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Results for “molecular docking”

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PubMed2002

Exploring the structure and activity of haloalkane dehalogenase from Sphingomonas paucimobilis UT26: evidence for product- and water-mediated inhibition.

The hydrolysis of haloalkanes to their corresponding alcohols and inorganic halides is catalyzed by alpha/beta-hydrolases called haloalkane dehalogenases. The study of haloalkane dehalogenases is vital for the development of these enzymes if they are to be utilized for bioremediation of organohalide-contaminated industrial waste. We report the kinetic and structural analysis of the haloalkane dehalogenase from Sphingomonas paucimobilis UT26 (LinB) in complex with each of 1,2-dichloroethane and 1,2-dichloropropane and the reaction product of 1-chlorobutane turnover. Activity studies showed very weak but detectable activity of LinB with 1,2-dichloroethane [0.012 nmol s(-1) (mg of enzyme)(-1)] and 1,2-dichloropropane [0.027 nmol s(-1) (mg of enzyme)(-1)]. These activities are much weaker compared, for example, to the activity of LinB with 1-chlorobutane [68.2 nmol s(-1) (mg of enzyme)(-1)]. Inhibition analysis reveals that both 1,2-dichloroethane and 1,2-dichloropropane act as simple competitive inhibitors of the substrate 1-chlorobutane and that 1,2-dichloroethane binds to LinB with lower affinity than 1,2-dichloropropane. Docking calculations on the enzyme in the absence of active site water molecules and halide ions confirm that these compounds could bind productively. However, when these moieties were included in the calculations, they bound in a manner similar to that observed in the crystal structure. These data provide an explanation for the low activity of LinB with small, chlorinated alkanes and show the importance of active site water molecules and reaction products in molecular docking.

Amino Acid Sequence↗

PubMed2005

Dynamic force spectroscopy of parallel individual Mucin1-antibody bonds.

We used atomic force microscopy to measure the binding forces between Mucin1 (MUC1) peptide and a single-chain variable fragment (scFv) antibody selected from a scFv library screened against MUC1. This binding interaction is central to the design of molecules used for targeted delivery of radioimmunotherapeutic agents for prostate and breast cancer treatment. Our experiments separated the specific binding interaction from nonspecific interactions by tethering the antibody and MUC1 molecules to the atomic force microscope tip and sample surface with flexible polymer spacers. Rupture force magnitude and elastic characteristics of the spacers allowed identification of the rupture events corresponding to different numbers of interacting proteins. We used dynamic force spectroscopy to estimate the intermolecular potential widths and equivalent thermodynamic off rates for monovalent, bivalent, and trivalent interactions. Measured interaction potential parameters agree with the results of molecular docking simulation. Our results demonstrate that an increase of the interaction valency leads to a precipitous decline in the dissociation rate. Binding forces measured for monovalent and multivalent interactions match the predictions of a Markovian model for the strength of multiple uncorrelated bonds in a parallel configuration. Our approach is promising for comparison of the specific effects of molecular modifications as well as for determination of the best configuration of antibody-based multivalent targeting agents.

Amino Acid Sequence↗

PubMed2006

Synthesis, in vitro and in silico evaluation of l-tyrosine containing PPARalpha/gamma dual agonists.

A novel series of l-tyrosine derivatives have been reported with potential PPARalpha/gamma dual agonistic activity. In vitro cell based PPARalpha/gamma transactivation studies have shown compound 4a and compound 4f to be the most potent PPARgamma and PPARalpha activators, respectively. Molecular docking studies performed on these series of compounds have complemented the experimental results and have led to interesting inferences.

Computational Biology↗

PubMed2005

Development of a three-dimensional model for the N-methyl-D-aspartate NR2A subunit.

NR2 subunits of N-methyl-d-aspartic acid (NMDA) receptors are known to bind the neurotransmitter glutamate, competitive agonists, and antagonists. Since crystallographic data of these proteins are not available, we built a homology model of the ligand binding domain of the NR2A subunit. A consensus binding mode of selected AP5-like NMDA antagonists has been ascertained using molecular docking. The present 3D model gives insights for the design of new NMDA subtype selective compounds.

Amino Acid Sequence↗

PubMed2002

Crystal structure of the platelet glycoprotein Ib(alpha) N-terminal domain reveals an unmasking mechanism for receptor activation.

Glycoprotein Ib (GPIb) is a platelet receptor with a critical role in mediating the arrest of platelets at sites of vascular damage. GPIb binds to the A1 domain of von Willebrand factor (vWF-A1) at high blood shear, initiating platelet adhesion and contributing to the formation of a thrombus. To investigate the molecular basis of GPIb regulation and ligand binding, we have determined the structure of the N-terminal domain of the GPIb(alpha) chain (residues 1-279). This structure is the first determined from the cell adhesion/signaling class of leucine-rich repeat (LRR) proteins and reveals the topology of the characteristic disulfide-bonded flanking regions. The fold consists of an N-terminal beta-hairpin, eight leucine-rich repeats, a disulfide-bonded loop, and a C-terminal anionic region. The structure also demonstrates a novel LRR motif in the form of an M-shaped arrangement of three tandem beta-turns. Negatively charged binding surfaces on the LRR concave face and anionic region indicate two-step binding kinetics to vWF-A1, which can be regulated by an unmasking mechanism involving conformational change of a key loop. Using molecular docking of the GPIb and vWF-A1 crystal structures, we were also able to model the GPIb.vWF-A1 complex.

Amino Acid Sequence↗

PubMed2003

Strategy of computer-aided drug design.

Modern strategies of computer-aided drug design (CADD) are reviewed. The task of CADD in the pipeline of drug discovery is accelerating of finding the new lead compounds and their structure optimization for the following pharmacological tests. The main directions in CADD are based on the availability of the experimentally determined three-dimensional structure of the target macromolecule. If spatial structure is known the methods of structure-based drug design are used. In the opposite case the indirect methods of CADD based on the structures of known ligands (ligand-based drug design) are used. The interrelationship between the main directions of CADD is reviewed. The main CADD approaches of molecule de novo design and database mining are described. They include methods of molecular docking, de novo design, design of pharmacophore and quantity structure-activity relationship models. New ways and perspectives of CADD are discussed.

Computational Biology↗

PubMed2005

An effective simulation of aqueous micellar aggregates by computational models.

We have computationally studied the interaction modes, localization and orientation of a benzene (Bz) molecule on the surface of micelles formed by cetyltrimethylammonium salts CTAX. Experimental 1H-NMR data on complexation shifts induced by Bz on the polar head hydrogens and on the adjacent methylene hydrogens of CTAX have been interpreted using a computational approach that combines an automatic molecular docking procedure with a calculation module that accounts for NMR complexation shifts due to ring current diamagnetic anisotropy. Three different models were used to reduce the complexity of the micellar system. Computational results, in good agreement with available experimental data, point to a preferential localization of the Bz molecule along the CTAX alkyl tail, about 3.9 angstroms away from the charged nitrogen. The Bz molecular plane is predicted perpendicular to the C-H bonds of the alkyl tail. The good results obtained with the simplest model suggest that it could be used to study more complex systems involving surfactants endowed with molecular recognition or catalytic abilities.

Catalysis↗

PubMed2006

Chemogenomics approaches to G-protein coupled receptor lead finding.

G-protein coupled receptors (GPCRs) are promising targets for the discovery of novel drugs. In order to identify novel chemical series, high-throughput screening (HTS) is often complemented by rational chemogenomics lead finding approaches. We have compiled a GPCR directed screening set by ligand-based virtual screening of our corporate compound database. This set of compounds is supplemented with novel libraries synthesized around proprietary scaffolds. These target-directed libraries are designed using the knowledge of privileged fragments and pharmacophores to address specific GPCR subfamilies (e.g., purinergic or chemokine-binding GPCRs). Experimental testing of the GPCR collection has provided novel chemical series for several GPCR targets including the adenosine A1, the P2Y12, and the chemokine CCR1 receptor. In addition, GPCR sequence motifs linked to the recognition of GPCR ligands (termed chemoprints) are identified using homology modeling, molecular docking, and experimental profiling. These chemoprints can support the design and synthesis of compound libraries tailor-made for a novel GPCR target.

Animals↗

PubMed2004

Structure-based virtual screening and biological evaluation of potent and selective ADAM12 inhibitors.

We describe a series of potent and selective inhibitors of ADAM12 that were discovered using computational screening of a focused virtual library. The initial structure-based virtual screening selected 64 compounds from a 3D database of 67,062 molecules. Being evaluated by a cell-based ADAM12 activity assay, compounds 5, 11, 14, 16 were further identified as the potent and selective inhibitors of ADAM12 with low nanomolar IC50 values. The mechanism underlying the potency and selectivity of a representative compound, 5, was investigated through molecular docking studies.

ADAM Proteins↗

PubMed2000

Oligomerization reduces heparin affinity but enhances receptor binding of fibroblast growth factor 2.

The biological response of cells to fibroblast growth factors (FGFs) depends on heparan sulphate glycosaminoglycans sharing particular structural motifs. Heparin induced FGF dimerization has been suggested to mediate receptor dimerization and activation. Here we demonstrate that heparin-derived oligosaccharides that promote receptor binding and activation specifically induce the dimerization of basic FGF (FGF2). These heparin-induced dimers of FGF2 acquire high affinity for receptor binding and are biologically active. Using biotinylated FGF2 bound to immobilized streptavidin gradually saturated with biotin, enabled a quantitative analysis of heparin-dependent and heparin-independent FGF2 monomers and oligomers. Streptavidin induced FGF2 dimers bind and activate FGF receptors only in the presence of heparin. An excess of streptavidin, forcing biotin-FGF2 into monomers, reduces receptor binding and blocks FGF-dependent cell proliferation. All these suggest predominant receptor binding and activation by heparin associated FGF2 oligomers. Unexpectedly, heparin induced dimers and higher order oligomers lose most of their affinity towards heparin. Direct binding of soluble FGF receptors (FGFRs) to either monomers or dimers of FGF2, immobilized on heparin, confirm the preferred association of FGFRs with dimers of FGF2. Computerized molecular docking predicts a cis-oriented FGF2 dimer, stabilized by heparin, which complies with all the experimental data.

Animals↗

PubMed1995

Hydration of nucleic acid fragments: comparison of theory and experiment for high-resolution crystal structures of RNA, DNA, and DNA-drug complexes.

A computationally efficient method to describe the organization of water around solvated biomolecules is presented. It is based on a statistical mechanical expression for the water-density distribution in terms of particle correlation functions. The method is applied to analyze the hydration of small nucleic acid molecules in the crystal environment, for which high-resolution x-ray crystal structures have been reported. Results for RNA [r(ApU).r(ApU)] and DNA [d(CpG).d(CpG) in Z form and with parallel strand orientation] and for DNA-drug complexes [d(CpG).d(CpG) with the drug proflavine intercalated] are described. A detailed comparison of theoretical and experimental data shows positional agreement for the experimentally observed water sites. The presented method can be used for refinement of the water structure in x-ray crystallography, hydration analysis of nuclear magnetic resonance structures, and theoretical modeling of biological macromolecules such as molecular docking studies. The speed of the computations allows hydration analyses of molecules of almost arbitrary size (tRNA, protein-nucleic acid complexes, etc.) in the crystal environment and in aqueous solution.

Crystallography, X-Ray↗

PubMed2004

Binding crevice for TT-232 in a homology model of type 1 somatostatin receptor.

Somatostatin receptor type 1 was modelled based on the atomic structure of bovine rhodopsin. Possible ways of binding interaction between somatostatin receptor type 1 and TT-232, a cycloheptapeptide analogue of somatostatin with broad therapeutic potential, were analysed by molecular docking. The twelve TT-232 conformations, obtained by NMR measurements in H(2)O-D(2)O mixture, were similar, disclosing a consensus backbone conformation. Several residues interacting with TT-232, such as Val133, Asp137 (helix 3), Arg197 (helix 4), Phe287, Gln291, Asn294 (helix 6), Ser305, and Tyr313 (helix 7), were found. In accordance, in vitro binding experiments indicated high-affinity binding of TT-232 to (125)I labelled somatostatin sites in brain membranes. The single binding crevice obtained by docking may allow the design and discovery of new peptidomimetics of TT-232 in the future.

Amino Acid Sequence↗

PubMed2006

Impact of species-dependent differences on screening, design, and development of MAO B inhibitors.

The impact of species-dependent differences between human and rat MAO B on inhibitor screening was evidenced for two classes of compounds, coumarin and 5H-indeno[1,2-c]pyridazin-5-one derivatives. All examined compounds have shown a greater inhibitor potency toward human MAO B than toward rat MAO B. Moreover, no correlation was found between human and rat pIC(50) values. These divergences have important implications for the design and development of drugs involved in the MAO B metabolic pathway, suggesting that results obtained using rat enzyme cannot be extrapolated to human CNS, a priori. Indeed, the selection of a hit compound for lead generation could be different using human rather than rat enzyme. Moreover, the influence of substituents on the in vitro inhibition of human MAO B was markedly different between homogeneous series of coumarin and 5H-indeno[1,2-c]pyridazin-5-one derivatives, suggesting different binding modes, a hypothesis clearly supported by molecular docking simulations of inhibitors into the active site of human MAO B.

Animals↗

PubMed2006

Solid-phase synthesis and pharmacological evaluation of a library of peptidomimetics as potential farnesyltransferase inhibitors: an approach to new lead compounds.

Oncogenic Ras proteins whose activation is farnesylation by farnesyltransferase have been seen as important targets for novel anticancer drugs. Inhibitors of this enzyme have already been developed as potential anti-cancer drugs, particularly by rational design based on the structure of the CA(1)A(2)X carboxyl terminus of Ras. Synthesis of a peptidomimetics library via solid-phase synthesis using the Multipin method is described here. The most active hits on cellular assays were resynthesized and enzymatic activity was measured. Compounds A1, A5 and A7 present significant activity on the isolated enzyme (IC(50)=117, 57.3 and 28.5 nM) and their molecular docking in the active site of the enzyme provides details on key interactions with the protein.

Enzyme Inhibitors↗

PubMed2005

[Progress in the molecular mechanisms of nuclear coactivator PGC-1].

Peroxisome proliferators-activated receptor-gamma coactivator-1 is broadly involved in several key cellular pathways including mitochondrial biogenesis, hepatic gluconeogenesis via interacting with many transcription factors, which is highly valuable to maintain the energy balance of organisms. This review especially focuses on the recent progress in the molecular docking, histone acetylation, RNA processing basing on the structure of PGC-1 gene and amino acid sequence. Besides, the prospect of PGC-1 in applications of metabolic syndromes has been discussed also.

Acetylation↗

PubMed2006

Conformational analysis of the blue-light sensing protein YtvA reveals a competitive interface for LOV-LOV dimerization and interdomain interactions.

The Bacillus subtilis protein YtvA is related to plant phototropins in that it senses UVA-blue-light by means of the flavin binding LOV domain, linked to a nucleotide-binding STAS domain. The structural basis for interdomain interactions and functional regulation are not known. Here we report the conformational analysis of three YtvA constructs, by means of size exclusion chromatography, circular dichroism (CD) and molecular docking simulations. The isolated YtvA-LOV domain (YLOV, aa 25-126) has a strong tendency to dimerize, prevented in full-length YtvA, but still observed in YLOV carrying the N-terminal extension (N-YLOV, aa 1-126). The analysis of CD data shows that both the N-terminal cap and the linker region (aa 127-147) between the LOV and the STAS domain are helical and that the central beta-scaffold is distorted in the LOV domains dimers. The involvement of the central beta-scaffold in dimerization is supported by docking simulation of the YLOV dimer and the importance of this region is highlighted by light-induced conformational changes, emerging from the CD data analysis. In YtvA, the beta-strand fraction is notably less distorted and distinct light-driven changes in the loops/turn fraction are detected. The data uncover a common surface for LOV-LOV and intraprotein interaction, involving the central beta-scaffold, and offer hints to investigate the molecular basis of light-activation and regulation in LOV proteins.

Amino Acid Sequence↗

PubMed2006

Comparative and pharmacophore model for deacetylase SIRT1.

Sirtuins are NAD-dependent histone deacetylases, which cleave the acetyl-group from acetylated proteins, such as histones but also the acetyl groups from several transcription factors, and in this way can change their activities. Of all seven mammalian SirTs, the human sirtuin SirT1 has been the most extensively studied. However, there is no crystal structure or comparative model reported for SirT1. We have therefore built up a three-dimensional comparison model of the SirT1 protein catalytic core (domain area from residues 244 to 498 of the full length SirT1) in order to assist in the investigation of active site-ligand interactions and in the design of novel SirT1 inhibitors. In this study we also propose the binding-mode of recently reported set of indole-based inhibitors in SirT1. The site of interaction and the ligand conformation were predicted by the use of molecular docking techniques. To distinguish between active and inactive compounds, a post-docking filter based on H-bond network was constructed. Docking results were used to investigate the pharmacophore and to identify a filter for database mining.

Amino Acid Sequence↗

PubMedDate not supplied

Binding of fatty acids to beta-cryptogein: quantitative structure-activity relationships and design of selective protein mutants.

Binding of fatty acids to cryptogein, the proteinaceous elicitor from Phytophthora, was studied by using molecular docking and quantitative structure-activity relationships analysis. Fatty acids bind to the groove located inside the cavity of cryptogein. The structure-activity model was constructed for the set of 27 different saturated and unsaturated fatty acids explaining 87% (81% cross-validated) of the quantitative variance in their binding affinity. The difference in binding between saturated and unsaturated fatty acids was described in the model by three electronic descriptors: the energy of the lowest unoccupied molecular orbital, the energy of the highest occupied molecular orbital, and the heat of formation. The presence of double bonds in the ligand generally resulted in stronger binding. The difference in binding within the group of saturated fatty acids was explained by two steric descriptors, i.e., ellipsoidal volume and inertia moment of length, and one hydrophobicity descriptor, i.e., lipophility. The developed model predicted strong binding for two biologically important molecules, geranylgeranyol and farnesol playing an important role in plant signaling as lipid anchors of some membrane proteins. Elicitin mutants selectively binding only one type of ligand were designed for future experimental studies.

Algal Proteins↗