-designed ligands. New NMR techniques (SAR by NMR) allow the construction of high-affinity ligands from small molecules with much lower affinities. Computer-aided drug design uses building, linking, and/or rigid docking procedures to search for ligands for a certain binding site. Scoring functions provide a rank order of the designed ligands according to their estimated binding affinities. Further developments in computer-aided drug design are automated approaches for the flexible alignment of molecules, the flexible docking of ligands to their binding sites, and the stepwise assembly of synthetically easily accessible ligands from combinatorial libraries of fragments.
TL;DR: A computer program (SANDOCK) has been developed for the automated docking of small ligands to a target protein and has been used to successfully identify novel ligands.
TL;DR: The complex structure of glucose oxidase (GOX) with the substrate glucose was determined using a docking algorithm and subsequent molecular dynamics simulations and indicate that the redox reaction of GOX differs from the corresponding reaction of free flavins as a consequence of the protein environment.
Abstract: The complex structure of glucose oxidase (GOX) with the substrate glucose was determined using a docking algorithm and subsequent molecular dynamics simulations. Semiempirical quantum chemical calculations were used to investigate the role of the enzyme and FAD co-enzyme in the catalytic oxidation of glucose. On the basis of a small active site model, substrate binding residues were determined and heats of formation were computed for the enzyme substrate complex and different potential products of the reductive half reaction. The influence of the protein environment on the active site model was estimated with a point charge model using a mixed QM/MM method. Solvent effects were estimated with a continuum model. Possible modes of action are presented in relation to experimental data and discussed with respect to related enzymes. The calculations indicate that the redox reaction of GOX differs from the corresponding reaction of free flavins as a consequence of the protein environment. One of the active site histidines is involved in substrate binding and stabilization of potential intermediates, whereas the second histidine is a proton acceptor. The former one, being conserved in a series of oxidoreductases, is also involved in the stabilization of a C4a-hydroperoxy dihydroflavin in the course of the oxidative half reaction.
TL;DR: This report elucidates the binding site of a nucleotide inhibitor of HIV-1 integrase, and possibly a component of the enzyme polynucleotide binding site.
Abstract: HIV-1 integrase is essential for viral replication and can be inhibited by antiviral nucleotides. Photoaffinity labeling with the 3′-azido-3′-deoxythymidine (AZT) analog 3′,5-diazido-2′,3′-dideoxyuridine 5′-monophosphate (5N3-AZTMP) and proteolytic mapping identified the amino acid 153–167 region of integrase as the site of photocrosslinking. Docking of 5N3-AZTMP revealed the possibility for strong hydrogen bonds between the inhibitor and lysines 156, 159, and 160 of the enzyme. Mutation of these residues reduced photocrosslinking selectively. This report elucidates the binding site of a nucleotide inhibitor of HIV-1 integrase, and possibly a component of the enzyme polynucleotide binding site.
Journal Article•
TL;DR: Three-dimensional homology models of cytochromes P450 (P450) 2B1 and P450 3A4 have been utilized along with site-directed mutagenesis to elucidate the molecular determinants of substrate specificity and suggest that the substrate and effector bind at adjacent sites within a single large cavity in P4503A4.
Abstract: Three-dimensional homology models of cytochromes P450 (P450) 2B1 and P450 3A4 have been utilized along with site-directed mutagenesis to elucidate the molecular determinants of substrate specificity. Most of the key residues identified in 2B enzymes fall within five substrate recognition sites (SRSs) and have counterparts in bacterial P450 residues that regulate substrate binding or access. Docking of inhibitors into 2B models has provided a plausible explanation for changes in susceptibility to mechanism-based inactivation that accompany particular amino acid side-chain replacements. These studies provide a basis for predicting drug interactions due to P450 inhibition and for rational inhibitor design. In addition, the location of P450 3A4 residues capable of influencing homotropic stimulation by substrates and heterotropic stimulation by flavonoids has been identified. Steroid hydroxylation by the wild-type enzyme exhibits sigmoidal kinetics, indicative of positive cooperativity. Based on the 3A4 model and single-site mutants, a double mutant in SRS-2 has been constructed that exhibits normal Michaelis-Menten kinetics. Results of modeling and mutagenesis studies suggest that the substrate and effector bind at adjacent sites within a single large cavity in P450 3A4. A thorough understanding of the location and structural requirements of the substrate-binding and effector sites in cytochrome P450 3A4 should prove valuable in rationalizing and predicting interactions among the multitude of drugs and other compounds that bind to the enzyme.
TL;DR: Overall, the results provide a structure-based rationale for ligand recognition that is consistent both with site-directed mutagenesis experiments and structure-function relationship data.
Abstract: The three-dimensional structure, dynamics, and binding modes of representative kappa-opioid agonists of the arylacetamide class (U50, 488; U69,593; U62,066; CI-977; ICI199,441; ICI197,067; BRL52,537; and BRL52,656) have been investigated using molecular modeling techniques. Systematic exploration of the conformational space of the ligand combined with molecular dynamics (MD) simulations in water revealed consistent conformational preferences for all the kappa-agonists in this series. The results were further compared with available X-ray and 1D- and 2D-NMR data to identify potential "lead" conformers for molecular docking. Ligand binding modes were initially determined using automated docking of two of the ligands (U50,488 and BRL52,537) to the kappa-opioid receptor. Extrapolation of the predicted binding mode to other members in this ligand series revealed similar docking preferences, with each ligand docked along the receptor helical axis. The binding modes were further refined using MD simulations of the receptor-ligand complexes. The results show a that salt bridge is formed between the amino proton of the ligands and the carboxylate group of Asp138 in TM3. This interaction most likely serves as a key anchoring point for the agonist association. Additional ligand contacts were noted with kappa-specific residues Ile294, Leu295, and Ala298, which may, in part, explain the kappa-selectivity in this series. In comparing the arylacetamides with opiate-based ligands, no evidence was found to link these classes through a common binding motif (except for the ion pair). The binding site model was also applied to explain the enantiomeric preference of U50,488 and to provide insight to the mu/kappa-selectivity of representative ligands in this series. Overall, the results provide a structure-based rationale for ligand recognition that is consistent both with site-directed mutagenesis experiments and structure-function relationship data.
TL;DR: The similarity between the bound conformations of the ligand from the 3D-SAR analysis and those found in the docking protocol suggests that this methodology is valid for the prediction of bound ligand conformations and the modeling of the structure ofThe ligand-RNA complexes.
Abstract: An approach to the modeling of ligand−RNA complexes has been developed by combining three-dimensional structure−activity relationship (3D-SAR) computations with a docking protocol. The ability of 3...
TL;DR: A series of synthetic receptors capable of binding to the calmodulin-binding domain of calcineurin (CN393-414) was designed, synthesized and characterized, with apparent dissociation constants ranging from 0.2 microM to >50 microM.
TL;DR: A general pharmacophore map for hA3ANTs has been derived and it is hypothesize that the receptor binding properties of different A3 antagonist derivatives are due to recognition at a common region inside the receptorbinding site and, consequently, a common electrostatic potential profile.
Abstract: Molecular modeling studies were conducted on various chemically diverse classes of human A3 adenosine receptor antagonists (hA3ANTs), such as adenines, xanthines, triazoloquinazolines, flavonoids, thiazolopyridines, 6-phenyl-1,4-dihydropyridines, and 6-phenylpyridines. Using a combination of ab initio quantum mechanical calculations, electrostatic potential map comparison, and the steric and electrostatic alignment (SEAL) method, a general pharmacophore map for hA3ANTs has been derived. Based on the proposed pharmacophore map, we hypothesize that the receptor binding properties of different A3 antagonist derivatives are due to recognition at a common region inside the receptor binding site and, consequently, a common electrostatic potential profile. A model of the human A3 receptor, docked with the triazoloquinazoline reference ligand CGS 15953 (9-chloro-2-(2-furyl)[1,2,4]triazolo[1,5-c]quinazolin-5-amine), was built and analyzed to help interpret these results. All other antagonist structures were docked...
TL;DR: The potential P450 enzymic interactions, inhibition and induction of omeprazole are discussed in the light of molecular modelling and QSAR (quantitative structure-activity relationship) studies on related compounds.