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PubMed2006

Arylthiopyrrole (AThP) derivatives as non-nucleoside HIV-1 reverse transcriptase inhibitors: synthesis, structure-activity relationships, and docking studies (part 1).

Novel arylthio isopropyl pyridinylmethylpyrrolemethanol (AThP) derivatives 3-5, which are related to capravirine (S-1153), were synthesized and tested for their ability to block the replication cycle of HIV-1 in infected cells. The newly synthesized AThPs are active in the concentration range of 0.008-53 microM. Even if compounds 3-5 are generally less potent than S-1153, their SI values are in some cases similar to that of the reference drug. In fact, the cytotoxicities of AThPs are generally lower than that of S-1153. Compound 4e was the most active derivative of this series in cell-based assays; its potency is similar to that of S-1153 (EC(50)=8 and 3 nM, respectively), as is its selectivity index (SI=6250 and 7000, respectively). AThP derivatives were proven to target HIV-1 RT. In fact, compounds 3-5 generally inhibited the viral enzyme at concentrations similar to those observed in cell-based assays. A selected number of AThPs (4k and 5a,e) were tested against clinically relevant drug-resistant forms of recombinant reverse transcriptase (rRT) carrying the K103N and Y181I mutations. Carbamate 5e showed an approximate 240-fold decrease in activity against Y181I, but only a 10-fold loss in potency against the K103N rRT form. Docking calculations were also performed to investigate the binding mode of compounds 2, 4e, 4j, 4k and 5e into the non-nucleoside binding site of HIV-1 RT and to rationalize some structure-activity relationships and resistance data.

Binding Sites↗
PubMed2007

Design, syntheses, biological evaluation, and docking studies of 2-substituted 5-methylsulfonyl-1-phenyl-1H-indoles: potent and selective in vitro cyclooxygenase-2 inhibitors.

Four series of 5-methylsulfonyl-1-phenyl-1H-indole-2-carboxylic acid alkyl esters (family A), -2-carbonitriles (family B), -2-carboxamides (family C), and 2-benzoyl-5-methylsulfonyl-1-phenyl-1H-indoles (family D) were prepared and evaluated for their ability to inhibit purified cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1). Family D compounds have the best COX-1/COX-2 inhibition ratios and potencies. According to docking studies, these molecules appear to bind the COX-2 binding site differently than indomethacin, with the insertion of the substituent at the 2-position in the hydrophobic pocket of the enzyme and the 1-position phenyl ring in the trifluoromethyl zone. Among the group of compounds evaluated, 2-(4-chlorobenzoyl)-1-(4-chlorophenyl)-5-methylsulfonyl-1H-indole and 2-(4-chlorophenyl)-5-methylsulfonyl-1-(4-trifluoromethylphenyl)-1H-indole emerged as the most potent (respective IC(50) values: 46 and 43 nM), and selective (respective selectivity indexes: >2163 and >2331) COX-2 inhibitors.

Algorithms↗
PubMed2002

Docking protein SNT1 is a critical mediator of fibroblast growth factor signaling during Xenopus embryonic development.

The docking protein SNT1/FRS2 (fibroblast growth factor receptor substrate 2) is implicated in the transmission of extracellular signals from several growth factor receptors to the mitogen-activated protein (MAP) kinase signaling cascade, but its biological function during development is not well characterized. Here, we show that the Xenopus homolog of mammalian SNT1/FRS-2 (XSNT1) plays a critical role in the appropriate formation of mesoderm-derived tissue during embryogenesis. XSNT1 has an expression pattern that is quite similar to the fibroblast growth factor receptor-1 (FGFR1) during Xenopus development. Ectopic expression of XSNT1 markedly enhanced the embryonic defects induced by an activated FGF receptor, and increased the MAP kinase activity as well as the expression of a mesodermal marker in response to FGF receptor signaling. A loss-of-function study using antisense XSNT1 morpholino oligonucleotides (XSNT-AS) shows severe malformation of trunk and posterior structures. Moreover, XSNT-AS disrupts muscle and notochord formation, and inhibits FGFR-induced MAP kinase activation. In ectodermal explants, XSNT-AS blocks FGFR-mediated induction of mesoderm and the accompanying elongation movements. Our results indicate that XSNT1 is a critical mediator of FGF signaling and is required for early Xenopus development.

Adaptor Proteins, Signal Transducing↗
PubMed1997

Ligation of the T cell antigen receptor induces tyrosine phosphorylation of p105CasL, a member of the p130Cas-related docking protein family, and its subsequent binding to the Src homology 2 domain of c-Crk.

p105CasL (CasL) is a recently identified signaling molecule closely related to the p130Cas (Crk-associated substrate) docking protein. CasL has a single Src homology (SH) 3 domain in its N-terminal portion followed by multiple consensus motifs for binding to SH2 domains. Like original p130Cas, CasL undergoes tyrosine phosphorylation upon integrin-mediated cell adhesion. In the present report, we provide direct evidence that CasL is also involved in T cell antigen receptor (TcR)-mediated signal transduction. In binding studies in vitro using glutathione-S-transferase fusion proteins, we have identified 105- and 120-kDa phosphotyrosyl proteins (pp105 and pp120, respectively) tightly bound to the SH2 domain of the Crk adapter protein in the H9 human T cell line after stimulation through the CD3/TcR complex. pp120, but not pp105, also bound to the SH3 of another adapter protein, Ash/Grb2. Immunoblotting with specific antibodies revealed that pp120 and pp105 were identical to the c-cbl proto-oncogene product (p120cbl) and CasL, respectively. Association between Crk and tyrosine-phosphorylated CasL after TcR stimulation was also confirmed in vivo. CasL phosphorylation induced by TcR ligation reached maximal levels within 2 min and rapidly declined thereafter, whereas the integrin-dependent response occurred slowly and was more prolonged. Finally, we demonstrated that Crk/CasL association occurred in peripheral blood T lymphocytes in response to TcR engagement. Our findings suggest that CasL is involved in T cell activation signals and resides at a point where two distinct receptor-mediated signaling pathways converge. This provides one mechanism by which integrins may mediate T cell co-stimulation.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Molecular dynamics simulation and automated docking of the pro-apoptotic Bax protein and its complex with a peptide designed from the Bax-binding domain of anti-apoptotic Ku70.

Bax, a multi-domain protein belonging to the large family of Bcl-2 proteins, has a pivotal role for the initiation of the cytochrome c-mediated apoptosis, a vital physiologic process to eliminate damaged or unwanted cells. In response to specific stimuli Bax translocates from cytosol to mitochondria outer membrane where a process of oligomerization occurs with pore formation through which cytochrome c and other death molecules escape. The pro-death action of Bax is regulated by the interaction with other pro-survival proteins. However, the conformational changes and the structural details necessary for homo and hetero interaction with other regulating proteins are largely unknown. This article reports a combined investigation of molecular dynamics (MD) simulation and automated docking that evidence the molecular regions of Bax involved in the binding with anti-apoptotic exapeptide (Bip) designed from Ku70, a subunit of the protein complex essential for non-homologous DNA repair but that inhibits also the Bax translocation to mitochondria. Since Bip suppresses apoptosis induced by several anti-cancer drugs, it appears relevant to achieve a better understanding of the structural and dynamical aspects that characterize the Bip-Bax complex in view of potential therapeutic implications. The present results show that the Bax region with the highest affinity for Bip is located in proximity of BH3 homology domain of Bax and also involves the alpha-helices 1 and 8. Moreover, the comparison of essential motions of Bax at 300 and 400 K before and after the formation of the complex with Bip evidences how the binding with the exa-peptide affects the collective motions of specific molecular districts of Bax considered to have functional relevance.

Amino Acid Sequence↗
PubMed2002

Transition state docking: a probe for noncovalent catalysis in biological systems. Application to antibody-catalyzed ester hydrolysis.

A strategy for pinpointing favorable noncovalent interactions between transition states and active sites of biological catalysts is described. This strategy combines high-level quantum mechanical calculations of transition state geometries with an automated docking procedure using AutoDock. By applying this methodology to antibody-catalyzed hydrolyses of aryl esters (by the 48G7, CNJ206, and 17E8 families of antibodies), varying levels of catalysis are explained in terms of specific hydrogen bonding interactions between combining site residues and transition states. Although these families of antibodies were produced in separate experiments by different researchers using related but different haptens, the mechanism of transition state stabilization appears to be highly conserved. Despite being elicited in response to anionic phosphonate haptens, the best catalysts often utilize hydrogen bond acceptors to stabilize transition states. A mutant of antibody CNJ206, designed based on this observation and predicted to be a better catalyst, is proposed. In the case of antibody 48G7, affinity maturation is shown to produce a catalyst that is highly selective for one of two enantiomeric transition states from a nonselective germline precursor.

Amino Acids↗
PubMed2003

Specific empirical free energy function for automated docking of carbohydrates to proteins.

We present an automated docking protocol specifically optimized to predict the structure and affinity of a protein-carbohydrate complex. A scoring function was developed based on a training set of 30 protein-carbohydrate complexes of known structure and affinity. Combinations of several models for hydrogen bonding, torsional entropy loss, and solvation were tested for their ability to fit the training set data, and the best model was used with AutoDock. The electrostatic empirical coefficient is larger than in a previously obtained model using a training set comprised of various types of protein-ligand complexes, indicating that electrostatic interactions play a more important role in determining the affinity between a carbohydrate and a protein. The differences in the relative weighting of the empirical coefficients in the model yields predicted free energies for the training set with a standard error of 1.403 kcal/mol. The new scoring function was tested on 17 Aspergillus niger glucoamylase inhibitors for which binding energies had been determined experimentally. Free energies of complex formation were predicted with a residual standard error of 1.101 kcal/mol. The new scoring function therefore provides a robust method for predicting free energies of formation and optimal conformations of carbohydrate-protein complexes.

Algorithms↗
PubMed2003

Docking macromolecules with flexible segments.

We address a major obstacle to macromolecular docking algorithms by presenting a new method that takes into account the induced conformational adjustment of flexible loops situated at a protein/macromolecule interface. The method, MC2, is based on a multiple copy representation of the loops, coupled with a Monte Carlo conformational search of the relative position of the macromolecules and their side chain conformations. The selection of optimal loop conformations takes place during Monte Carlo cycling by the iterative adjustment of the weight of each copy. We describe here the parameterization of the method and trials on a protein-DNA complex of known 3-D structure, involving the Drosophila prd paired domain protein and its target oligonucleotide Wenqing, X. et al., Cell 1995, 80, 639. We demonstrate that our algorithm can correctly configure and position this protein, despite its relatively complex interactions with both grooves of DNA.

Algorithms↗
PubMed2004

Accurate and efficient generalized born model based on solvent accessibility: derivation and application for LogP octanol/water prediction and flexible peptide docking.

A novel method for fast and accurate evaluation of the generalized Born radii in macromolecular solvation electrostatics calculations is proposed, based on the solvent accessibility of the first two solvation layers around an atom. The reverse generalized Born radii calculated by the method have correlation coefficient of 98.7% and RMSD of 0.031 A(-1) with the values obtained using a precise but significantly slower numerical boundary element solution. The method is applied to derive an estimate of the free solvation energy difference between octanol and water and to predict LogP octanol-water. A nine-parameter model is optimized on an 81 compound training set and applied to predict LogP(ow) for an external evaluation set of 19 drug molecules with RMSD of 0.9. The new GB approximation is also tested in Monte Carlo docking simulations of the fully flexible p53 peptide fragment to MDM2. The best energy solution found in the simulations has RMSD of 2.8 A to the X-ray structure.

Algorithms↗
PubMedDate not supplied

Low-mode docking search in iGluR homology models implicates three residues in the control of ligand selectivity.

Homology models of the ionotropic rat kainate receptor iGluR6, based on the ligand binding domains of iGluR2, were constructed. A systematic analysis by low-mode docking searches of kainic acid in homology models of the native iGluR6 receptor, chimeric (iGluR2 and iGluR6) receptors and mutant receptors have identified three residues which influence the conformation of kainic acid in the binding core and hence the affinity for kainic acid. These residues are Leu650, Thr649 and Leu704, all located in domain 2. Leu650 has previously been implicated in the control of selectivity of iGluR2. However, this is the first report that suggests that Thr649 and Leu704 play a role in receptor selectivity.

Amino Acid Sequence↗
PubMedDate not supplied

Molecular basis for regulation of Src by the docking protein p130Cas.

The docking protein p130Cas (Cas) becomes tyrosine-phosphorylated in its central substrate domain in response to extracellular stimuli such as integrin-mediated cell adhesion, and transmits signals through interactions with various intracellular signaling molecules such as the adaptor protein Crk. Src-family kinases (SFKs) bind a specific site in the carboxyl-terminal region of Cas and subsequently SFKs phosphorylate progressively the substrate domain in Cas. In this study crystallography, mutagenesis and binding assays were used to understand the molecular basis for Cas interactions with SFKs. Tyrosine phosphorylation regulates binding of Cas to SFKs, and the primary site for this phosphorylation, Y762, has been proposed. A phosphorylated peptide corresponding to Cas residues 759MEDpYDYVHL767 containing the key phosphotyrosine was crystallized in complex with the SH3-SH2 domain of the SFK Lck. The results provide the first structural data for this protein-protein interaction. The motif in Cas 762pYDYV binds to the SH2 domain in a mode that mimics high-affinity ligands, involving dual contacts of Y762 and V765 with conserved residues in SFK SH2 domains. In addition, Y764 is in position to make an electrostatic contact after phosphorylation with a conserved SFK arginine that mediates interactions with other high-affinity SH2 binders. These new molecular data suggest that Cas may regulate activity of Src as a competing ligand to displace intramolecular interactions that occur in SFKs (between the C-terminal tail and the SH2 domain) and restrain and down-regulate the kinase in an inactive form.

Allosteric Regulation↗
PubMed2002

Inhibition of trypsin by cowpea thionin: characterization, molecular modeling, and docking.

Higher plants produce several families of proteins with toxic properties, which act as defense compounds against pests and pathogens. The thionin family represents one family and comprises low molecular mass cysteine-rich proteins, usually basic and distributed in different plant tissues. Here, we report the purification and characterization of a new thionin from cowpea (Vigna unguiculata) with proteinase inhibitory activity. Cowpea thionin inhibits trypsin, but not chymotrypsin, binding with a stoichiometry of 1:1 as shown with the use of mass spectrometry. Previous annotations of thionins as proteinase inhibitors were based on their erroneous identification as homologues of Bowman-Birk family inhibitors. Molecular modeling experiments were used to propose a mode of docking of cowpea thionin with trypsin. Consideration of the dynamic properties of the cowpea thionin was essential to arrive at a model with favorable interface characteristics comparable with structures of trypsin-inhibitor complexes determined by X-ray crystallography. In the final model, Lys11 occupies the S1 specificity pocket of trypsin as part of a canonical style interaction.

Amino Acid Sequence↗
PubMed2003

Fold recognition, homology modeling, docking simulations, kinetics analysis and mutagenesis of ATP/CTP:tRNA nucleotidyltransferase from Methanococcus jannaschii.

ATP/CTP:tRNA nucleotidyltransferases (NTases) and poly(A) polymerases (PAPs) belong to the same superfamily and their catalytic domains are remotely related. Based on the results of fold-recognition analysis and comparison of secondary structure patterns, we predicted that these two NTase families share three domains, corresponding to "palm," "fingers," and "fingernails" in the PAP crystal structure. A homology model of tRNA NTase from Methanococcus jannaschii was constructed. Energy minimization calculations of enzyme-nucleotide complexes and computer-aided docking of nucleotides onto the enzyme's surface were carried out to explore possible ATP and CTP binding sites. Theoretical models were used to guide experimental analysis. Recombinant His-tagged enzyme was expressed in Escherichia coli, and kinetic properties were characterized. The apparent K(M) for CTP was determined to be 38 microM, and the apparent K(M) for ATP was 21 microM. Three mutations of basic amino acids to alanine were created in a highly conserved region predicted to be in the vicinity of the nucleotide binding site. A deletion was also constructed to remove the C-terminal structural domain defined by the model; it retained about 1% of wild type enzymatic activity using CTP as co-substrate, confirming that detectable catalytic activity is exhibited by the N-terminal domain, as defined by the model. Our results suggest a mechanism of differential ATP and CTP binding, which explains how the tRNA NTase, having only one catalytic site, utilizes different nucleotide triphosphates depending on the nature of the tRNA substrate.

Adenosine Triphosphate↗
PubMed2003

Guided docking: first step to locate potential binding sites.

The long-range electrostatic forces of the targets in round 2 of the Critical Assessment of PRediction of Interactions (CAPRI) experiment were examined and a simple guided docking method, based on these forces, was applied. The method described consists of calculating an initial rigid body trajectory and an optional final, fully flexible refinement stage. Although only limited success was found in predicting the final complexes, some interesting information was discovered. In particular, the long-range forces seem to give some insight into the unusual binding mode of target 4 while raising some questions about target 7, which warrant further investigation.

Algorithms↗
PubMed2003

Filtering and selection of structural models: combining docking and NMR.

It is generally accepted that protein structures are more conserved than protein sequences, and 3D structure determination by computer simulations have become an important necessity in the postgenomic area. Despite major successes no robust, fast, and automated ab initio prediction algorithms for deriving accurate folds of single polypeptide chains or structures of intermolecular complexes exist at present. Here we present a methodology that uses selection and filtering of structural models generated by docking of known substructures such as individual proteins or domains through easily obtainable experimental NMR constraints. In particular, residual dipolar couplings and chemical shift mapping are used. Heuristic inclusion of chemical or biochemical knowledge about point-to-point interactions is combined in our selection strategy with the NMR data and commonly used contact potentials. We demonstrate the approach for the determination of protein-protein complexes using the EIN/HPr complex as an example and for establishing the domain-domain orientation in a chimeric protein, the recently determined hybrid human-Escherichia. coli thioredoxin.

Algorithms↗
PubMed2004

Relative free energy of binding and binding mode calculations of HIV-1 RT inhibitors based on dock-MM-PB/GS.

Tetrahydroimidazo-[4,5,l-jk][1,4]-benzodiazepin-2-(1H)-one (TIBO) derivatives are important nonnucleoside human immunodeficiency virus-1 reverse transcriptase inhibitors (NNRTI). Several TIBO derivatives have shown high potency to inhibit reverse transcriptase (RT) and one (Tivirapine) has entered into clinical trials. The free energy of binding (FEB) is a numerical way to express the binding affinity of a ligand to its receptor and has been applied in screening candidates in rational drug design. In this work, the FEB of 42 TIBOs in RT was studied. Relative FEB is expressed in the form of a linear combination of vdW, electrostatic, solvation, and nonpolar solvation energy terms. The predicted FEB activity of the TIBOs studied has a good correlation (r(2) = 0.8680, q(2) = 0.8298) with respect to the experimental activity (pIC(50)). Based on the data reported here, the Finite Difference Poisson Boltzmann with a Gaussian Smooth Dielectric Constant Function method (PB/GS) solvation energy term is very important in predicting the binding affinity of TIBOs in RT. In summary, the Dock-Molecular Mechanics (MM)-PB/GS method is a promising technique in predicting ligand/receptor binding affinity and it can be used to screen relatively large sets of molecules in a reasonable amount of computer time.

Anti-HIV Agents↗
PubMed2005

Hypocrea jecorina (Trichoderma reesei) Cel7A as a molecular machine: A docking study.

Hypocrea jecorina (formerly Trichoderma reesei) Cel7A has a catalytic domain (CD) and a cellulose-binding domain (CBD) separated by a highly glycosylated linker. Very little is known of how the 2 domains interact to degrade crystalline cellulose. Based on the interaction energies and forces on cello-oligosaccharides computationally docked to the CD and CBD, we propose a molecular machine model, where the CBD wedges itself under a free chain end on the crystalline cellulose surface and feeds it to the CD active site tunnel. Enzyme-substrate interactions produce the forces required to pull cellulose chains from the surface and also to help the enzyme move on the cellulose chain for processive hydrolysis. The energy to generate these forces is ultimately derived from the chemical energy of glycosidic bond breakage.

Binding Sites↗
PubMed2005

Performance of the first protein docking server ClusPro in CAPRI rounds 3-5.

To evaluate the current status of the protein-protein docking field, the CAPRI experiment came to life. Researchers are given the receptor and ligand 3-dimensional (3D) coordinates before the cocrystallized complex is published. Human predictions of the complex structure are supposed to be submitted within 3 weeks, whereas the server ClusPro has only 24 h and does not make use of any biochemical information. From the 10 targets analyzed in the second evaluation meeting of CAPRI, ClusPro was able to predict meaningful models for 5 targets using only empirical free energy estimates. For two of the targets, the server predictions were assessed to be among the best in the field. Namely, for Targets 8 and 12, ClusPro predicted the model with the most accurate binding-site interface and the model with the highest percentage of nativelike contacts, among 180 and 230 submissions, respectively. After CAPRI, the server has been further developed to predict oligomeric assemblies, and new tools now allow the user to restrict the search for the complex to specific regions on the protein surface, significantly enhancing the predictive capabilities of the server. The performance of ClusPro in CAPRI Rounds 3-5 suggests that clustering the low free energy (i.e., desolvation and electrostatic energy) conformations of a homogeneous conformational sampling of the binding interface is a fast and reliable procedure to detect protein-protein interactions and eliminate false positives. Not including targets that had a significant structural rearrangement upon binding, the success rate of ClusPro was found to be around 71%.

Algorithms↗