Showing papers on "Docking (molecular) published in 1996"

Rapid, electrostatically assisted association of proteins

Abstract: The rapid association of barnase and its intracellular inhibitor barstar has been analysed from the effects of mutagenesis and electrostatic screening. A basal association rate constant of 105 M−1 s−1 is increased to over 5×109 M−1s−1 by electrostatic forces. The association between the oppositely charged proteins proceeds through the rate-determining formation of an early, weakly specific complex, which is dominated by long-range electrostatic interactions, followed by precise docking to form the high affinity complex. This mode of binding is likely to be used widely in nature to increase association rate constants between molecules and its principles may be used for protein design.

Scoring noncovalent protein-ligand interactions: a continuous differentiable function tuned to compute binding affinities.

Abstract: Exploitation of protein structures for potential drug leads by molecular docking is critically dependent on methods for scoring putative protein-ligand interactions. An ideal function for scoring must exhibit predictive accuracy and high computational speed, and must be tolerant of variations in the relative protein-ligand molecular alignment and conformation. This paper describes the development of an empirically derived scoring function, based on the binding affinities of protein-ligand complexes coupled with their crystallographically determined structures. The function's primary terms involve hydrophobic and polar complementarity, with additional terms for entropic and solvation effects. The issue of alignment/conformation dependence was solved by constructing a continuous differentiable nonlinear function with the requirement that maxima in ligand conformation/alignment space corresponded closely to crystallographically determined structures. The expected error in the predicted affinity based on cross-validation was 1.0 log unit. The function is sufficiently fast and accurate to serve as the objective function of a molecular-docking search engine. The function is particularly well suited to the docking problem, since it has spatially narrow maxima that are broadly accessible via gradient descent.

Molecular docking towards drug discovery

Abstract: Fueled by advances in molecular structure determination, tools for structure-based drug design are proliferating rapidly. Lead discovery through searching of ligand databases with molecular docking techniques represents an attractive alternative to high-throughout random screening. The size of commercial databases imposes severe computational constraints on molecular docking, compromising the level of calculational detail permitted for each putative ligand. We describe alternative philosophies for docking which effectively address this challenge. With respect to the dynamic aspects of molecular recognition, these strategies lie along a spectrum of models bounded by the Lock-and-Key and Induced-Fit theories for ligand binding. We explore the potential of a rigid model in exploiting species specificity and of a tolerant model in predicting absolute ligand binding affinity. Current molecular docking methods are limited primarily by their ability to rank docked complexes; we therefore place particular emphasis on this aspect of the problem throughout our validation of docking strategies.

Placement of medium-sized molecular fragments into active sites of proteins.

Abstract: We present an algorithm for placing molecular fragments into the active site of a receptor. A molecular fragment is defined as a connected part of a molecule containing only complete ring systems. The algorithm is part of a docking tool, called FlexX, which is currently under development at GMD. The overall goal is to provide means of automatically computing low-energy conformations of the ligand within the active site, with an accuracy approaching the limitations of experimental methods for resolving molecular structures and within a run time that allows for docking large sets of ligands. The methods by which we plan to achieve this goal are the explicit exploitation of molecular flexibility of the ligand and the incorporation of physicochemical properties of the molecules. The algorithm for fragment placement, which is the topic of this paper, is based on pattern recognition techniques and is able to predict a small set of possible positions of a molecular fragment with low flexibility within seconds on a workstation. In most cases, a placement with rms deviation below 1.0 A with respect to the X-ray structure is found among the 10 highest ranking solutions, assuming that the receptor is given in the bound conformation.

Discovery of novel, non-peptide HIV-1 protease inhibitors by pharmacophore searching

Abstract: Fifteen novel non-peptide HIV-1 protease inhibitors were identified by flexible 3D database pharmacophore searching of the NCI DIS 3D database. The pharmacophore query used in the search was derived directly from the X-ray determined structures of protease/inhibitor complexes. These 15 inhibitors, belonging to nine different chemical classes, are promising leads for further development. The two best inhibitors found, NSC 32180, a "dimer" of 4-hydroxycoumarin, and NSC 117027, a "tetramer" of 2-hydroxy quinone, had ID50 values of 0.32 and 0.75 microM for HIV-1 protease inhibition, respectively, and two other inhibitors had ID50 values close to 1 microM. Among the potent inhibitors, NSC 158393 not only demonstrated activity against HIV-1 protease (ID50 1.7 microM) but also exhibited promising antiviral activity in HIV-1-infected CEM-SS cells (EC50 = 11.5 microM). Validation of the pharmacophore used in the search was accomplished by conformational analysis. The binding modes of the most potent inhibitor found in our studies, NSC 32180, were predicted employing docking and molecular dynamics techniques.

Exploring the energy landscapes of molecular recognition by a genetic algorithm: Analysis of the requirements for robust docking of HIV‐1 protease and FKBP‐12 complexes

Abstract: Energy landscapes of molecular recognition are explored by performing "semi-rigid" docking of FK-506 and rapamycin with the Fukisawa binding protein (FKBP-12), and flexible docking simulations of the Ro-31-8959 and AG-1284 inhibitors with HIV-1 protease by a genetic algorithm. The requirements of a molecular recognition model to meet thermodynamic and kinetic criteria of ligand-protein docking simultaneously are investigated using a family of simple molecular recognition energy functions. The critical factor that determines the success rate in predicting the structure of ligand-protein complexes is found to be the roughness of the binding energy landscape, in accordance with a minimal frustration principle. The results suggest that further progress in structure prediction of ligand-protein complexes can be achieved by designing molecular recognition energy functions that generate binding landscapes with reduced frustration.

Docking enzyme-inhibitor complexes using a preference-based free-energy surface.

Abstract: We present a docking scheme that utilizes both a surface complementarity screen as well as an energetic criterion based on surface area burial. Twenty rigid enzyme/inhibitor complexes with known coordinate sets are arbitrarily separated and reassembled to an average all-atom rms (root mean square) deviation of 1.0 A from the native complexes. Docking is accomplished by a hierarchical search of geometrically compatible triplets of surface normals on each molecule. A pruned tree of possible bound configurations is built up using successive consideration of larger and larger triplets. The best scoring configurations are then passed through a free-energy screen where the lowest energy member is selected as the predicted native state. The free energy approximation is derived from observations of surface burial by atom pairs across the interface of known enzyme/inhibitor complexes. The occurrence of specific atom-atom surface burial, for a set of complexes with well-defined secondary structure both in the bound and unbound states, is parameterized to mimic the free energy of binding. The docking procedure guides the inhibitor into its native state using orientation and distance-dependent functions that reproduce the ideal model of free energies with an average rms deviation of 0.9 kcal/mol. For all systems studied, this docking procedure identifies a single, unique minimum energy configuration that is highly compatible with the native state.

Synthesis, Biological Activity, and Molecular Modeling Studies of Selective 5-HT2C/2B Receptor Antagonists

Abstract: The synthesis and biological activity are reported for a series of analogues of the previously published indole urea 2 (SB-206553), designed to probe the 5-HT(2C) receptor binding site. Small molecule modeling studies have been used to define a region in space which is allowed at the 5-HT(2C) receptor but disallowed at the 5-HT(2A) receptor. In a complementary approach, docking of 2 into our model of the 5-HT(2C) receptor has allowed us to propose a novel primary binding interaction for this series of diaryl ureas, involving a potential double hydrogen-bonding interaction between the urea carbonyl oxygen of the ligand and two serine residues in the receptor. The difference of two valine residues in the 5-HT(2C) receptor for leucine residues in the 5-HT(2A) receptor is believed to account for the observed 5-HT(2C)/5-HT(2A) selectivity with 2.

Enantioselective binding of α-pinene and of some cyclohexanetriol derivatives by cyclodextrin hosts: A molecular modeling study†

Abstract: We have used molecular modeling to investigate the enantioselective separation of the monoterpene α-pinene on permethylated β-cyclodextrin and on α-cyclodextrin and the enantioselective separation of three cyclohexanetriol derivatives on permethylated β-cyclodextrin. Using the Consistent Valence Force Field (CVFF) from Insight/Discover, we have carried out systematic rigid-body docking grid searches on each of the optical antipodes of the organic guest molecules interacting with the cyclodextrins, followed by minimizations of the low-energy docked structures. A statistical mechanical analysis of the minimized energies yields data that agree in four out of five cases with the experimental elution order of enantiomers. The computed energies of the rigid-body docking before minimizations do not agree with the experimental results, suggesting that a conformational induced fit of the cyclodextrins upon binding of the organic guests may be involved in the mechanism of the chiral recognition. © 1996 by John Wiley & Sons, Inc.

Comparative docking studies on ligand binding to the multispecific antibodies IgE-La2 and IgE-Lb4

Abstract: A large comparative study is presented in which the binding of approximately 30 different ligands to two IgE antibodies (La2 and Lb4) is analyzed by means of an automated-docking procedure based on simulated annealing. The method is able to reproduce experimentally verified binding orientations, as shown by application to the Ig-AN02-hapten complex. The main address of the study is to investigate the concept of antibody multispecificity. Problems and usefulness of docking in this context are discussed. The results indicate reasons for multispecific binding properties and how they can be understood from the topology of the binding site. Though similar in general behaviour, the two antibodies show interesting differences in their binding characteristics. The binding sites of both antibodies are described and the main interacting residues revealed.

Molecular Dynamics Docking Driven by NMR‐Derived Restraints to Determine the Structure of the Calicheamicin γ1I Oligosaccharide Domain Complexed to Duplex DNA

Abstract: Calicheamicin γ1I is a natural product that has recently received much attention for its potent cytotoxic activity and its ability to bind and cleave duplex DNA in a sequence‐specific manner. The solution structure of the calicheamicin oligosaccharide domain has been determined in complex with the DNA duplex d(GCATCCTAGC)·d(GCTAGGATGC) containing the high‐affinity binding site d(TCCT), using a restrained molecular dynamics‐based conformational search. The input data consists of 229 DNA–DNA, 14 drug–drug and 17 drug–DNA NOE‐derived distance constraints, 32 DNA hydrogen bond constraints and 91 DNA and eight drug torsion angle constraints for a total of 383 NMR‐derived constraints. Novel strategies were utilized for generating DNA starting structures and for docking the ligand into the DNA minor groove to ensure the extensive sampling of conformational space consistent with the input data. The conformation of the complex is represented by an ensemble of 20 structures that have an average pairwise root mean square deviation of 0.94 Å for the binding region. This ensemble was carefully selected as the minimum population of structures which represents all of the conformational space allowed by the experimental constraints. The ensemble was analyzed for interactions between the oligosaccharide and DNA that stabilize the structure of the complex and account for the binding specificity.

Atp-lipids - protein anchor and energy source in two dimensions

Abstract: The ubiquitous function of ATP as energy equivalent in nature has resulted in a common folding pattern of ATP-binding proteins. Their binding pocket tolerates modifications of the adenine ring to some extend, whereas those of the triphosphate group strongly affect the binding affinity. In consequence, immobilized C8- and N6-modified ATP analogues are frequently used for affinity purification of ATPases or kinases. To combine this unique recognition principle with the fascinating properties of self-assembly, we have synthesized a novel class of hydrolyzable and nonhydrolyzable ATP-lipids where the nucleotides are covalently attached via C8- or N6-position of the adenine ring to a synthetic lipid. These ATP-lipids were characterized by various enzyme assays in micellar solution, resulting in ATPase and competition activities that are comparable to their free counterparts. The specific docking of actin as a model of an ATP-binding protein to ATP-lipid monolayers was followed by film balance technique and epi...

Comparative molecular field analysis of haptens docked to the multispecific antibody IgE(Lb4)

Abstract: Using comparative molecular field analysis (CoMFA), three-dimensional quantitative structure-activity relationships were developed for 27 haptens which bind to the monoclonal antibody IgE(Lb4). In order to obtain an alignment for these structurally very diverse antigens, the compounds were docked to a previously modeled receptor structure using the automated docking program AUTODOCK (Goodsell, D.S.; Olson, A.J. Proteins: Struct., Funct., Genet. 1990, 8, 195-202). Remarkably, this alignment method yielded highly consistent QSAR models, as indicated by the corresponding cross-validated r2 values (0.809 for a model with carbon as probe atom, 0.773 for a model with hydrogen as probe atom). Conventional alignment failed in providing a basis for self-consistent CoMFAs. Amino acids Tyr H 50, Tyr H 52, and Trp H 95 of the receptor appeared to be of crucial importance for binding of various antigens. These findings are consistent with earlier considerations of aromatic residues being responsible for the multispecificity of certain immunoglobulins.

The binding mode of an E-64 analog to the active site of cathepsin B.

Abstract: Two binding modes of the isobutyl-NH-Eps-Leu-Pro inhibitor to cathepsin B have been proposed. Molecular docking using an empirical force field was carried out to distinguish between the two modes. The search began with manual docking, followed by random perturbations of the docking conformation and cycles of Monte Carlo minimization. Finally, molecular dynamics was carried out for the most favorable docking conformations. The present calculations predict that the isobutyl-NH-Eps-Leu-Pro inhibitor preferentially binds to the S' rather than the S subsites of cathepsin B. The S' binding mode prediction is supported by the X-ray crystal structure of cathepsin B bound to a closely related ethyl-O-Eps-Ile-Pro inhibitor, which was found to bind in the S'subsite with the C-terminal epoxy ring carbon making a covalent bond to the sulfur atom of Cys29. This agreement, in turn, validates our docking strategy. Furthermore, the calculations provide evidence that the dominant contribution to the total stabilization energy of the enzyme-inhibitor complex stems from the strong electrostatic interaction between the negatively charged C-terminal carboxylate group of the ligand and the positively charged imidazolium rings of His110 and His111. The latter are stabilized and held in an optimal orientation for interactions with the C-terminal end of the ligand through a salt bridge between the side chains of His110 and Asp22. By comparison with the crystal structure, some insight into the specificity of the epoxyldipeptide family towards cathepsin B inhibition has been extracted. Both the characteristics of the enzyme (e.g. subsite size and hydrophobicity) as well as the nature of the inhibitor influence the selectivity of an inhibitor towards an enzyme.

Docking of Conformationally Flexible Proteins

Abstract: In this work we present and apply a 3-D pattern matching algorithm developed to solve structural recognition problems in molecular biology. The ability to automatically predict molecular interactions, is important in rational drug design and discovery, as well as a research tool in biomolecular structural recognition. Docking of a pair of molecules involves finding a proper partial fit between their molecular surfaces, as molecules interact at their surface. The generation of docked binding modes between two associating molecules depends on their 3-D structures and on their conformational flexibility, namely hinge-bending induced transitions. In hinge-bending, relatively rigid molecular subparts rotate on hinge(s) with respect to each other. This type of movements can occur in either of the two participating molecules, i.e., in the ligand or in the receptor molecule. Current automated docking techniques enable hinge bending flexibility in small ligands (e.g., drug molecules). Our approach allows hinge induced motions to exist in either diverse size ligands or variable size receptors (e.g., enzymes). We achieve this by the extension of the generalized Hough transform and Geometric Hashing techniques, which were originally developed for partially occluded articulated (flexible) object recognition in Computer Vision & Robotics. We show experimental results obtained by applying the algorithm on pairs of molecules allowing hinge-bending in either of the molecules for both complexed (bound) and unbound molecular configurations. We also discuss additional implications and applications of our approach.

Substrate docking algorithms and the prediction of substrate specificity.

Abstract: Publisher Summary This chapter describes the substrate docking algorithms and the prediction of substrate specificity. The utility of computer-assisted molecular docking for the prediction of cytochrome P450 substrates has been explored. P450cam is used as the model P450 enzyme because several high resolution crystal structures are available for it, although the approach should be applicable to any other isoform of P450 for which an active site structure is available. The chapter reviews computational approaches to analysis of the two subsequent steps, the degree of uncoupling, and the site specificity of the oxidation process. There are a number of programs available that can be used to predict whether a given small molecule will bind to a macromolecular receptor. DOCK has been used for the prediction of small molecules that bind to and inhibit a variety of enzymes. Future developments in this area should include utilization of the continuing improvements in ligand docking programs, such as, conformationally flexible searching, minimization of ligand/receptor complexes during searches, and more sophisticated scoring algorithms.

Inhibition mechanisms of staurosporine and H7 to cAMP-dependent protein kinase through docking study

Abstract: Inhibition mechanisms of staurosporine and H7 to cAMP-dependent protein kinase have been investigated through docking studies. For each molecule, the energetically most stable docking model was searched by using the conformationally flexible automatic docking program ADAM without any presumptions. The results explain well the observation that staurosporine does not bind to the enzyme competitively with H7, even though the two compounds competitively inhibit ATP binding.

Characterization of a Novel Reverse-orientation Model for a Peptide/MHC Complex Putatively Associated with Type I Diabetes Mellitus

Abstract: Molecular modeling techniques were used to generate structures of several HLA-DQ proteins associated with insulin-dependent diabetes mellitus (IDDM). A peptide fragment from glutamic acid decarboxylase (GAD), a known IDDM autoantigen, binds to certain HLA-DQ molecules positively associated with IDDM. Modeling studies were used to explore possible binding interactions between this GAD peptide and several HLA-DQ molecules. Based on the characterization of anchor pockets in the HLA-DQ binding groove and of peptide side chains, a novel binding mode was proposed. This binding mode predicts the GAD peptide is positioned in the binding groove in the direction opposite the orientation observed for class I proteins and the class II DR1, DR3, and I-Ek proteins. Peptide docking exercises were performed to construct models of the HLA-DQ/peptide complexes, and the resulting models have been used to design peptide binding experiments to test this “reverse-orientation” binding mode. A variety of experimental results are consistent with the proposed model and suggest that some peptide ligands of class II molecules may bind in a reversed orientation within the binding groove.

The mu- and delta-opioid pharmacophore conformations of cyclic beta-casomorphin analogues indicate docking of the Phe3 residue to different domains of the opioid receptors.

Abstract: Cyclic beta-casomorphin analogues with a D-configured amino acid residue in position 2, such as Tyr-c[-Xaa-Phe-Pro-Gly-] and Tyr-c[-Xaa-Phe-D-Pro-Gly-] (Xaa = D-A2bu, D-Orn, D-Lys) were found to bind to the mu-opioid receptor as well as to the delta-opioid receptor, whereas the corresponding L-Xaa2 derivatives are nearly inactive at both. Low-energy conformers of both active and nearly inactive derivatives have been determined in a systematic conformational search or by molecular dynamics simulations using the TRIPOS force field. The obtained conformations were compared with regard to a model for mu-selective opiates developed by Brandt et al. [Drug Des. Discov., 10 (1993) 257]. Superpositions as well as electrostatic, lipophilic and hydrogen bounding similarities with the delta-opioid receptor pharmacophore conformation of t-Hpp-JOM-13 proposed by Mosberg et al. [J. Med. Chem., 37 (1994) 4371, 4384] were used to establish the probable delta-pharmacophoric cyclic beta-casomorphin conformations. These conformations were also compared with a delta-opioid agonist (SNC 80) and the highly potent antagonist naltrindole. These investigations led to a prediction of the mu- and delta-pharmacophore structures for the cyclic beta-casomorphins. Interestingly, for the inactive compounds such conformations could not be detected. The comparison between the mu- and delta-pharmacophore conformations of the cyclic beta-casomorphins demonstrates not only differences in spatial orientation of both aromatic groups, but also in the backbone conformations of the ring part. In particular, the differences on phi2 and psi2 (mu approximately 70 degrees, -80 degrees; delta approximately 165 degrees, 55 degrees) cause a completely different spatial arrangement of the cyclized peptide rings when all compounds are matched with regard to maximal spatial overlap of the tyrosine residue. Assuming that both the mu- and delta-pharmacophore conformations bind with the tyrosine residue in a similar orientation at the same transmembrane domain X of their receptors, the side chain of Phe3 as a second binding site has to dock with different domains.