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PubMed2005

Two pockets in the active site of maize sesquiterpene synthase TPS4 carry out sequential parts of the reaction scheme resulting in multiple products.

One of the most interesting features of terpene synthases is their ability to form multiple products with different carbon skeletons from a single prenyl diphosphate substrate. The maize sesquiterpene synthase TPS4, for example, produces a mixture of 14 different olefinic sesquiterpenes. To understand the complex TPS4 reaction mechanism, we modeled the active site cavity and conducted docking simulations with the substrate farnesyl diphosphate, several predicted carbocation intermediates, and the final reaction products. The model suggests that discrete steps of the reaction sequence are controlled by two different active site pockets, with the conformational change of the bisabolyl cation intermediate causing a shift from one pocket to the other. Site-directed mutagenesis and measurements of mutant activity in the presence of (E,E)- and (Z,E)-farnesyl diphosphate as substrates were employed to test this model. Amino acid alterations in pocket I indicated that early steps of the catalytic process up to the formation of the monocyclic bisabolyl cation are probably localized in this compartment. Mutations in pocket II primarily inhibited the formation of bicylic compounds, suggesting that secondary cyclizations of the bisabolyl cation are catalyzed in pocket II.

Amino Acid Sequence↗

PubMed1998

Structure-based design of N-[2-(1-piperidinylethyl)]-N'-[2-(5-bromopyridyl)]-thiourea and N-[2-(1-piperazinylethyl)]-N'-[2-(5-bromopyridyl)]-thiourea as potent non-nucleoside inhibitors of HIV-1 reverse transcriptase.

A novel computer model of the HIV reverse transcriptase (RT) non-nucleoside inhibitor (NNI) binding pocket, which was generated using high resolution crystal structure information from 9 individual RT/NNI complexes, revealed previously unrecognized ligand derivatization sites for phenethylthiazolylthiourea (PETT) derivatives. Spatial gaps surrounding the pyridyl ring of the active PETT derivative trovirdine were discovered during modeling procedures. Docking studies using the computer-generated model of the binding pocket (composite binding pocket) suggested that the replacement of the planar pyridyl ring of trovirdine with a nonplanar piperidinyl or piperazinyl ring, which occupy larger volumes, would better fill the spacious Wing 2 region of the butterfly-shaped NNI binding pocket. The anti-HIV activity of the synthesized heterocyclic compounds N-[2-(1-piperidinylethyl)]-N'-[2-(5-bromopyridyl)]-thiourea and N-[2-(1-piperazinylethyl)]-N'-[2-(5-bromopyridyl)]-thiourea was examined in HTLVIIIB-infected peripheral blood mononuclear cells. Both compounds were more potent than trovirdine and abrogated HIV replication at nanomolar concentrations without any evidence of cytotoxicity.

Antiviral Agents↗

PubMed1998

Structure-based design of ligands for protein basic domains: application to the HIV-1 Tat protein.

A methodology has been developed for designing ligands to bind a flexible basic protein domain where the structure of the domain is essentially known. It is based on an empirical binding free energy function developed for highly charged complexes and on Monte Carlo simulations in internal coordinates with both the ligand and the receptor being flexible. HIV-1 encodes a transactivating regulatory protein called Tat. Binding of the basic domain of Tat to TAR RNA is required for efficient transcription of the viral genome. The structure of a biologically active peptide containing the Tat basic RNA-binding domain is available from NMR studies. The goal of the current project is to design a ligand which will bind to that basic domain and potentially inhibit the TAR-Tat interaction. The basic domain contains six arginine and two lysine residues. Our strategy was to design a ligand for arginine first and then a superligand for the basic domain by joining arginine ligands with a linker. Several possible arginine ligands were obtained by searching the Available Chemicals Directory with DOCK 3.5 software. Phytic acid, which can potentially bind multiple arginines, was chosen as a building block for the superligand. Calormetric binding studies of several compounds to methylguanidine and Arg-/Lys-containing peptides were performed. The data were used to develop an empirical binding free energy function for prediction of affinity of the ligands for the Tat basic domain. Modeling of the conformations of the complexes with both the superligand and the basic domain being flexible has been carried out via Biased Probability Monte Carlo (BPMC) simulations in internal coordinates (ICM 2.6 suite of programs). The simulations used parameters to ensure correct folding, i.e., consistent with the experimental NMR structure of a 25-residue Tat peptide, from a random starting conformation. Superligands for the basic domain were designed by joining together two molecules of phytic acid with peptidic and peptidomimetic linkers. The linkers were refined by varying the length and side chains of the linking residues, carrying out BPMC simulations, and evaluation of the binding free energy for the best energy conformation. The dissociation constant of the best ligand designed is estimated to be in the low- to mid-nanomolar range.

Amino Acid Sequence↗

PubMed2004

Computer-aided design, synthesis, and anti-HIV-1 activity in vitro of 2-alkylamino-6-[1-(2,6-difluorophenyl)alkyl]-3,4-dihydro-5-alkylpyrimidin-4(3H)-ones as novel potent non-nucleoside reverse transcriptase inhibitors, also active against the Y181C variant.

Dihydro-alkoxy-benzyl-oxopyrimidines (DABOs) are a family of potent NNRTIs developed in the past decade. Attempts to improve their potency and selectivity led to thio-DABOs (S-DABOs), DATNOs, and difluoro-thio-DABOs (F(2)-S-DABOs). More recently, we reported the synthesis and molecular modeling studies of a novel conformationally constrained subtype of the S-DABO series characterized by the presence of substituents on the methylene linkage connecting the pyrimidine ring to the aryl moiety (Mai, A., et al. J. Med. Chem. 2001, 44, 2544-2554). Now we report the computer-aided design, synthesis, and biological evaluation of four new DABO prototypes (5-alkyl-2-cyclopentylamino-6-[1-(2,6-difluorophenyl)alkyl]-3,4-dihydropyrimidin-4(3H)-ones, F(2)-NH-DABOs) in which the sulfur atom of the related F(2)-S-DABOs is replaced by an amino group. For these studies, we used as a reference model the cocrystallized MKC-442/RT complex. Docking studies with Autodock of the newly designed F(2)-NH-DABOs on the ligand-derived RT confirmed the findings previously described for the F(2)-S-DABOs. The F(2)-NH-DABO binding mode resembles that reported for F(2)-S-DABOs, with the difference that the NH moiety at the C-2 position represents a new anchor site for ligand/enzyme complexation. The predicted inhibition constant (K(i)) values by the internal scoring function of Autodock, and the predicted IC(50) values by the application of a VALIDATE II/HIV-RT model strongly suggested the synthesis of the designed amino-DABOs. F(2)-NH-DABOs were shown to be highly active in both anti-RT and anti-HIV biological assays with IC(50) and EC(50) comparable with that of the reference compound MKC-442. Interestingly, 2-cyclopentylamino-6-[1-(2,6-difluorophenyl)ethyl]-3,4-dihydro-5-methyl pyrimidin-4(3H)-one (9d) was active against the Y181C HIV-1 mutant strain at submicromolar concentration, with a resistance value similar to that of efavirenz, the last FDA-approved NNRTI for AIDS therapy, and 2-fold lower than that of its 2-cyclopentylthio counterpart 8d. The introduction in 9d of a new anchor point (pyrimidine C-2 NH group), with the formation of a new hydrogen bond with Lys101, could compensate for the lack of positive hydrophobic ligand/NNBP interactions due to the Tyr181 to Cys181 mutation.

Cell Line↗

PubMed1999

Automated docking of maltose, 2-deoxymaltose, and maltotetraose into the soybean beta-amylase active site.

In this study, products and substrates were docked into the active site of beta-amylase using the simulated annealing algorithm AutoDock. Lowest-energy conformers reproduced known crystallographic atom positions within 0.4 to 0.8 A rmsd. Docking studies were carried out with both open and closed configurations of the beta-amylase mobile flap, a loop comprising residues 96 to 103. Ligands with two rings docked within the cleft near the active site when the flap was open, but those with four rings did not. The flap must be closed for alpha-maltotetraose to adopt a conformation allowing it to dock near the crystallographically determined subsites. The closed flap is necessary for productive but not for nonproductive binding, and therefore it plays a essential role in catalysis. The gain in total binding energy upon closing of the flap for alpha-maltose docked to subsites -2, -1 and +1, +2 is about 22 kcal/mol, indicating more favorable interactions are possible with the flap closed. Larger intermolecular interaction energies are observed for two alpha-maltose molecules docked to subsites -2, -1 and +1, +2 than for one alpha-maltotetraose molecule docked from subsites -2 to +2, suggesting that it is only upon cleavage of the alpha-1,4 linkage that optimal closed-flap binding can occur with the crytallographically determined enzyme structure.

Binding Sites↗

PubMed2000

Cytochrome P450 catalyzed nitric oxide synthesis: a theoretical study.

Similar to nitric oxide synthase (NOS) cytochrome P450 isoforms (e.g. 3A and 4E) can produce nitric oxide from arginine. Although the active site of both proteins contains a protoporphyrin IX unit having an axial cystein ligand, their effectiveness in the synthesis of NO differs significantly. Now the molecular basis of this functional difference was investigated. A homology model for cytochrome P450 3A4 was refined and compared to the X-ray structure of iNOS. We found the active site of iNOS to be more readily accessible for the substrate than that of P450. Docking calculations were performed using the Monte Carlo conformational analysis technique on all internal and external degrees of freedom of arginine and active site residues as well. The lowest energy conformation of the cytochrome P450 3A4-substrate complex was compared to the high resolution X-ray structure of the iNOS-arginine complex. Comparison of substrate orientations revealed that arginine binds in a similar conformation in both enzymes. In contrast to iNOS we found, however, that in P450 partially negative propionate side chains of protoporphyrin IX are located on the opposite side of the heme plane. As a result of this and the absence of other negatively charged residues the distal (substrate binding) side of P450 should be less negative than that of NOS and therefore its affinity toward the partially positive arginine is reduced. Comparison of molecular electrostatic potentials calculated within the active site of the proteins supports this proposal. Reduced affinity in combination with limited substrate access might be responsible for the less effective NO synthesis of cytochrome P450 observed experimentally.

Arginine↗

PubMed2003

Protein-based virtual screening of chemical databases. II. Are homology models of G-Protein Coupled Receptors suitable targets?

The aim of the current study is to investigate whether homology models of G-Protein-Coupled Receptors (GPCRs) that are based on bovine rhodopsin are reliable enough to be used for virtual screening of chemical databases. Starting from the recently described 2.8 A-resolution X-ray structure of bovine rhodopsin, homology models of an "antagonist-bound" form of three human GPCRs (dopamine D3 receptor, muscarinic M1 receptor, vasopressin V1a receptor) were constructed. The homology models were used to screen three-dimensional databases using three different docking programs (Dock, FlexX, Gold) in combination with seven scoring functions (ChemScore, Dock, FlexX, Fresno, Gold, Pmf, Score). Rhodopsin-based homology models turned out to be suitable, indeed, for virtual screening since known antagonists seeded in the test databases could be distinguished from randomly chosen molecules. However, such models are not accurate enough for retrieving known agonists. To generate receptor models better suited for agonist screening, we developed a new knowledge- and pharmacophore-based modeling procedure that might partly simulate the conformational changes occurring in the active site during receptor activation. Receptor coordinates generated by this new procedure are now suitable for agonist screening. We thus propose two alternative strategies for the virtual screening of GPCR ligands, relying on a different set of receptor coordinates (antagonist-bound and agonist-bound states).

Adrenergic beta-2 Receptor Agonists↗

PubMed1993

Matching chemistry and shape in molecular docking.

We have added a chemical filter to the ligand placement algorithm of the molecular docking program DOCK. DOCK places ligands in receptors using local shape features. Here we label these shape features by chemical type and insist on complementary matches. We find fewer physically unrealistic complexes without reducing the number of complexes resembling the known ligand-receptor configurations. Approximately 10-fold fewer complexes are calculated and the new algorithm is correspondingly 10-fold faster than the previous shape-only matching. We tested the new algorithm's ability to reproduce three known ligand-receptor complexes: methotrexate in dihydrofolate reductase, deoxyuridine monophosphate in thymidylate synthase and pancreatic trypsin inhibitor in trypsin. The program found configurations within 1 A of the crystallographic mode, with fewer non-native solutions compared with shape-only matching. We also tested the program's ability to retrieve known inhibitors of thymidylate synthase and dihydrofolate reductase by screening molecular databases against the enzyme structures. Both algorithms retrieved many known inhibitors preferentially to other compounds in the database. The chemical matching algorithm generally ranks known inhibitors better than does matching based on shape alone.

Algorithms↗

PubMed1998

A dimeric crystal structure for the N-terminal two domains of intercellular adhesion molecule-1.

The 3.0-A structure of a 190-residue fragment of intercellular adhesion molecule-1 (ICAM-1, CD54) reveals two tandem Ig-superfamily (IgSF) domains. Each of two independent molecules dimerizes identically with a symmetry-related molecule over a hydrophobic interface on the BED sheet of domain 1, in agreement with dimerization of ICAM-1 on the cell surface. The residues that bind to the integrin LFA-1 are well oriented for bivalent binding in the dimer, with the critical Glu-34 residues pointing away from each other on the periphery. Residues that bind to rhinovirus are in the flexible BC and FG loops at the tip of domain 1, and these and the upper half of domain 1 are well exposed in the dimer for docking to virus. By contrast, a residue important for binding to Plasmodium falciparum-infected erythrocytes is in the dimer interface. The presence of A' strands in both domains 1 and 2, conserved hydrogen bonds at domain junctions, and elaborate hydrogen bond networks around the key integrin binding residues in domain 1 make these domains suited to resist tensile forces during adhesive interactions. A subdivision of the intermediate (I) set of IgSF domains is proposed in which domain 1 of ICAM-1 and previously described I set domains belong to the I1 set and domain 2 of ICAM-1, ICAM-2, and vascular cell adhesion molecule-1 belong to the I2 set.

Amino Acid Sequence↗

PubMed2006

Structure modeling, ligand binding, and binding affinity calculation (LR-MM-PBSA) of human heparanase for inhibition and drug design.

Human heparanase is an endo-beta-D-glycosidase that cleaves heparan sulphate (HS) chains in the extracellular matrix and basement membrane. It is known that the cleavage of HS by heparanase results in cell invasion and metastasis of cancer. Therefore, heparanase is considered an important target for cancer drug development. The three-dimensional structure of heparanase would be useful in the rational design of inhibitors targeted to the enzyme; however, the three-dimensional structure has not yet been determined. In our effort to design inhibitors, we developed a three-dimensional structure of heparanase using a homology-modeling approach. The homology-built structure is consistent to previous bioinformatics and site-mutation experimental results. The heparanase features a (alpha/beta)(8) TIM-barrel fold with two glutamate residues (Glu225 and Glu343) located in the active-site cleft. This feature supports the putative mechanism of proton donor and nucleophilic sites. Docking simulations yielded 41 complex structures, which indicate that the bound inhibitor could block ligand binding into the catalytic site. A free energy of binding model was established for 25 heparanase inhibitors with a training set of 25 heparanase inhibitors using the linear response MM-PBSA approach (LR-MM-PBSA). The correlation between calculated and experimental activity was 0.79 and the reliability of the model was validated with leave-one-out cross-validation method. Its predictive capability was further validated using a test set of 16 inhibitors similar to the training set of inhibitors. The correlation between the predicted and observed activities is significantly improved by the protein "induced-fit" that accounts for the flexibility of the receptor. These interaction and pharmacophore elements provide a unique insight to the rational design of new ligands targeted to the enzyme.

Amino Acid Sequence↗

PubMed2005

Structural considerations for the rational design of selective anti-trypanosomal agents: the role of the aromatic clusters at the interface of triosephosphate isomerase dimer.

Seven benzothiazoles were successfully docked into the interface of both human and trypanosomal triosephosphate isomerases, and the binding free energies of each complex were calculated using the program AutoDock. Structural and energetical analysis of the complexes showed that large benzothiazoles could form more stable complexes with trypanosomal triosephosphate isomerase than with human triosephosphate isomerase. Thus, we hypothesize that the distribution of the residues forming the aromatic clusters at the enzyme's interface and the size of the inhibitors might play a crucial role in the selective inhibition of TcTIM. Following the findings here presented, it is possible to better determine the structural elements involved in the origin of the selectivity at the trypanosomal triosephosphate isomerase interface, and to enable efficient anti-trypanosomal drug design strategies.

Animals↗

PubMed2003

Unique conformer selection of human growth-regulatory lectin galectin-1 for ganglioside GM1 versus bacterial toxins.

Endogenous lectins induce effects on cell growth by binding to antennae of natural glycoconjugates. These complex carbohydrates often present more than one potential lectin-binding site in a single chain. Using the growth-regulatory interaction of the pentasaccharide of ganglioside GM(1) with homodimeric galectin-1 on neuroblastoma cell surfaces as a model, we present a suitable strategy for addressing this issue. The approach combines NMR spectroscopic and computational methods and does not require isotope-labeled glycans. It involves conformational analysis of the two building blocks of the GM(1) glycan, i.e., the disaccharide Galbeta1-3GalNAc and the trisaccharide Neu5Acalpha2-3Galbeta1-4Glc. Their bound-state conformations were determined by transferred nuclear Overhauser enhancement spectroscopy. Next, measurements on the lectin-pentasaccharide complex revealed differential conformer selection regarding the sialylgalactose linkage in the tri- versus pentasaccharide (Phi and Psi value of -70 degrees and 15 degrees vs 70 degrees and 15 degrees, respectively). To proceed in the structural analysis, the characteristic experimentally detected spatial vicinity of a galactose unit and Trp68 in the galectin's binding site offered a means, exploiting saturation transfer from protein to carbohydrate protons. Indeed, we detected two signals unambiguously assigned to the terminal Gal and the GalNAc residues. Computational docking and interaction energy analyses of the entire set of ligands supported and added to experimental results. The finding that the ganglioside's carbohydrate chain is subject to differential conformer selection at the sialylgalactose linkage by galectin-1 and GM(1)-binding cholera toxin (Phi and Psi values of -172 degrees and -26 degrees, respectively) is relevant for toxin-directed drug design. In principle, our methodology can be applied in studies aimed at blocking galectin functionality in malignancy and beyond glycosciences.

Acetylgalactosamine↗

PubMed2007

Simulating alpha/beta selectivity at the human thyroid hormone receptor: consensus scoring using multidimensional QSAR.

We present a consensus-scoring study on the human thyroid hormone receptor alpha and beta using two receptor-modeling concepts (software Quasar and Raptor) that are based on multidimensional QSAR and allow for the explicit simulation of induced fit. The binding mode of 82 agonists and indirect antagonists, spanning an activity range of seven orders of magnitude in K(i), was identified through flexible docking to the respective X-ray crystal structures (Yeti software) and represented by a 4D data set with up to four conformations per compound. The receptor surrogates for the thyroid alpha receptor converged at a cross-validated r(2) of 0.846/0.919 (64 training compounds; for Quasar and Raptor, respectively) and yielded a predictive r(2) of 0.812/0.814 (18 test compounds); the models for the thyroid beta receptor resulted in a cross-validated r(2) of 0.823/0.909 and a predictive r(2) of 0.665/0.796, respectively. Consensus was achieved as, on average, the calculated activities of the training set differ only by a factor of 2.2 in K(i) and those of the test set by a factor of 2.8 when predicted by Quasar and Raptor, respectively.

Binding Sites↗

PubMed2001

Hydrophobicity and functionality maps of farnesyltransferase.

Farnesyltransferase (FTase) catalyzes the attachment of a 15-carbon isoprenoid moiety, farnesyl, through a thioether linkage to a cysteine near the C-terminus of oncogenic Ras proteins. These transform animal cells to a malignant phenotype when farnesylated. Hence, FTase is an interesting target for the development of antitumor agents. In this work we first investigate the active site of FTase by mapping its hydrophobic patches. Then the program SEED is used to dock functional groups into the active site by an exhaustive search and efficient evaluation of the binding energy with solvation. The electrostatic energy is SEED is based on the continuum dielectric approximation and consists of screened intermolecular energy and protein and fragment desolvation terms. The results are found to be consistent with the sequence variability of the tetrapeptide substrate. The distribution of functional groups (functionality maps) on the substrate binding site allows for identification of modifications of the tetrapeptide sequence that are consistent with potent peptidic inhibitors. Furthermore, the best minima of benzene match corresponding moieties of an inhibitor in clinical trials. The functionality maps are also used to design a library of disubstituted indoles that might prevent the binding of the protein substrates.

Alkyl and Aryl Transferases↗

PubMed1999

Inhibition of influenza A virus replication by compounds interfering with the fusogenic function of the viral hemagglutinin.

Several compounds that specifically inhibited replication of the H1 and H2 subtypes of influenza virus type A were identified by screening a chemical library for antiviral activity. In single-cycle infections, the compounds inhibited virus-specific protein synthesis when added before or immediately after infection but were ineffective when added 30 min later, suggesting that an uncoating step was blocked. Sequencing of hemagglutinin (HA) genes of several independent mutant viruses resistant to the compounds revealed single amino acid changes that clustered in the stem region of the HA trimer in and near the HA2 fusion peptide. One of the compounds, an N-substituted piperidine, could be docked in a pocket in this region by computer-assisted molecular modeling. This compound blocked the fusogenic activity of HA, as evidenced by its inhibition of low-pH-induced cell-cell fusion in infected cell monolayers. An analog which was more effective than the parent compound in inhibiting virus replication was synthesized. It was also more effective in blocking other manifestations of the low-pH-induced conformational change in HA, including virus inactivation, virus-induced hemolysis of erythrocytes, and susceptibility of the HA to proteolytic degradation. Both compounds inhibited viral protein synthesis and replication more effectively in cells infected with a virus mutated in its M2 protein than with wild-type virus. The possible functional relationship between M2 and HA suggested by these results is discussed.

Amantadine↗

PubMed2001

Immunoglobulin cross-reactivity examined by library screening, crystallography and docking studies.

Antibodies are extremely diverse with respect to their specificities and affinities for target molecules. Despite rigorous selection, some antibodies are cross-reactive whereby they recognize their natural antigens along with other molecules. In this review, we discuss our efforts toward understanding the cross-reactivity of selected immunoglobulins. Investigations that are discussed employed screens of combinatorial peptide libraries, crystallography of ligand-protein complexes, and computer-based peptide docking simulations. In the first example, two different antibodies (NC6.8 and NC10.14) bound the same trisubstituted guanidine (NC174) with similar affinities, but utilized predominantly dissimilar binding strategies. However, there was one common binding strategy, in which the cyanophenyl portion of NC174 was inserted end-on into the binding crevices of the NC6.8 and NC10.14 antibodies. In the second example, scanning of peptide libraries and X-ray crystallography were used to design and test synthetic peptides for binding to the Mcg L chain dimer. Again, end-on insertion was favored for all peptides larger than dipeptides in the voluminous Mcg binding cavity. Finally, automated docking was used for rapid predictions of complexes for the Fv molecule from a broadly cross-reactive human IgM (Mez) and nearly two thousand peptides. Certain amino acids, including the aromatic residues Trp and Phe, functioned as anchoring groups in automated docking. Anchoring groups acted in most of the peptides that were otherwise accommodated by a variety of binding strategies in the docked complexes. We suggest that anchoring of at least a portion of a ligand in a binding site is a common mechanism for antibody recognition.

Binding Sites, Antibody↗

PubMed1996

The binding of propranolol at 5-hydroxytryptamine1D beta T355N mutant receptors may involve formation of two hydrogen bonds to asparagine.

Although the beta-adrenergic receptor antagonist (-)-propranolol binds with relatively low affinity at human 5-hydroxytryptamine1D beta receptors (Ki = 10,200 nM), it displays significantly higher affinity (Ki = 17 nM) at its species homolog, 5-HT1B receptors, and at a mutant 5-HT1D beta receptor (Ki = 16 nM), where the threonine residue at position 355 (T355) is replaced with an asparagine residue (i.e., a T355N mutant). Propranolol contains two oxygen atoms, an ether oxygen atom and a hydroxyl oxygen atom, and it has been speculated that the enhanced affinity of propranolol for the T355N mutant receptor is related to the ability of the asparagine residue to hydrogen bond with the ether oxygen atom. However, the specific involvement of the propranolol oxygen atoms in binding to the wild-type and T355N mutant 5-HT1D beta receptors has never been addressed experimentally. A modification of a previously described 5-HT1D beta receptor graphic model was mutated by replacement of T355 with asparagine. Propranolol was docked with the wild-type and T355N mutant 5-HT1D beta receptor models in an attempt to understand the difference in affinity of the ligand for the receptors. The binding models suggest that the asparagine residue of the mutant receptor can form hydrogen bonds with both oxygen atoms of propranolol, whereas the threonine moiety of the wild-type receptor can hydrogen-bond only to one oxygen atom. To test this hypothesis, we prepared and examined several analogues of propranolol that lacked either one or both oxygen atoms. The results of radioligand binding experiments are consistent with the hypothesis that both oxygen atoms of propranolol could participate in binding to the mutant receptor, whereas only the ether oxygen atom participates in binding to the wild-type receptor. As such, this is the first investigation of serotonin receptors that combines the use of molecular modeling, mutant receptors generated by site-directed mutagenesis, and synthesis to investigate structure/affinity relationships.

Adrenergic beta-Antagonists↗

PubMed1994

Docking analysis of a series of benzylamino acetylcholinesterase inhibitors with a phthalimide, benzoyl, or indanone moiety.

The enzyme-binding mode of a series of acetylcholinesterase inhibitors has been analyzed on the basis of the crystal structure of the Torpedo enzyme using docking programs DOCK and directed-DOCK. The inhibitors have a benzyl group connected to tertiary ammonium nitrogen at one end and a phthalimide, benzoyl, or indanone moiety at the other. Our modeling results have indicated that the benzyl group interacts with Trp 84, which is located near the bottom of the binding pocket and is postulated to be the quaternary ammonium binding site for acetylcholine. The other aromatic ring has been found to interact with Trp 279 at the peripheral hydrophobic site. In addition, the hydrogen-bonding interaction between a carbonyl group of the inhibitor and Tyr 121 OH seems to play an important role. Our active-orientation model is, at least qualitatively, consistent with structure-activity data for more than 50 compounds and should be useful for the design of more potent inhibitors.

Acetylcholinesterase↗