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Results for “Molecular Docking Simulation”

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PubMed1995

Determination of the NMR solution structure of a specific DNA complex of the Myb DNA-binding domain.

The solution structure of a specific DNA complex of the minimum DNA-binding domain of the mouse c-Myb protein was determined by distance geometry calculations using a set of 1732 nuclear Overhauser enhancement (NOE) distance restraints. In order to determine the complex structure independent of the initial guess, we have developed two different procedures for the docking calculation using simulated annealing in four-dimensional space (4D-SA). One is a multiple-step procedure, where the protein and the DNA were first constructed independently by 4D-SA using only the individual intramolecular NOE distance restraints. Here, the initial structure of the protein was a random coil and that of the DNA was a typical B-form duplex. Then, as the starting structure for the next docking procedure, the converged protein and DNA structures were placed in random molecular orientations, separated by 50 A. The two molecules were docked by 4D-SA utilizing all the restraints, including the additional 66 intermolecular distance restraints. The second procedure comprised a single step, in which a random-cell protein and a typical B-form DNA duplex were first placed 70 A from each other. Then, using all the intramolecular and intermolecular NOE distance restraints, the complex structure was constructed by 4D-SA. Both procedures yielded the converged complex structures with similar quality and structural divergence, but the multiple-step procedure has much better convergence power than the single-step procedure. A model study of the two procedures was performed to confirm the structural quality, depending upon the number of intermolecular distance restraints, using the X-ray structure of the engrailed homeodomain-DNA complex.

Animals↗

PubMed2004

Recovering the true targets of specific ligands by virtual screening of the protein data bank.

The Protein Data Bank (PDB) has been processed to extract a screening protein library (sc-PDB) of 2148 entries. A knowledge-based detection algorithm has been applied to 18,000 PDB files to find regular expressions corresponding to either protein, ions, co-factors, solvent, or ligand atoms. The sc-PDB database comprises high-resolution X-ray structures of proteins for which (i) a well-defined active site exists, (ii) the bound-ligand is a small molecular weight molecule. The database has been screened by an inverse docking tool derived from the GOLD program to recover the known target of four unrelated ligands. Both the database and the inverse screening procedures are accurate enough to rank the true target of the four investigated ligands among the top 1% scorers, with 70-100 fold enrichment with respect to random screening. Applying the proposed screening procedure to a small-sized generic ligand was much less accurate suggesting that inverse screening shall be reserved to rather selective compounds.

Algorithms↗

PubMed1999

Protein-protein recognition: exploring the energy funnels near the binding sites.

We present a rapidly executable minimal binding energy model for molecular docking and use it to explore the energy landscape in the vicinity of the binding sites of four different enzyme inhibitor complexes. The structures of the complexes are calculated starting with the crystal structures of the free monomers, using DOCK 4.0 to generate a large number of potential configurations, and screening with the binding energy target function. In order to investigate possible correlations between energy and variation from the native structure, we introduce a new measure of similarity, which removes many of the difficulties associated with root mean square deviation. The analysis uncovers energy gradients, or funnels, near the binding site, with decreasing energy as the degree of similarity between the native and docked structures increases. Such energy funnels can increase the number of random collisions that may evolve into productive stable complex, and indicate that short-range interactions in the precomplexes can contribute to the association rate. The finding could provide an explanation for the relatively rapid association rates that are observed even in the absence of long-range electrostatic steering.

Algorithms↗

PubMed2005

Docking to single-domain and multiple-domain proteins: old and new challenges.

The diverse selection of targets in the CAPRI experiments provides grounds for determining the limits of our rigid-body docking program MolFit, and for extending it. We find that the sensitivity of MolFit is high, enabling it to produce reasonably accurate docking solutions when the structures undergo moderate local conformation changes upon complex formation or when the docked molecules are modeled. Yet the ranks of these solutions are sometimes too low to meet the requirements of CAPRI assessment. This indicates that the selectivity of MolFit, which was optimized for docking of unbound X-ray structures, and which relies on the availability of external data from biochemical and bioinformatic sources, needs readjustment in order to meet the challenges presented by NMR or modeled structures. A different challenge is presented by large global conformation changes such as movements of domains. We show that such changes can be accommodated within the rigid-body approximation by employing rigid multibody multistage docking procedures. We also address the difficulty of ranking results from 2-body and multibody docking scans in cases in which there are no external data favoring one option over the other.

Algorithms↗

PubMed2007

Towards in silico lead optimization: scores from ensembles of protein/ligand conformations reliably correlate with biological activity.

Accurately ranking protein/ligand interactions and distinguishing subtle differences between homologous compounds in a virtual focused library in silico is essential in a structure-based drug discovery program. In order to establish a predictive model to design novel inhibitors of dihydrofolate reductase (DHFR) from the parasitic protozoa, Cryptosporidium hominis, we docked a series of 30 DHFR inhibitors with measured inhibition constants against the crystal structure of the protein. By including protein flexibility and averaging the energies of the 25 lowest protein/ligand conformers we obtained more accurate total nonbonded energies from which we calculated a predicted biological activity. The calculated and measured biological activities showed reliable correlations of 72.9%. Additionally, visual analysis of the ensemble of protein/ligand conformations revealed alternative ligand binding pockets in the active site. Using the same principles we then created a homology model of DHFR from Toxoplasma gondii and docked 11 inhibitors. A correlation of 50.2% between docking score and activity validates both the method and the model. The correlations presented here are particularly compelling considering the high structural similarity of the ligands and the fact that we have used structures derived from crystallographic data and homology modeling. These docking principles may be useful in any lead optimization study where accurate ranking of similar compounds is desired.

Algorithms↗

PubMedDate not supplied

Situs: A package for docking crystal structures into low-resolution maps from electron microscopy.

Three-dimensional image reconstructions of large-scale protein aggregates are routinely determined by electron microscopy (EM). We combine low-resolution EM data with high-resolution structures of proteins determined by x-ray crystallography. A set of visualization and analysis procedures, termed the Situs package, has been developed to provide an efficient and robust method for the localization of protein subunits in low-resolution data. Topology-representing neural networks are employed to vector-quantize and to correlate features within the structural data sets. Microtubules decorated with kinesin-related ncd motors are used as model aggregates to demonstrate the utility of this package of routines. The precision of the docking has allowed for the extraction of unique conformations of the macromolecules and is limited only by the reliability of the underlying structural data.

Animals↗

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↗

PubMed2004

Synthesis and anti-HIV-1 activity of 4-[4-(4,6-bisphenylamino-triazin-2-ylamino)-5-methoxy-2-methylphenylazo]-5-hydroxynaphthalene-2,7-disulfonic acid and its derivatives.

A structure-based design approach has been used to optimize a lead HIV-1 entry inhibitor targeted to the envelope glycoprotein gp41. The docking study on this lead compound revealed important structural requirements that need to be preserved as well as structural non-requirements that could be eliminated to substantially reduce the molecular size of the lead compound. Based on the results from docking study, a limited number of analogues were designed and synthesized. This approach yielded a new analogue (compound 4) that retained the anti-HIV-1 activity with reduced molecular size approaching towards more drug-like character.

Anti-HIV Agents↗

PubMed2006

The interaction of Phe472 with a fluorescent inhibitor bound to the complex of myosin subfragment-1 with nucleotide.

The fluorescent probe 3-[4-(3-phenyl-2-pyrazolin-1-yl)benzene-1-sulfonyl amido]phenylboronic acid (PPBA) acts as a fluorescent inhibitor for the ATPases of skeletal [Hiratsuka (1994) J. Biol. Chem. 269, 27251-27257] and Dictyostelium discoideum [Bobkov et al. (1997) J. Muscle Res. Cell Motil. 18, 563-571] myosins. The former paper suggested that, upon addition of excess nucleotides to the binary complex of subfragment-1 from skeletal myosin (S1) with PPBA, a stable ternary complex of S1 with PPBA and nucleotide is formed. Useful fluorescence properties of PPBA enable us to distinguish the conformation of the myosin ATPase at the ATP state from that at the ADP state. In the present paper, to determine the PPBA-binding site in the complexes, enzymatic and fluorescence properties of the S1.PPBA.nucleotide complexes were investigated. Upon formation of the ternary complex with ATP, a new peak appeared at 398 nm in the PPBA fluorescence spectrum. Experiments using model compounds of aromatic amino acid suggested that this fluorescence peak at 398 nm is originated from PPBA interacting with Phe residue(s). Taking into account differences in fluorescence spectra between complexes of S1 and those of subfragment-1 from D. discoideum myosin (S1dC), in the ternary complex of S1 formed with ATP, PPBA was suggested to interact with Phe residue(s) that is absent in S1dC. Docking simulation of PPBA on the S1.nucleotide complex revealed that Phe472 interacts with PPBA. Binding sites of PPBA and blebbistatin, an inhibitor showing high affinity and selectivity toward myosin II [Kovács et al. (2004) J. Biol. Chem. 279, 35557-35563], seem to overlap at least partly.

Adenosine Triphosphate↗

PubMed2004

Structure-based discovery of nonpeptidic small organic compounds to block the T cell response to myelin basic protein.

We have utilized a computational structure-based approach to identify nonpeptidic small organic compounds that bind to a human leukocyte antigen (HLA) DR1301 molecule (HLA-DR1301 or DR1301) and block the presentation of myelin basic protein peptide 152-165 (MBP 152-165) to T cells. A three-dimensional (3D) structure of DR1301 was derived by homology modeling followed by extensive molecular dynamics simulation for structural refinement. Computational structure-based database searching was performed to identify nonpeptidic small-molecule candidates from the National Cancer Institute (NCI) database containing over 150 000 compounds that can effectively interact with the peptide-binding groove of the HLA molecule. By in vitro testing of 106 candidate small molecules, two lead compounds were confirmed to specifically block IL-2 secretion by DR1301-restricted T cells in a dose-dependent and reversible manner. The specificity of blocking DR1301-restricted MBP presentation was further validated in a binding assay using an analogue of the most potent lead compound. Computational docking was performed to predict the three-dimensional binding model of these confirmed small molecule blockers to the DR1301 molecule and to gain structural insight into their interactions. Our results suggest that computational structure-based searching is an effective approach to discover nonpeptidic small organic compounds to block the interaction between DR1301 and T cells. The nonpeptidic small organic compounds identified in this study are useful pharmacological tools to study the interactions between HLA molecules and T cells and a starting point for the development of a novel therapeutic strategy for the treatment of multiple sclerosis (MS) or other immune-related disorders.

Animals↗

PubMed2005

Flexible docking in solution using metadynamics.

We apply our recently developed metadynamics method to the docking of ligands on flexible receptors in water solution. This method mimics the real dynamics of a ligand exiting or entering an enzyme and in so doing reconstructs the free energy surface. We apply it to four docking cases: beta-trypsin/benzamidine, beta-trypsin/chlorobenzamidine, immunoglobulin McPC-603/phosphocholine, and cyclin-dependent kinase 2/staurosporine. In every case studied, the method is able to predict the docked geometry and the free energy of docking. Its added value with respect to many other available methods is that it reconstructs the complete free energy surface, including all the relevant minima and the barriers between them.

Benzamidines↗

PubMed2000

Library design and virtual screening using multiple 4-point pharmacophore fingerprints.

The use of multiple potential 4-point three-dimensional (3-D) pharmacophores for the design of combinatorial libraries and for virtual screening is discussed. These 3-D pharmacophoric fingerprints can be calculated from both ligands and complementary to a protein site, with a common frame of reference, and can be very rapidly searched to identify common and different 4-point pharmacophoric shapes in compounds and protein sites. A new extension to the method for structure-based design is reported that uses the shape of the target site as an additional constraint. This enables the docking process, for example in library design and virtual screening, to be quantified in terms of how many, and which, pharmacophoric hypotheses can be matched by a compound or a library of compounds.

Combinatorial Chemistry Techniques↗

PubMed2000

Protein docking using spherical polar Fourier correlations.

We present a new computational method of docking pairs of proteins by using spherical polar Fourier correlations to accelerate the search for candidate low-energy conformations. Interaction energies are estimated using a hydrophobic excluded volume model derived from the notion of "overlapping surface skins," augmented by a rigorous but "soft" model of electrostatic complementarity. This approach has several advantages over former three-dimensional grid-based fast Fourier transform (FFT) docking correlation methods even though there is no analogue to the FFT in a spherical polar representation. For example, a complete search over all six rigid-body degrees of freedom can be performed by rotating and translating only the initial expansion coefficients, many unfeasible orientations may be eliminated rapidly using only low-resolution terms, and the correlations are easily localized around known binding epitopes when this knowledge is available. Typical execution times on a single processor workstation range from 2 hours for a global search (5 x 10(8) trial orientations) to a few minutes for a local search (over 6 x 10(7) orientations). The method is illustrated with several domain dimer and enzyme-inhibitor complexes and 20 large antibody-antigen complexes, using both the bound and (when available) unbound subunits. The correct conformation of the complex is frequently identified when docking bound subunits, and a good docking orientation is ranked within the top 20 in 11 out of 18 cases when starting from unbound subunits. Proteins 2000;39:178-194.

Algorithms↗

PubMed2005

Study of protein-protein interaction using conformational space annealing.

We apply conformational space annealing (CSA), an efficient global optimization method, to the study of protein-protein interaction. The CSA is incorporated into the Tinker molecular modeling package along with a B-spline method for CAPRI Round 5 experiments. We have used an energy function for the protein-protein interaction that consists of electrostatic interaction, van der Waals interaction, and solvation energy terms represented by the occupancy desolvation method. The parameters of the AMBER94 all-atom empirical force field are used. Each energy term is calculated by precalculated grid potentials and B-spline method approximation. The ligand protein is placed inside a sphere of 50 A radius centered at an appropriate location, and the CSA rigid docking studies are carried out to find stable complexes. Up to 10 complexes are selected using the K-mean clustering method and biological information when available. These complexes are energy-minimized for further refinement by considering the flexibility of interacting proteins. The results show that the CSA method has a potential for the study of protein-protein interaction.

Algorithms↗

PubMed2005

Modelling the structure of latexin-carboxypeptidase A complex based on chemical cross-linking and molecular docking.

We have determined the three-dimensional structure of the protein complex between latexin and carboxypeptidase A using a combination of chemical cross-linking, mass spectrometry and molecular docking. The locations of three intermolecular cross-links were identified using mass spectrometry and these constraints were used in combination with a speed-optimised docking algorithm allowing us to evaluate more than 3 x 10(11) possible conformations. While cross-links represent only limited structural constraints, the combination of only three experimental cross-links with very basic molecular docking was sufficient to determine the complex structure. The crystal structure of the complex between latexin and carboxypeptidase A4 determined recently allowed us to assess the success of this structure determination approach. Our structure was shown to be within 4 A r.m.s. deviation of Calpha atoms of the crystal structure. The study demonstrates that cross-linking in combination with mass spectrometry can lead to efficient and accurate structural modelling of protein complexes.

Algorithms↗

PubMed2006

Identification of some novel AHAS inhibitors via molecular docking and virtual screening approach.

Acetohydroxyacid synthase (AHAS; EC 2.2.1.6) catalyzes the first common step in branched-chain amino acid biosynthesis. This enzyme is an important target for the design of environmental-benign herbicides. Based on the crystal structure of AHAS/sulfonylurea complex, we have carried out computational screening of the ACD-3D database in order to look for novel non-sulfonylurea inhibitors of AHAS for the first time. Three novel compounds were found to inhibit plant AHAS in vitro among 14 procured compounds. One compound showed promising activity in vivo for rape root growth inhibition bioassay. This research provided useful clues for further design and discovery of AHAS inhibitors.

Acetolactate Synthase↗

PubMed1998

Human P2Y1 receptor: molecular modeling and site-directed mutagenesis as tools to identify agonist and antagonist recognition sites.

The molecular basis for recognition by human P2Y1 receptors of the novel, competitive antagonist 2'-deoxy-N6-methyladenosine 3', 5'-bisphosphate (MRS 2179) was probed using site-directed mutagenesis and molecular modeling. The potency of this antagonist was measured in mutant receptors in which key residues in the transmembrane helical domains (TMs) 3, 5, 6, and 7 were replaced by Ala or other amino acids. The capacity of MRS 2179 to block stimulation of phospholipase C promoted by 2-methylthioadenosine 5'-diphosphate (2-MeSADP) was lost in P2Y1 receptors having F226A, K280A, or Q307A mutations, indicating that these residues are critical for the binding of the antagonist molecule. Mutation of the residues His132, Thr222, and Tyr136 had an intermediate effect on the capacity of MRS 2179 to block the P2Y1 receptor. These positions therefore appear to have a modulatory role in recognition of this antagonist. F131A, H277A, T221A, R310K, or S317A mutant receptors exhibited an apparent affinity for MRS 2179 that was similar to that observed with the wild-type receptor. Thus, Phe131, Thr221, His277, and Ser317 are not essential for antagonist recognition. A computer-generated model of the human P2Y1 receptor was built and analyzed to help interpret these results. The model was derived through primary sequence comparison, secondary structure prediction, and three-dimensional homology building, using rhodopsin as a template, and was consistent with data obtained from mutagenesis studies. We have introduced a "cross-docking" procedure to obtain energetically refined 3D structures of the ligand-receptor complexes. Cross-docking simulates the reorganization of the native receptor structure induced by a ligand. A putative nucleotide binding site was localized and used to predict which residues are likely to be in proximity to agonists and antagonists. According to our model TM6 and TM7 are close to the adenine ring, TM3 and TM6 are close to the ribose moiety, and TM3, TM6, and TM7 are near the triphosphate chain.

Adenosine Diphosphate↗

PubMed2002

TreeDock: a tool for protein docking based on minimizing van der Waals energies.

Predicting protein-protein and protein-ligand docking remains one of the challenging topics of structural biology. The main problems are (i) to reliably estimate the binding free energies of docked states, (ii) to enumerate possible docking orientations at a high resolution, and (iii) to consider mobility of the docking surfaces and structural rearrangements upon interaction. Here we present a novel algorithm, TreeDock, that addresses the enumeration problem in a rigid-body docking search. By representing molecules as multidimensional binary search trees and by exploring a sufficient number of docking orientations such that two chosen atoms, one from each molecule, are always in contact, TreeDock is able to explore all clash-free orientations at very fine resolution in a reasonable amount of time. Due to the speed of the program, many contact pairs can be examined to search partial or complete surface areas. The deterministic systematic search of TreeDock is in contrast to most other docking programs that use stochastic searches such as Monte Carlo or simulated annealing methods. At this point, we have used the Lennard-Jones potential as the only scoring function and show that this can predict the correct docked conformation for a number of protein-protein and protein-ligand complexes. The program is most powerful if some information is known about the location of binding faces from NMR chemical-shift perturbation studies, orientation information from residual dipolar coupling, or mutational screening. The approach has the potential to include docking-site mobility by performing molecular dynamics or other randomization methods of the docking site and docking families to families of structures. The performance of the algorithm is demonstrated by docking three complexes of immunoglobulin superfamily domains, CD2 to CD58, the V(alpha) domain of a T-cell receptor to its V(beta) domain, and a T-cell receptor to a pMHC complex as well as a small molecule inhibitor to a phosphatase.

Algorithms↗