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PubMed2005

The docking technique for posterolateral corner reconstruction.

Posterolateral corner injuries of the knee are an uncommon but potentially debilitating injury. They are easily missed on physical examination and are often associated with alternate ligament pathology. When identified early, these injuries are best managed by primary repair with or without augmentation of the involved structures. However, chronic injuries are generally not amenable to primary repair and often require reconstruction. Experimental data suggest that the lateral collateral ligament and popliteofibular ligament present critical biomechanical restraints of the posterolateral aspect of the knee and should be incorporated into contemporary reconstruction techniques. We describe a novel method of reconstructing these critical components of the posterolateral corner using a new docking technique for fixation on the femur with a graft placed through a fibular head tunnel.

Humans↗

PubMed2005

The Cas family docking protein, HEF1, promotes the formation of neurite-like membrane extensions.

The Cas family proteins are a family of adhesion docking molecules that mediate protein-protein interactions and contribute to a number of signal transduction pathways. Recent studies of two family members, p130Cas and Sin, have suggested that they may play a role in neurite formation. The current study demonstrates that the third family member, HEF1, can also stimulate the formation of neurite-like processes, in the presence of Rho kinase inhibitors. The HEF1-promoted processes actively extend from the cell body and resemble neurites both in the manner of process extension and in the distribution of adhesion-associated molecules. The HEF1-promoted processes are dependent on the presence of an intact microtubule system and can be inhibited by co-expression of either constitutively active Rac or Cdc42 GTPase. Together, our data support a role for the Cas proteins in regulating cellular morphologies that contribute to tissue specialization.

Adaptor Proteins, Signal Transducing↗

PubMed2005

A common docking site for response regulators on the yeast phosphorelay protein YPD1.

In Saccharomyces cerevisiae, a multi-component phosphorelay signal transduction pathway mediates cellular responses to environmental stress. A histidine-containing phosphotransfer protein, YPD1, represents a bifurcation point between the SLN1-YPD1-SSK1 pathway responsible for osmotic stress responses and the SLN1-YPD1-SKN7 pathway involved in cell wall biosynthesis and cell cycle control. The phosphorelay protein YPD1 must physically interact with and transfer phosphoryl groups between three homologous response regulator domains, designated SLN1-R1, SSK1-R2, and SKN7-R3. In this comparative study, the molecular basis of interaction was examined between YPD1 and each of the three response regulator domains utilizing alanine scanning mutagenesis combined with a yeast two-hybrid assay. Results from the yeast two-hybrid assay indicate that all three response regulator domains bind to a common area, largely hydrophobic in nature, on the surface of YPD1. We postulate that other YPD1 surface residues surrounding this common docking site are involved in making specific interactions with one or more of the response regulator domains.

Alanine↗

PubMed2005

Fibril modelling by sequence and structure conservation analysis combined with protein docking techniques: beta(2)-microglobulin amyloidosis.

Obtaining atomic resolution structural models of amyloid fibrils is currently impossible, yet crucial for our understanding of the amyloid mechanism. Different pathways in the transformation of a native globular domain to an amyloid fibril invariably involve domain destabilization. Hence, locating the unstable segments of a domain is important for understanding its amyloidogenic transformation and possibly control it. Since relative conservation is suggested to relate to local stability, we performed an extensive, sequence and structure conservation analysis of the beta(2)-microglobulin (beta(2)-m) domain. Our dataset include 51 high resolution structures belonging to the "C1 set domain" family and 132 clustered PSI-BLAST search results. Segments of the beta(2)-m domain corresponding to strands A (residues 12-18), D (45-55) and G (91-95) were found to be less conserved and stable, while the central strands B (residues 22-28), C (36-41), E (62-70) and F (78-83) were found conserved and stable. Our findings are supported by accumulating observations from various experimental methods, including urea denaturation, limited proteolysis, H/D exchange and structure determination by both NMR and X-ray crystallography. We used our conservation findings together with experimental literature information to suggest a structural model for the polymerized unit of beta(2)-m. Pairwise protein docking and subsequent monomer stacking in the same manner suggest a fibril model consistent with the cross-beta structure.

Amyloid↗

PubMed2006

Prediction of the binding mode between BMS-378806 and HIV-1 gp120 by docking and molecular dynamics simulation.

BMS-378806 is a newly discovered small molecule that effectively blocks the binding of CD4 with gp120. The binding mode of this kind of inhibitor remains unknown. In this paper, AutoDock 3.0 in conjunction with molecular dynamics simulation, accommodating the receptor's flexibility, was used to explore the binding mode between BMS-378806 and gp120. Two structures, Mode I and Mode II, with the lowest docking energy were selected as different representative binding modes. The analysis of the results from the molecular dynamics simulation indicated that the binding of BMS-348806 in Mode II is more stable. The average structure of Mode II was analyzed and compared with the experimental data. The conclusion was that BMS-378806 inserts the azaindole ring deeply into the PHE43 cavity and makes contact with a number of residues in the cavity, on the cavity and near the cavity. This study benefits the understanding of the mechanism of this kind of inhibitor and may provide useful information for rational drug design.

Binding Sites↗

PubMed2003

SOCS-3 inhibits IL-12-induced STAT4 activation by binding through its SH2 domain to the STAT4 docking site in the IL-12 receptor beta2 subunit.

IL-12 promotes the proliferation of T cells as well as NK cells and plays a critical role in induction of the Th1 differentiation. IL-12 mediates its biological activities through activation of the receptor-associated JAK family kinases and STAT4, which is recruited to phosphorylated Tyr-800 in the human IL-12 receptor beta2 subunit (IL-12Rbeta2). Here we demonstrate that suppressor of cytokine signaling-3 (SOCS-3) is also recruited to IL-12Rbeta2 by the interaction involving the SOCS-3 SH2 domain and phosphorylated Tyr-800 in IL-12Rbeta2. Furthermore, SOCS-3, but not its SH2 domain-defective mutant, inhibited the IL-12-induced activation of DNA-binding and transcriptional activities of STAT4. These results suggest that SOCS-3, expressed at high levels in Th2 cells, plays an inhibitory role in STAT4-mediated IL-12 signaling by binding to the STAT4 docking site in IL-12Rbeta2, thus raising a possibility that SOCS-3 may play a role in regulation of Th differentiation.

Animals↗

PubMed2004

Binding site analysis of full-length alpha1a adrenergic receptor using homology modeling and molecular docking.

The recent availability of crystal structure of bovine rhodopsin offers new opportunities in order to approach the construction of G protein coupled receptors. This study focuses the attention on the modeling of full-length alpha(1a) adrenergic receptor (alpha(1a)-AR) due to its biological role and significant implications in pharmacological treatment of benign prostate hyperplasia. This work could be considered made up by two main steps: (a) the construction of full structure of alpha(1a)-AR, through homology modeling methods; (b) the automated docking of an endogenous agonist, norepinephrine, and of an antagonist, WB-4101, using BioDock program. The obtained results highlight the key residues involved in binding sites of both agonists and antagonists, confirming the mutagenesis data and giving new suggestions for the rational design of selective ligands.

Amino Acid Sequence↗

PubMed2004

Base docking model of the homomeric alpha7 nicotinic receptor-beta-amyloid(1-42) complex.

A homology model of the human alpha7 nicotinic receptor was constructed based on the acetylcholine-binding protein crystal structure. Subsequently, the three-dimensional structure of the complex between the alpha7 nicotinic receptor and the 42-amino acid beta-amyloid peptide was obtained for the first time with the aid of the ESCHER program, a well-known method for protein-protein docking. The final complex showed that the most important interactions occur between the residues V12-K28 from the peptide and the loop C of the receptor. The model agrees with many experimental data, and may be used as a base model for further detailed studies in order to gain insight into the binding and dynamics of the complex at molecular level and their correlation with the memory impairments characteristic of the Alzheimer's disease.

Amyloid beta-Peptides↗

PubMed2004

Organization of functional domains in the docking protein p130Cas.

The docking protein p130Cas becomes phosphorylated upon cell adhesion to extracellular matrix proteins, and is thought to play an essential role in cell transformation. Cas transmits signals through interactions with the Src-homology 3 (SH3) and Src-homology 2 domains of FAK or v-Crk signaling molecules, or with 14-3-3 protein, as well as phosphatases PTP1B and PTP-PEST. The large (130kDa), multi-domain Cas molecule contains an SH3 domain, a Src-binding domain, a serine-rich protein interaction region, and a C-terminal region that participates in protein interactions implicated in antiestrogen resistance in breast cancer. In this study, as part of a long-term goal to examine the protein interactions of Cas by X-ray crystallography and nuclear magnetic resonance spectroscopy, molecular constructs were designed to express two adjacent domains, the serine-rich domain and the Src-binding domain, that each participate in intermolecular contacts dependent on protein phosphorylation. The protein products are soluble, homogeneous, monodisperse, and highly suitable for structural studies to define the role of Cas in integrin-mediated cell signaling.

14-3-3 Proteins↗

PubMed2005

Docking protein Gab2 positively regulates glycoprotein VI-mediated platelet activation.

Gab2, a recently identified docking protein, contains a pleckstrin homology domain and potential binding sites for SH2 and SH3 domain-containing proteins. Gab2 has been shown to support growth, differentiation, and function in a number of haematopoietic cells, although its role in platelets remains to be determined. Here we report that cross-linking of the collagen receptor GPVI by the snake venom toxin convulxin stimulates tyrosine phosphorylation of Gab2. Furthermore, platelet aggregation induced by submaximal concentrations of convulxin is attenuated in the absence of Gab2, although recovery is seen with higher concentrations of the toxin. Consistent with this, tyrosine phosphorylation of Fc receptor gamma-chain, Syk, Btk, and phospholipase Cgamma2 by convulxin is reduced in the absence of Gab2. In comparison, the G protein-coupled receptor agonist, thrombin, does not induce phosphorylation of Gab2 and aggregation is unaltered in the absence of the toxin. These findings provide evidence for a functional role of Gab2 in supporting platelet activation by GPVI.

Adaptor Proteins, Signal Transducing↗

PubMed2006

On the human CYP2C9*13 variant activity reduction: a molecular dynamics simulation and docking study.

Cytochrome P450 2C9 (CYP2C9) plays a key role in the metabolism of clinical drugs. CYP2C9 is a genetically polymorphic enzyme and some of its allelic variants have less activity compared to the wild-type form. Drugs with a narrow therapeutic index may cause serious toxicity to the individuals who carry such allele. CYP2C9*13, firstly identified by some of the present authors in a Chinese poor metabolizer of lornoxicam, is characterized by mutation encoding Leu90Pro substitution. Kinetic experiments show that CYP2C9*13 has less catalytic activity in elimination of diclofenac and lornoxicam in vitro. In order to explore the structure-activity relationship of CYP2C9*13, the three-dimensional structure models of the substrate-free CYP2C9*1 and its variant CYP2C9*13 are constructed on the basis of the X-ray crystal structure of human CYP2C9*1 (PDB code 1R9O) by molecular dynamics simulations. The structure change caused by Leu90Pro replacement is revealed and used to explain the dramatic decrease of the enzymatic activity in clearance of the two CYP2C9 substrates: diclofenac and lornoxicam. The trans configuration of the bond between Pro90 and Asp89 in CYP2C9*13 is firstly identified. The backbone of residues 106-108 in CYP2C9*13 turns over and their side chains block the entrance for substrates accessing so that the entrance of *13 shrinks greatly than that in the wild-type, which is believed to be the dominant mechanism of the catalytic activity reduction. Consequent docking study which is consistent with the results of the kinetic experiments by Guo et al. identifies the most important residues for enzyme-substrate complexes.

Amino Acid Substitution↗

PubMed2005

Preparation of antitumor oxaliplatin/cisplatin docking dinuclear platinum complex.

A new dinuclear docking Pt(II) complex, (cis-diammine) (l-1,2-cyclohexanediamine)(mu-dichloro)-diplatinum(II) oxalate was synthesized by reacting oxaliplatin(l-OHP, [Pt(oxalato)(L-dach)]), L-dach = 1R, 2R-cyclohexanediamine), with cisplatin (CDDP). Elemental analysis of the compound indicated that it was 1:1 molar ratio complex of oxaliplatin and cisplatin. A plausible chemical structure has been proposed as Cl(-) bridged dinuclear complex, judged from its yellow coloration and NMR spectral analysis. This complex can be denoted as, i.e. [Pt(2)Cl(2)(NH(3))(2)(L-dach)](COO)(2) (L-OHP/CDDP). The complex showed higher cytotoxicity against L1210 than the parent complexes and low cross-resistance against L1210/CDDP and L1210/DACH. Its antitumor activity was also tested in vivo against murine leukemia L1210 cell lines. The complex showed much higher activity than the mixture(1:1 molar ratio) of oxaliplatin and cisplatin. The antitumor effect against L1210/CDDP was very high, showing collateral sensitivity, being similar to that of oxaliplatin, and against L1210/DACH it showed no cross-resistance.

Animals↗

PubMed2003

Structure-based drug design: synthesis, crystal structure, biological evaluation and docking studies of mono- and bis-benzo[b]oxepines as non-steroidal estrogens.

Mono- and bis-benzo[b]oxepine derivatives have been rationally synthesized to meet the molecular requirement for interaction with estrogen receptor. Bis-benzo[b]oxepines (7 and 9) and mono-benzo[b]oxepine (10) acquire geometry with phenolic groups disposed in a fashion to stimulate estrogen receptor. Structure-based investigation, in vivo activity and docking studies have been described and correlated to demonstrate a practical approach for suitable ligand design.

Drug Design↗

PubMed2004

Computational studies of COX-2 inhibitors: 3D-QSAR and docking.

The 3D-QSAR (three-dimensional quantitative structure-activity relationships) studies for 88 selective COX-2 (cyclooxygenase-2) inhibitors belonging to three chemical classes (triaryl rings, diaryl cycloalkanopyrazoles, and diphenyl hydrazides) were conducted using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). Partial least squares analysis produced statistically significant models with q(2) values of 0.84 and 0.79 for CoMFA and CoMSIA, respectively. The binding energies calculated from flexible docking were correlated with inhibitory activities by the least-squares fit method. The three chemical classes of inhibitors showed reasonable internal predictability (r(2)=0.51, 0.49, and 0.54), but the sulfonyl-containing inhibitors demonstrated distinctively low binding energy compared to the others. The electrostatic interaction energy between the Arg513 of the COX-2 active site and sulfonyl group of the triaryl rings seemed to have the responsibility for difference in binding energy. Comparative binding energy (COMBINE) analyses gave q(2) values of 0.64, 0.63, and 0.50 for triaryl rings, diaryl cycloalkanopyrazoles, and diphenyl hydrazides, respectively. In this COMBINE model, some protein residues were highlighted as particularly important for inhibitory activity. The combination of ligand-based and structure-based models provided an improved understanding in the interaction between the three chemical classes and the COX-2.

Binding Sites↗

PubMed2004

Inhibitory mode of indole-2-carboxamide derivatives against HLGPa: molecular docking and 3D-QSAR analyses.

The interaction of a series of indole-2-carboxamide compounds with human liver glycogen phosphorylase a (HLGPa) have been studied employing molecular docking and 3D-QSAR approaches. The Lamarckian Genetic Algorithm (LGA) of AutoDock 3.0 was employed to locate the binding orientations and conformations of the inhibitors interacting with HLGPa. The binding models were demonstrated in the aspects of inhibitor's conformation, subsite interaction, and hydrogen bonding. The very similar binding conformations of these inhibitors show that they interact with HLGPa in a very similar way. Good correlations between the calculated interaction free energies and experimental inhibitory activities suggest that the binding conformations of these inhibitors are reasonable. The structural and energetic differences in inhibitory potencies of indole-2-carboxamide compounds were reasonably explored. Using the binding conformations of indole-2-carboxamides, consistent and highly predictive 3D-QSAR models were developed by CoMFA and CoMSIA analyses. The q2 values are 0.697 and 0.622 for CoMFA and CoMSIA models, respectively. The predictive ability of these models was validated by four compounds that were not included in the training set. Mapping these models back to the topology of the active site of HLGPa leads to a better understanding of the vital indole-2-carboxamide-HLGPa interactions. Structure-based investigations and the final 3D-QSAR results provide clear guidelines and accurate activity predictions for novel inhibitor design.

Binding Sites↗

PubMed2004

A molecular docking study of estrogenically active compounds with 1,2-diarylethane and 1,2-diarylethene pharmacophores.

Numerous selective estrogen receptor modulators (SERMs) have been synthesized and assayed in recent years. The focus of this study is to apply coarse-grain molecular docking procedures coupled with fine-grain all-atom force field optimization strategies to shed light on the binding mechanisms of currently available estrogen receptor-active compounds. Although the mechanics of ligand binding in estrogen receptors is generally well understood, there is room for surprises. In this paper computational evidence corroborating the experimentally observed type I agonistic binding mode for estradiol (E2) and diethylstilbesterol (DES) and the type II antagonistic binding mode for 4-hydroxytamoxifen and raloxifen is presented. Included in this type I agonistic mode are the DES derivatives, transstilbene and 1,2-diaryldiaminoethane. In addition, a novel 'type II agonistic' binding mode for 2,3-diarylimidazolines, 4,5-diarylimidazoles, 2,3-diarylpiperazines is introduced. This mode is stabilized by suggesting alternative hydrogen bond anchor points in the ligand binding domain as potential leads for future drug design.

Computer Simulation↗

PubMed2005

Structure-based discovery of human L-xylulose reductase inhibitors from database screening and molecular docking.

Human L-xylulose reductase (XR) is an enzyme of the glucuronic acid/uronate cycle of glucose metabolism and is a possible target for treatment of the long-term complications of diabetes. In this study we utilised the molecular modelling program DOCK to analyse the 249,071 compounds of the National Cancer Institute Database and retrieved those compounds with high predicted affinity for XR. Several carboxylic acid-based compounds were tested and shown to inhibit XR. These included nicotinic acid (IC50=100 microM), benzoic acid (IC50=29 microM) and their derivatives. These results extend and improve upon the activities of known, commercially available inhibitors of XR such as the aliphatic fatty acid n-butyric acid (IC50=64 microM). To optimise the interaction between the inhibitor and the holoenzyme, the program GRID was used to design de novo compounds based on the inhibitor benzoic acid. The inclusion of a hydroxy-phenyl group and a phosphate to the benzoic acid molecule increased the net binding energy by 1.3- and 2.4-fold, respectively. The resultant compounds may produce inhibitors with improved specificity for XR.

Binding Sites↗

PubMed2005

Cell adhesion inhibitory activity of (d)-corynoline, a hexahydrobenzo[c]phenanthridine-type alkaloid, and its structure-activity relationship, studied by X-ray crystal structure analysis and molecular docking study.

Corynoline (1), a hexahydrobenzo[c]phenanthridine-type alkaloid, exhibited the concentration-dependent inhibition for the adhesion of human polymorphonuclear leukocyte and eosinophil to human umbilical vein cultured endothelial cell in the concentration range of showing no significant cytotoxicity for the cell: IC(50) value=72.4 microM for (d)-1 and 156.7 microM for (l)-1. This shows the potent anti-inflammatory and/or immunosuppressive activity of 1. To elucidate possible structure-activity relationship, the conformational/structural feature of (d)-1 was investigated by X-ray crystal structure analysis and molecular orbital energy calculations, and the docking study was performed for its interaction with the D1-domain of ICAM-1 (intracellular adhesion molecule-1). A plausible model was proposed, in which all polar atoms of (d)-1 are linked by hydrogen bonds or electrostatic interactions with the functional residues of ICAM-1, that have been supposed to be necessary for the binding with LFA-1 (leukocyte function-associated antigen-1). This suggests the potent inhibitory activity of 1 for the ICAM-1/LFA-1 adhesion and would be important on developing the clinically usable drugs for the inflammatory diseases.

Berberine Alkaloids↗