共查询到20条相似文献,搜索用时 78 毫秒
1.
Summary We have performed docking studies with the SYSDOC program on acetylcholinesterase (AChE) to predict the binding sites in AChE of huperzine A (HA), which is a potent and selective, reversible inhibitor of AChE. The unique aspects of our docking studies include the following: (i) Molecular flexibility of the guest and the host is taken into account, which permits both to change their conformations upon binding. (ii) The binding energy is evaluated by a sum of energies of steric, electrostatic and hydrogen bonding interactions. In the energy calculation no grid approximation is used, and all hydrogen atoms of the system are treated explicitly. (iii) The energy of cation- interactions between the guest and the host, which is important in the binding of AChE, is included in the calculated binding energy. (iv) Docking is performed in all regions of the host's binding cavity. Based on our docking studies and the pharmacological results reported for HA and its analogs, we predict that HA binds to the bottom of the binding cavity of AChE (the gorge) with its ammonium group interacting with Trp 84, Phe 330, Glu 199 and Asp 72 (catalytic site). At the the opening of the gorge with its ammonium group partially interacting with Trp 279 (peripheral site). At the catalytic site, three partially overlapping subsites of HA were identified which might provide a dynamic view of binding of HA to the catalytic site. 相似文献
2.
The binding of (partial) agonists in the binding pocket of biogenic amine receptors induces a conformational change from the
inactive to the active state of the receptors. There is only little knowledge about the binding pathways of ligands into binding
pocket on molecular level. So far, it was not possible with molecular dynamic simulations to observe the ligand binding and
receptor activation. Furthermore, there is nearly nothing known, in which state of ligand binding, the receptor gets activated.
The aim of this study was to get more detailed insight into the process of ligand binding and receptor activation. With the
recently developed LigPath algorithm, we scanned the potential energy surface of the binding process of dimeric histaprodifen, a partial agonist at
the histamine H 1-receptor, into the guinea pig histamine H 1-receptor, taking also into account the receptor activation. The calculations exhibited large conformational changes of Trp 6.48 and Phe 6.55 during ligand binding and receptor activation. Additionally, conformational changes were also observed for Phe 6.52, Tyr 6.51 and Phe 6.44. Conformational changes of Trp 6.48 and Phe 6.52 are discussed in literature as rotamer toggle switch in context with receptor activation. Additionally, the calculations
indicate that the binding of dimeric histaprodifen, accompanied by receptor activation is energetically preferred. In general,
this study gives new, theoretical insights onto ligand binding and receptor activation on molecular level. 相似文献
3.
DSIP and its fourteen analogs as well as three short peptides were synthesized by solid phase method. The design of the analogs was based on the consideration of the introduction of D-amino acid into the molecules to inhibit the enzymatic hydrolysis and the introduction of amino acids with a hydrophobic side chain. The modification was placed on the position of 1, 3, 4, 5, 8 and 9, e.g. D- Trp 1, Tyr 1, Tyr 1 Phe 5, D-Trp 1 Phe 8, Trp 3,4, D-Trp 1,3,4 Phe 8, D-Trp3 ,4 Phe 8 D-Glu 9, D-pF-Phe 3,4 Phe 8 D-Glu 9, Phe 5, Glu 5 Asp 9, Tyr 6 Asp 9, Asp 9 and Ala 7-DSIP as well as Trp-Ala-Gly-Gly-Asp, Trp-Ala-Gly-Gly-Glu and Trp-Gly-Glu. DSIP and Phe 5-DSIP were also prepared by pentafluorophenyl ester method. The purity of the synthetic peptides was checked by amino acid analysis, elemental analysis, thin layer chromatography and paper electrophoresis. The biological assay showed that the analogs of D-Trp 1, Tyr 1, Tyr 1 Phe 5 and Ala 7-DSIP as well as three short peptides were inactive whereas Phe 5-DSIP showed similar activity as that of synthetic DSIP. 相似文献
4.
Thioredoxin reductase 1 (TrxR1) is an oxidoreductase playing the important role in the tumor cells. It is a new type of drug therapy target. Most of the existing TrxR1 inhibitors act directly covalently on the active sites. Herein, molecular docking-based virtual screening approach was used to screen inhibitors with new binding site of TrxR1 from the SPECS database. After experimental test, compound 22 was identified as the reversibility inhibitor of TrxR1 U498C mutant (It has similar structure and function to replace the wild-type TrxR1 which is difficult to express) with IC 50 value of 15.31 ± 0.57 μM. The molecular docking results showed that the interaction between compound 22 and TrxR1 was centered on inactive site Trp 114. Furthermore, phenazine compounds 24– 30 with similar structures as 22 were also screened out from our phenazine database. Compounds 24– 27 had longer chain structures and better inhibitory activity than compound 22, while compounds 28– 30 were the opposite. Compounds 24– 27 can be more stably bound in the protein cavity on Trp 114 than compounds 28– 30. Then we verified amino acids centered on Trp 114 can regulate TrxR1 activity by amino acids mutation. Taken together, A new inhibition site are found that can regulate TrxR1 U498C mutant activity by acting on amino acids sequence at inactive sites centered on Trp 114 and can provide ideas for the discovery and research of new TrxR1 inhibitors. 相似文献
5.
Inhibition of pathogenic protein aggregation may be an important and straightforward therapeutic strategy for curing amyloid diseases. Small‐molecule aggregation inhibitors of Alzheimer’s amyloid‐β (Aβ) are extremely scarce, however, and are mainly restricted to dye‐ and polyphenol‐type compounds that lack drug‐likeness. Based on the structure‐activity relationship of cyclic Aβ16–20 ( cyclo‐[KLVFF]), we identified unique pharmacophore motifs comprising side‐chains of Leu 2, Val 3, Phe 4, and Phe 5 residues without involvement of the backbone amide bonds to inhibit Aβ aggregation. This finding allowed us to design non‐peptidic, small‐molecule aggregation inhibitors that possess potent activity. These molecules are the first successful non‐peptidic, small‐molecule aggregation inhibitors of amyloids based on rational molecular design. 相似文献
6.
The paper describes the construction, validation and application of a structure-based 3D QSAR model of novel acetylcholinesterase (AChE) inhibitors. Initial use was made of four X-ray structures of AChE complexed with small, non-specific inhibitors to create a model of the binding of recently developed aminopyridazine derivatives. Combined automated and manual docking methods were applied to dock the co-crystallized inhibitors into the binding pocket. Validation of the modelling process was achieved by comparing the predicted enzyme-bound conformation with the known conformation in the X-ray structure. The successful prediction of the binding conformation of the known inhibitors gave confidence that we could use our model to evaluate the binding conformation of the aminopyridazine compounds. The alignment of 42 aminopyridazine compounds derived by the docking procedure was taken as the basis for a 3D QSAR analysis applying the GRID/GOLPE method. A model of high quality was obtained using the GRID water probe, as confirmed by the cross-validation method (q 2
LOO=0.937, q 2
L50% O=0.910). The validated model, together with the information obtained from the calculated AChE-inhibitor complexes, were considered for the design of novel compounds. Seven designed inhibitors which were synthesized and tested were shown to be highly active. After performing our modelling study the X-ray structure of AChE complexed with donepezil, an inhibitor structurally related to the developed aminopyirdazines, has been made available. The good agreement found between the predicted binding conformation of the aminopyridazines and the one observed for donepezil in the crystal structure further supports our developed model. 相似文献
7.
Two rare guanidine-type alkaloids, Buthutin A (1) and Buthutin B (2), along with two other compounds (3, 4), were isolated from Buthus martensii Karsch, and determined using extensive spectroscopic data analysis and high resolution-mass spectrometry. Compound 1 showed the most potent inhibition on AChE and BChE with IC 50 values of 7.83 ± 0.06 and 47.44 ± 0.95 μM, respectively. Kinetic characterization of compound 1 confirmed a mixed-type of AChE inhibition mechanism in accordance with the docking results, which shows its interaction with both catalytic active (CAS) and peripheral anionic (PAS) sites. The specific binding of compound 1 to PAS domain of AChE was also confirmed experimentally. Moreover, compounds 1 and 3 exhibited satisfactory biometal binding abilities toward Cu 2+, Fe 2+, Zn 2+ and Al 3+ ions. These results provide a new evidence for further development and utilization of B. martensii in health and pharmaceutical products. 相似文献
8.
Naringin, as a component universal existing in the peel of some fruits or medicinal plants, was usually selected as the material to synthesise bioactive derivates since it was easy to gain with low cost. In present investigation, eight new acacetin-7- O-methyl ether Mannich base derivatives ( 1– 8) were synthesised from naringin. The bioactivity evaluation revealed that most of them exhibited moderate or potent acetylcholinesterase (AChE) inhibitory activity. Among them, compound 7 (IC 50 for AChE = 0.82 ± 0.08 μmol?L ?1, IC 50 for BuChE = 46.30 ± 3.26 μmol?L ?1) showed a potent activity and high selectivity compared with the positive control Rivastigmine (IC 50 for AChE = 10.54 ± 0.86 μmol?L ?1, IC 50 for BuChE = 0.26 ± 0.08 μmol?L ?1). The kinetic study suggested that compound 7 bind to AChE with mix-type inhibitory profile. Molecular docking study revealed that compound 7 could combine both catalytic active site (CAS) and peripheral active site (PAS) of AChE with four points (Trp84, Trp279, Tyr70 and Phe330), while it could bind with BuChE via only His 20. 相似文献
10.
The V2 vasopressin renal receptor (V2R), which controls antidiuresis in mammals, is a member of the large family of heptahelical transmembrane (7TM) G protein-coupled receptors (GPCRs). Using the automated GPCR modeling facility available via Internet (http://expasy.hcuge.ch/swissmod/SWISS-MODEL.html) for construction of the 7TM domain in accord with the bovine rhodopsin (RD) footprint, and the SYBYL software for addition of the intra- and extracellular domains, the human V2R was modeled. The structure was further refined and its conformational variability tested by the use of a version of the Constrained Simulated Annealing (CSA) protocol developed in this laboratory. An inspection of the resulting structure reveals that the V2R (likewise any GPCR modeled this way) is much thicker and accordingly forms a more spacious TM cavity than most of the hitherto modeled GPCR constructs do, typically based on the structure of bacteriorhodopsin (BRD). Moreover, in this model the 7TM helices are arranged differently than they are in any BRD-based model. Thus, the topology and geometry of the TM cavity, potentially capable of receiving ligands, is in this model quite different than it is in the earlier models. In the subsequent step, two ligands, the native [arginine 8]vasopressin (AVP) and the selective agonist [d-arginine 8]vasopressin (DAVP) were inserted, each in two topologically non-equivalent ways, into the TM cavity and the resulting structures were equilibrated and their conformational variabilities tested using CSA as above. The best docking was selected and justified upon consideration of ligand-receptor interactions and structure-activity data. Finally, the amino acid residues were indicated, mainly in TM helices 3-7, as potentially important in both AVP and DAVP docking. Among those Cys 112, Val 115-Lys 116, Gln 119, Met 123 in helix 3; Glu 174 in helix 4; Val 206, Ala 210, Val 213-Phe 214 in helix 5; Trp 284, Phe 287-Phe 288, Gln 291 in helix 6; and Phe 307, Leu 310, Ala 314 and Asn 317 in helix 7 appeared to be the most important ones. Many of these residues are invariant for either the GPCR superfamily or the neurophyseal (vasopressin V2R, V1aR and V1bR and oxytocin OR) subfamily of receptors. Moreover, some of the equivalent residues in V1aR have already been found critical for the ligand affinity [Mouillac et al., J. Biol. Chem, 270 (1995) 25771]. 相似文献
11.
Four cyclic peptides, diandrine A–D ( 1 – 4 ), were isolated from the MeOH extract of Formosan Drymaria diandra. Their structures were elucidated by chemical and spectroscopic analyses as cyclo(‐Gly 1‐Pro 2‐Trp 3‐Pro 4‐Tyr 5‐Phe 6‐), cyclo(‐Gly 1‐Pro 2‐Leu 3‐Pro 4‐Leu 5‐Trp 6‐Ser 7‐Ser 8‐), cyclo(Gly 1‐Gly 2‐Pro 3‐Tyr 4‐Trp 5‐Pro 6‐), and cyclo(Gly 1‐Gly 2‐Pro 3‐Tyr 4‐Trp 5‐Pro 6‐), respectively. Compounds 3 and 4 were stable conformational isomers. Cyclopeptide 1 showed a selective inhibitory effect on collagen‐induced platelet aggregation with an IC50 value of 44.2 μM . 相似文献
13.
Thirty-two new stemofoline analogues were prepared from didehydrostemofoline for studies as AChE inhibitors. C-3 Side-chain modified amino, carbamate, triazole and oxazole stemofoline derivatives were prepared. In general the amine derivatives were found to be stronger inhibitors of AChE than their alcohol analogues that we previously reported. Compounds 5 and 26, with small C-3 side-chain substituents, were two of the most active inhibitors. Preliminary molecular docking studies suggested that these compounds may inhibit AChE by binding horizontally along the passage of the active-site gorge and block access to acetylcholine. 相似文献
14.
A computational model of the transmembrane domain of the human 5-HT 4 receptor complexed with the GR113808 antagonist was constructed from the crystal structure of rhodopsin and the putative residues of the ligand-binding site, experimentally determined by site-directed mutagenesis. The recognition mode of GR113808 consist of: (i) the ionic interaction between the protonated amine and Asp 3.32; (ii) the hydrogen bond between the carbonylic oxygen and Ser 5.43; (iii) the hydrogen bond between the ether oxygen and Asn 6.55; (iv) the hydrogen bond between the C-H groups adjacent to the protonated piperidine nitrogen and the electrons of Phe 6.51; and (v) the - aromatic-aromatic interaction between the indole ring and Phe 6.52.This computational model offers structural indications about the role of Asp 3.32, Ser 5.43, Phe 6.51, Phe 6.52, and Asn 6.55 in the experimental binding affinities. Asp 3.32Asn mutation does not affect the binding of GR113808 because the loss of binding affinity from an ion pair to a charged hydrogen bond is compensated by the larger energetical penalty of Asp to disrupt its side chain environment in the ligand-free form, and the larger interaction between Phe 6.51 and the piperidine ring of the ligand in the mutant receptor. In the Phe 6.52Val mutant the indole ring of the ligand replaces the interaction with Phe 6.52 by a similarly intense interaction with Tyr 5.38, with no significant effect in the binding of GR113808. The mutation of Asn 6.55 to Leu replaces the hydrogen bond of the ether oxygen of the ligand from Asn 6.55 to Cys 5.42, with a decrease of binding affinity that approximately equals the free energy difference between the SHO and NHO hydrogen bonds.Because these residues are also present in the other members of the neurotransmitter family of G protein-coupled receptors, these findings will also serve for our understanding of the binding of related ligands to their cognate receptors. 相似文献
15.
Summary The application of capillary zone electrophoresis to the study of interactions between Bacillus subtilis tryptophanyl-tRNA synthetase (TrpRS) and tRNA Trp is described. Significant changes in peak shape of tRNA Trp incubated with TrpRS indicated the occurrence of interactions between TrpRS and tRNA Trp in pH 8.0 Tris-HCl buffer containing 0.1 mmol L −1 EDTA and 1 mmol L −1−5 mmol L −1 mgCl 2. Addition of Mg 2+ decreased the electrophoretic mobility of tRNA Trp, which illustrated that conformation of tRNA Trp depended on Mg 2+. The dissociation constant of the TrpRS-tRNA Trp complex was estimated to be 0.63 μmol L −1 at 25°C in buffer solution. 相似文献
16.
A combined ligand- and target-based approach was used to analyse the interaction models of Cryptosporidium parvum inosine 5’-monophosphate dehydrogenase (C pIMPDH) with selective inhibitors. First, a ligand-based pharmacophore model was generated from 20 NAD + competitive C pIMPDH inhibitors with the HipHop module. The characteristic of the NAD + binding site of C pIMPDH was then described, and the binding modes of the representative inhibitors were studied by molecular docking. The combination of the pharmacophore model and the docking results allowed us to evaluate the pharmacophore features and structural information of the NAD + binding site of C pIMPDH. This research supports the proposal of an interaction model inside the NAD + binding site of C pIMPDH, consisting of four key interaction points: two hydrophobic-aromatic groups, a hydrophobic-aliphatic group and a hydrogen bond donor. This study also provides guidance for the design of more potent C pIMPDH inhibitors for the treatment of Cryptosporidium infections. 相似文献
18.
The designed molecular structures have been subjected to computational analysis for calculating their physicochemical properties and drug likeness. The calculated data indicate that most of the compound possess the bioactivity score in the active zone. Synthetic approach to the target compounds is straightforward and easy to handle. Structures of the new compounds are supported by FT-IR, 1H, and 13C NMR, and mass spectra. Antimicrobial tests of the products against pathogens (S. aureus, S. epidermidis, E. coli, and P. mirabilis) indicate the products as active or highly active. Their cyto-toxicity is determined to be 92–98% at concentration of 3.125 µmol/L. The molecular docking analysis carried out for the target compounds against the receptor Glc-N-6P exhibits low binding energy and various binding sites of those. 相似文献
19.
A series of novel cyclic urea molecules 5,6-dihydroxy-1,3-diazepane-2,4,7-trione as HIV-1 protease inhibitors were designed
using computational techniques. The designed molecules were compared with the known cyclic urea molecules by performing docking
studies, calculating their ADME (Absorption, Distribution, Metabolism, and Excretion) properties and protein ligand interaction
energy. These novel molecules were designed by substituting the P
1/ P′
1 positions (4
th
and 7
th
position of 1, 3-diazepan-2-one) with double bonded oxygens. This reduces the molecular weight and increases the bioavailability,
indicating better ADME properties. The docking studies showed good binding affinity towards HIV-1 protease. The biological
activity of these inhibitors were predicted by a model equation generated by the regression analysis between biological activity
(log 1/ K
i
) of known inhibitors and their protein ligand interaction energy. The synthetic studies are in progress.
相似文献
20.
Garcinia species are reported to possess antimicrobial, anti-inflammatory, anticancer, anti-HIV and anti-Alzheimer's activities. This study aimed to investigate the in vitro cholinesterase enzyme inhibitory activities of garcihombronane C ( 1), garcihombronane F ( 2), garcihombronane I ( 3), garcihombronane N ( 4), friedelin ( 5), clerosterol ( 6), spinasterol glucoside ( 7) and 3β-hydroxy lup-12,20(29)-diene ( 8) isolated from Garcinia hombroniana, and to perform molecular docking simulation to get insight into the binding interactions of the ligands and enzymes. The cholinesterase inhibitory activities were evaluated using acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. In this study, compound 4 displayed the highest concentration-dependent inhibition of both AChE and BChE. Docking studies exhibited that compound 4 binds through hydrogen bonds to amino acid residues of AChE and BChE. The calculated docking and binding energies also supported the in vitro inhibitory profiles of IC 50. In conclusion, garcihombronanes C, F, I and N ( 1– 4) exhibited dual and moderate inhibitory activities against AChE and BChE. 相似文献
|