Abstract
Protein-ligand blind docking is a powerful method for exploring the binding sites of receptors and the corresponding binding poses of ligands. It has seen wide applications in pharmaceutical ...and biological researches. Previously, we proposed a blind docking server, CB-Dock, which has been under heavy use (over 200 submissions per day) by researchers worldwide since 2019. Here, we substantially improved the docking method by combining CB-Dock with our template-based docking engine to enhance the accuracy in binding site identification and binding pose prediction. In the benchmark tests, it yielded the success rate of ∼85% for binding pose prediction (RMSD < 2.0 Å), which outperformed original CB-Dock and most popular blind docking tools. This updated docking server, named CB-Dock2, reconfigured the input and output web interfaces, together with a highly automatic docking pipeline, making it a particularly efficient and easy-to-use tool for the bioinformatics and cheminformatics communities. The web server is freely available at https://cadd.labshare.cn/cb-dock2/.
Graphical Abstract
Graphical Abstract
CB-Dock2 integrates the structure-based and template-based blind docking algorithms.
It has been recently suggested that (1) CH chondrites and the CB
b/CH-like chondrite Isheyevo contain two populations of chondrules formed by different processes: (i) magnesian non-porphyritic ...(cryptocrystalline and barred) chondrules, which are similar to those in the CB chondrites and formed in an impact-generated plume of melt and gas resulted from large-scale asteroidal collision, and (ii) porphyritic chondrules formed by melting of solid precursors in the solar nebula. (2) Porphyritic chondrules in Isheyevo and CH chondrites are different from porphyritic chondrules in other carbonaceous chondrites (
Krot et al., 2005, 2008a,b). In order to test these hypotheses, we measured
in situ oxygen isotopic compositions of porphyritic (magnesian, Type I and ferroan, Type II) and non-porphyritic (magnesian and ferroan cryptocrystalline) chondrules from Isheyevo and CB
b chondrites MAC 02675 and QUE 94627, paired with QUE 94611, using a Cameca ims-1280 ion microprobe.
On a three-isotope oxygen diagram (
δ
17O vs.
δ
18O), compositions of chondrules measured follow approximately slope-1 line. Data for 19 magnesian cryptocrystalline chondrules from Isheyevo, 24 magnesian cryptocrystalline chondrules and 6 magnesian cryptocrystalline silicate inclusions inside chemically-zoned Fe,Ni-metal condensates from CB
b chondrites have nearly identical compositions:
Δ
17O
=
−2.2
±
0.9‰, −2.3
±
0.6‰ and −2.2
±
1.0‰ (2
σ), respectively. These observations and isotopically light magnesium compositions of cryptocrystalline magnesian chondrules in CB
b chondrites (
Gounelle et al., 2007) are consistent with their single-stage origin, possibly as gas-melt condensates in an impact-generated plume. In contrast,
Δ
17O values for 11 Type I and 9 Type II chondrules from Isheyevo range from −5‰ to +4‰ and from −17‰ to +3‰, respectively. In contrast to typical chondrules from carbonaceous chondrites, seven out of 11 Type I chondrules from Isheyevo plot above the terrestrial fractionation line. We conclude that (i) porphyritic chondrules in Isheyevo belong to a unique population of objects, suggesting formation either in a different nebular region or at a different time than chondrules from other carbonaceous chondrites; (ii) Isheyevo, CB and CH chondrites are genetically related meteorites: they contain non-porphyritic chondrules produced during the same highly-energetic event, probably large-scale asteroidal collision; (iii) the differences in mineralogy, petrography, chemical and whole-rock oxygen isotopic compositions between CH and CB chondrites are due to various proportions of the nebular and the impact-produced materials.
The use of cucurbit8uril as a molecular host has emerged in the chemical literature as a reliable strategy for the creation of dynamic chemical systems, owing to its ability to form homo‐ and ...heteroternary complexes in aqueous media with appropriate molecular switches as guests. In this manner, CB8‐based supramolecular switches can be designed in a predictable and modular fashion, through the selection of appropriate guests able to condition the redox, photochemical, or pH‐triggered behavior of tailored multicomponent systems. Furthermore, CB8 allows the implementation of dual/triple and linear/orthogonal stimuli‐dependent properties into these molecular devices by a careful selection of the guests. This versatility in their design gives these supramolecular switches great potential for the rational development of new materials, in which their function is not only determined by the custom‐made stimuli‐responsiveness, but also by the transient aggregation/disaggregation of homo‐ or heteromeric building blocks.
Switch that: The capability of cucurbit8uril as a molecular host to form homo‐ and heteroternary complexes in aqueous media has fueled its use in supramolecular switches. The use of those dynamic systems is especially interesting since they can be reversibly transformed by the application of external stimuli, such as light, redox potential, or pH, and even allow the implementation of orthogonal stimuli responsiveness.
Abstract We present an updated determination of the values of $$\vert V_{cb} \vert ,$$ | V cb | , $$R(D^*)$$ R ( D ∗ ) and $$\vert V_{ub} \vert /\vert V_{cb} \vert $$ | V ub | / | V cb | based on the ...new data on semileptonic $$B \rightarrow D^* \ell \nu _\ell $$ B → D ∗ ℓ ν ℓ decays by the Belle and Belle-II Collaborations and on the recent theoretical progress in the calculation of the form factors relevant for semileptonic $$B \rightarrow D^* \ell \nu _\ell $$ B → D ∗ ℓ ν ℓ and $$B_s \rightarrow K \ell \nu _\ell $$ B s → K ℓ ν ℓ decays. In particular we present results derived by applying either the Dispersive Matrix (DM) method of Di Carlo et al. (Phys Rev D 104:054502, 2021), Martinelli et al. (Phys Rev D 104:094512, 2021), Martinelli et al. (Phys Rev D 105:034503, 2022), Martinelli et al. (Eur Phys J C 82:1083, 2022), Martinelli et al. (JHEP 08:022, 2022) and Martinelli et al. (Phys Rev D 106:093002, 2022) or the more standard Boyd–Grinstein–Lebed (BGL) (Boyd et al. in Phys Rev D 56:6895, 1997) approach to the most recent values of the form factors determined in lattice QCD. Using all the available lattice results for the form factors from the DM method we get the theoretical value $$R^{\textrm{th}}(D^*) = 0.262 \pm 0.009$$ R th ( D ∗ ) = 0.262 ± 0.009 and we extract from a bin-per-bin analysis of the experimental data the value $$\vert V_{cb} \vert = (39.92 \pm 0.64) \cdot 10^{-3}.$$ | V cb | = ( 39.92 ± 0.64 ) · 10 - 3 . Our result for $$R(D^*)$$ R ( D ∗ ) is consistent with the latest experimental world average $$R^{\textrm{exp}}(D^*) = 0.284 \pm 0.012$$ R exp ( D ∗ ) = 0.284 ± 0.012 (HFLAV Collaboration in Preliminary average of R ( D ) and $$R(D^*)$$ R ( D ∗ ) as for Summer 2023. See https://hflav-eos.web.cern.ch/hflav-eos/semi/summer23/html/RDsDsstar/RDRDs.html ) at the $$\simeq 1.5\,\sigma $$ ≃ 1.5 σ level. Our value for $$\vert V_{cb} \vert $$ | V cb | is compatible with the latest inclusive determinations $$\vert V_{cb} \vert ^{\textrm{incl}} = (41.97 \pm 0.48) \cdot 10^{-3}$$ | V cb | incl = ( 41.97 ± 0.48 ) · 10 - 3 (Finauri and Gambino in The $$q^2$$ q 2 moments in inclusive semileptonic B decays. arXiv:2310.20324 ) and $$\vert V_{cb} \vert ^{\textrm{incl}} = (41.69\pm 0.63) \cdot 10^{-3}$$ | V cb | incl = ( 41.69 ± 0.63 ) · 10 - 3 (Bernlochner et al. in JHEP 10:068, 2022) within $$\simeq 2.6$$ ≃ 2.6 and $$\simeq 2.0$$ ≃ 2.0 standard deviations, respectively. From a reappraisal of the calculations of $$\vert V_{ub} \vert / \vert V_{cb} \vert ,$$ | V ub | / | V cb | , we also obtain $$\vert V_{ub} \vert / \vert V_{cb} \vert = 0.087\pm 0.009$$ | V ub | / | V cb | = 0.087 ± 0.009 in good agreement with the result $$\vert V_{ub} \vert / \vert V_{cb} \vert = 0.0844\pm 0.0056$$ | V ub | / | V cb | = 0.0844 ± 0.0056 from the latest FLAG review (Flavour Lattice Averaging Group (FLAG) Collaboration in Phys J C 82:869, 2022).
As the number of elucidated protein structures is rapidly increasing, the growing data call for methods to efficiently exploit the structural information for biological and pharmaceutical purposes. ...Given the three-dimensional (3D) structure of a protein and a ligand, predicting their binding sites and affinity are a key task for computer-aided drug discovery. To address this task, a variety of docking tools have been developed. Most of them focus on docking in the preset binding sites given by users. To automatically predict binding modes without information about binding sites, we developed a user-friendly blind docking web server, named CB-Dock, which predicts binding sites of a given protein and calculates the centers and sizes with a novel curvature-based cavity detection approach, and performs docking with a popular docking program, Autodock Vina. This method was carefully optimized and achieved ~70% success rate for the top-ranking poses whose root mean square deviation (RMSD) were within 2 Å from the X-ray pose, which outperformed the state-of-the-art blind docking tools in our benchmark tests. CB-Dock offers an interactive 3D visualization of results, and is freely available at http://cao.labshare.cn/cb-dock/.
Clozapine is an atypical antipsychotic drug that is very efficacious in treating psychosis, but the risk of severe cardiotoxicity limits its clinical use. The present study investigated the harmful ...effects of clozapine on myocardium and assessed the involvement of cannabinoid receptors in its cardiotoxicity.
Clozapine alone or in combination with selective cannabinoid receptor antagonists or agonists were used to treat mice and cardiomyocytes.
Clozapine induced myocardial inflammation and infiltration 7 days after i.p. injection. Mice survival rate and myocardial infiltration, and fibrotic lesions were dose-dependently worsened by clozapine. Clozapine decreased major endocannabinoid levels in sera and cultured cardiomyocytes. Cannabinoid CB
receptors decreased in clozapine-treated hearts and were translocated from cytomembranes to cytoplasm and nuclei, whereas CB
receptors increased in clozapine-treated hearts and inversely translocated from nuclei to the cytomembrane. Selective antagonists of CB
receptors, rimonabant and AM281, but not its selective agonist arachidonyl-2'-chloroethylamide, ameliorated clozapine-induced myocardial inflammatory infiltration and fibrotic lesions. In contrast, selective agonists of CB
receptors, AM1241 and JWH-133, but not its selective antagonist AM630, blunted clozapine-mediated cardiotoxicity in mice. In cultured cardiomyocytes, clozapine increased the pro-inflammatory factor IL-1β and the concentrations of myocardial injury markers (LDH and aspartate aminotransferase); these effects were reversed by either a CB
antagonist or CB
agonist and further prevented by combined pretreatments.
Our data provide evidence that cannabinoid CB
and CB
receptors have opposite effects and selective antagonists of CB
or agonists of CB
receptors might confer protective effects against clozapine in myocardium.
The synthesis and pharmacology of 47 1-alkyl-3-(1-naphthoyl)indoles (R
=
C
3H
7 and C
5H
11, R′
=
H and CH
3) is described. Naphthoyl substituents include 4- and 7-alkyl groups, plus 2, 4, 6, and ...7-methoxy groups. Three of these compounds are highly selective CB
2 receptor agonists.
In an effort to improve indole-based CB
2 cannabinoid receptor ligands and also to develop SAR for both the CB
1 and CB
2 receptors, 47 indole derivatives were prepared and their CB
1 and CB
2 receptor affinities were determined. The indole derivatives include 1-propyl- and 1-pentyl-3-(1-naphthoyl)indoles both with and without a 2-methyl substituent. Naphthoyl substituents include 4- and 7-alkyl groups as well as 2-, 4-, 6-, 7-methoxy and 4-ethoxy groups. The effects of these substituents on receptor affinities are discussed and structure–activity relationships are presented. In the course of this work three new highly selective CB
2 receptor agonists were identified, 1-propyl-3-(4-methyl-1-naphthoylindole (JWH-120), 1-propyl-2-methyl-3-(6-methoxy-1-naphthoylindole (JWH-151), and 1-pentyl-3-(2-methoxy-1-naphthoylindole (JWH-267). GTPγS assays indicated that JWH-151 is a full agonist at CB
2, while JWH-120 and JWH-267 are partial agonists. Molecular modeling and receptor docking studies were carried out on a set of 3-(4-propyl-1-naphthoyl)indoles, a set of 3-(6-methoxy-1-naphthoyl)indoles and the pair of
N-pentyl-3-(2-methoxy-1-naphthoyl)indoles. Docking studies indicated that the CB
1 receptor affinities of these compounds were consistent with their aromatic stacking interactions in the aromatic microdomain of the CB
1 receptor.
The cannabinoid receptor 1 (CB
) is the principal target of the psychoactive constituent of marijuana, the partial agonist Δ
-tetrahydrocannabinol (Δ
-THC). Here we report two agonist-bound crystal ...structures of human CB
in complex with a tetrahydrocannabinol (AM11542) and a hexahydrocannabinol (AM841) at 2.80 Å and 2.95 Å resolution, respectively. The two CB
-agonist complexes reveal important conformational changes in the overall structure, relative to the antagonist-bound state, including a 53% reduction in the volume of the ligand-binding pocket and an increase in the surface area of the G-protein-binding region. In addition, a 'twin toggle switch' of Phe200
and Trp356
(superscripts denote Ballesteros-Weinstein numbering) is experimentally observed and appears to be essential for receptor activation. The structures reveal important insights into the activation mechanism of CB
and provide a molecular basis for predicting the binding modes of Δ
-THC, and endogenous and synthetic cannabinoids. The plasticity of the binding pocket of CB
seems to be a common feature among certain class A G-protein-coupled receptors. These findings should inspire the design of chemically diverse ligands with distinct pharmacological properties.
Stringent relations between the B(∗) → D(∗) form factors exist in the heavy quark limit and the leading symmetry breaking corrections are known. We reconsider their uncertainty and role in the ...analysis of recent Belle data for B → D(∗)ℓν with model-independent parametrizations and in the related prediction of R(D(∗)). We find |Vcb| = 41.5(1.3) 10−3 and |Vcb| = 40.6(− 1.3+ 1.2) 10−3 using input from Light Cone Sum Rules, and R(D∗) = 0.260(8).
Endocannabinoids are critically involved in brain reward functions, mediated by activation of CB
receptors, reflecting their high density in the brain. However, the recent discovery of CB
receptors ...in the brain, particularly in the midbrain dopamine neurons, has challenged this view and inspired us to re-examine the roles of both CB
and CB
receptors in the effects of cannabis.
In the present study, we used the electrical intracranial self-stimulation paradigm to evaluate the effects of various cannabinoid drugs on brain reward in laboratory rats and the roles of CB
and CB
receptors activation in brain reward function(s).
Two mixed CB
/ CB
receptor agonists, Δ
-tetrahydrocannabinol (Δ
-THC) and WIN55,212-2, produced biphasic effects-mild enhancement of brain-stimulation reward (BSR) at low doses but inhibition at higher doses. Pretreatment with a CB
receptor antagonist (AM251) attenuated the low dose-enhanced BSR, while a CB
receptor antagonist (AM630) attenuated high dose-inhibited BSR. To confirm these opposing effects, rats were treated with selective CB
and CB
receptor agonists. These compounds produced significant BSR enhancement and inhibition, respectively.
CB
receptor activation produced reinforcing effects, whereas CB
receptor activation was aversive. The subjective effects of cannabis depend on the balance of these opposing effects. These findings not only explain previous conflicting results in animal models of addiction but also explain why cannabis can be either rewarding or aversive in humans, as expression of CB
and CB
receptors may differ in the brains of different subjects.
![Cucurbit[8]uril (CB[8])‐Bas...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/1433-7851/small "Cucurbit[8]uril (CB[8])‐Based Supramolecular Switches")
PDF
