L. (Magnoliaceae) is a plant of considerable medicinal significance; its flowers and seeds have been used in various traditional remedies. Radioligand binding assays of
-hexane seeds extract showed ...displacement of radioligand for cannabinoid (CB1 and CB2) and opioid δ (delta), κ (kappa), and µ (mu) receptors. Bioactivity-guided fractionation afforded 4-
-methylhonokiol (
), magnolol (
), and honokiol (
), which showed higher binding to cannabinoid rather than opioid receptors in radioligand binding assays. Compounds
-
, together with the dihydro analog of
(
), displayed selective affinity towards CB2R (K
values of 0.29, 1.4, 1.94, and 0.99 μM, respectively), compared to CB1R (K
3.85, 17.82, 14.55, and 19.08 μM, respectively). An equal mixture of
and
(1:1 ratio) showed additive displacement activity towards the tested receptors compared to either
or
alone, which in turn provides an explanation for the strong displacement activity of the
-hexane extract. Due to the unavailability of an NMR or X-ray crystal structure of bound neolignans with the CB1 and CB2 receptors, a docking study was performed to predict ligand-protein interactions at a molecular level and to delineate structure-activity relationships (SAR) of the neolignan analogs with the CB1 and CB2 receptors. The putative binding modes of neolignans
and previously reported related analogs (
,
,
,
,
,
, and
) into the active site of the CB1 and CB2 receptors were assessed for the first time via molecular docking and binding free-energy (∆G) calculations. The docking and ∆G results revealed the importance of a hydroxyl moiety in the molecules that forms strong H-bonding with Ser383 and Ser285 within CB1R and CB2R, respectively. The impact of a shift from a hydroxyl to the methoxy group on experimental binding affinity to CB1R versus CB2R was explained through ∆G data and the orientation of the alkyl chain within the CB1R. This comprehensive SAR, influenced by the computational study and the observed in vitro displacement binding affinities, has indicated the potential of magnolia neolignans for developing new CB agonists for potential use as analgesics, anti-inflammatory agents, or anxiolytics.
The synthetic benzimidazole opioid etazene (which has a 70-times higher analgesic activity than morphine), a recreational drug, has gained popularity as a novel psychoactive substance (NPS) on the ...illegal/darknet market; however, no experimental information is available at the molecular level on the binding mechanism and putative binding site of etazene and its metabolites at the µ-opioid receptor (MOR). In the present study, we investigated the metabolism of etazene in human liver microsomes using ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS). We also explored the possibilities of MOR activation by etazene and its metabolites by studying their binding mechanisms and interaction profiles at an active-state MOR model via molecular docking, binding free energy calculations, and all-atom molecular dynamics (MD) simulations. The putative metabolites of etazene were also predicted using the ADMET Predictor 10.1. The molecular docking studies and free energy calculations showed that etazene and its metabolites (M1, M2, and M5-M7) exhibited strong predicted binding affinity at MOR and showed overlapped binding orientation with MOR-bound agonist BU72, which was co-crystallized in the MOR X-ray crystal structure (PDB ID: 5C1M). MD also confirmed the stability of the MOR-etazene and MOR-M6 complexes. These results suggest that etazene and its metabolites may act as strong MOR agonists, highlighting the necessity of experimental validation. The insights from this study, such as key interactions between etazene and its metabolites and the MOR, will allow authorities to predict potential analogs and clarify the target-protein interactions associated with this illicit substance, granting advanced or rapid reactions to confiscating or banning potential emerging drugs.
This study aimed to design anticancer theobromine derivatives inhibiting VEGFR-2. The new compounds were tested
to evaluate their effectiveness against MCF-7 and HepG2 cancer cell lines. Among these ...compounds, 15a showed the highest cytotoxicity against HepG2, with an IC
value of 0.76 μM, and significant anti-proliferative effects on MCF-7, with an IC
value of 1.08 μM. Notably, the selectivity index of 15a against the two cancer cells was 98.97 and 69.64, respectively. Moreover, 15a demonstrated potent VEGFR-2 inhibitory activity (IC
= 0.239 μM). Further investigations revealed that 15a induced apoptosis in HepG2 cells, significantly increasing early-stage and late-stage apoptosis percentages from 3.06% and 0.71% to 29.49% and 9.63%, respectively. It also upregulated caspase-3 and caspase-9 levels by 3.45-fold and 2.37-fold, respectively compared to control HepG2 cells. Additionally, 15a inhibited the migration and wound healing ability of HepG2 cells. Molecular docking confirmed the binding affinities of the semi-synthesized compounds to VEGFR-2, consistent with
results. Several computational analyses (DFT, MD simulations, MM-GBSA, PLIP, and essential dynamics) supported the stability of the 15a-VEGFR-2 complex. Overall, the biological and computational findings suggest that compound 15a could be a promising lead compound for the development of a novel apoptotic anticancer agent.
Valuing diversity leads to scientific excellence, the progress of science and, most importantly, it is simply the right thing to do. We must value diversity not only in words, but also in actions.
A Diverse View of Science to Catalyse Change Urbina‐Blanco, César A.; Jilani, Safia Z.; Speight, Isaiah R. ...
Angewandte Chemie (International ed.),
October 12, 2020, Letnik:
59, Številka:
42
Journal Article
Recenzirano
Odprti dostop
Valuing diversity leads to scientific excellence, the progress of science and most importantly, it is simply the right thing to do. We can value diversity not only in words, but also in actions.
A Diverse View of Science to Catalyse Change Urbina‐Blanco, César A.; Jilani, Safia Z.; Speight, Isaiah R. ...
Angewandte Chemie,
October 12, 2020, Letnik:
132, Številka:
42
Journal Article
Synthetic cannabinoids, including some from the John W. Huffman (JWH) family, emerged on the drug scene around 2004 as “alternative marijuana,” despite being considerably more potent than marijuana. ...Like Δ9-tetrahydrocannabinol (THC), the principal psychoactive ingredient in marijuana, synthetic cannabinoids have also been found to interact with cannabinoid receptors CB1 and CB2, found in the brain, immune system, and peripheral organs. The JWH compounds and other synthetic cannabinoids have become important subjects of research in the forensic science community due to their drug-abuse potential, undetectability under routine drug screening, and unpredictable toxicity. In this study, an active-state CB1 receptor model was used to assess the receptor-ligand interactions between the CB1 receptor and ligands from the JWH synthetic cannabinoid family, as well as some newly designed JWH-like virtual compounds, labeled as MGCS compounds, using docking, binding free-energy calculations (ΔG), and molecular dynamics simulations (MDs). The calculated ΔG revealed that the carbonyl group between the naphthalene and the indole, characteristic of the JWH family, and the length of the N-linked alkyl chain were two important structural characteristics that influenced the predicted CB1 binding affinity, especially as increasing the length of the alkyl chain led to better predicted binding affinity. MDs and per-residue-breakdown results showed that the designed MGCS compounds with a pentyl chain attached to the naphthalene moiety and selected JWH compounds formed stable and strong hydrophobic interactions with the key residues Phe170, Phe174, Phe177, Phe200, Phe268, and Trp279 of the CB1 receptor. Comprehension of these critical interactions can help forensic chemists predict the structure of undiscovered families of synthetic cannabinoids.
Display omitted
•Synthetic cannabinoids, including the JWH family, emerged on the drug scene around 2004 as an “alternative marijuana.”.•Synthetic cannabinoids interact with CB1 cannabinoid receptor, leading to a drug-abuse potential.•An active-state CB1 receptor was used to assess receptor–ligand interactions with JWH and virtually-designed cannabinoids.•MD results showed that MGCS compounds with a pentylated naphthalene moiety exhibited strong CB1 interactions.
Magnolia grandiflora L. (Magnoliaceae) is a plant of considerable medicinal significance; its flowers and seeds have been used in various traditional remedies. Radioligand binding assays of n-hexane ...seeds extract showed displacement of radioligand for cannabinoid (CB1 and CB2) and opioid δ (delta), κ (kappa), and µ (mu) receptors. Bioactivity-guided fractionation afforded 4-O-methylhonokiol (1), magnolol (2), and honokiol (3), which showed higher binding to cannabinoid rather than opioid receptors in radioligand binding assays. Compounds 1–3, together with the dihydro analog of 2 (4), displayed selective affinity towards CB2R (Ki values of 0.29, 1.4, 1.94, and 0.99 μM, respectively), compared to CB1R (Ki 3.85, 17.82, 14.55, and 19.08 μM, respectively). An equal mixture of 2 and 3 (1:1 ratio) showed additive displacement activity towards the tested receptors compared to either 2 or 3 alone, which in turn provides an explanation for the strong displacement activity of the n-hexane extract. Due to the unavailability of an NMR or X-ray crystal structure of bound neolignans with the CB1 and CB2 receptors, a docking study was performed to predict ligand–protein interactions at a molecular level and to delineate structure-activity relationships (SAR) of the neolignan analogs with the CB1 and CB2 receptors. The putative binding modes of neolignans 1–3 and previously reported related analogs (4, 4a, 5, 5a, 6, 6a, and 6b) into the active site of the CB1 and CB2 receptors were assessed for the first time via molecular docking and binding free-energy (∆G) calculations. The docking and ∆G results revealed the importance of a hydroxyl moiety in the molecules that forms strong H-bonding with Ser383 and Ser285 within CB1R and CB2R, respectively. The impact of a shift from a hydroxyl to the methoxy group on experimental binding affinity to CB1R versus CB2R was explained through ∆G data and the orientation of the alkyl chain within the CB1R. This comprehensive SAR, influenced by the computational study and the observed in vitro displacement binding affinities, has indicated the potential of magnolia neolignans for developing new CB agonists for potential use as analgesics, anti-inflammatory agents, or anxiolytics.
Mississippi consistently ranks as one of the least healthy states in the United States (https://bit.ly/ 4647kAs). In 2017, Mississippi had the highest death rate in the nation from heart and kidney ...disease, and the second highest from stroke, diabetes, cancer, influenza or pneumonia, and septicemia (https://bit.ly/3LIu5BR). According to the America's Health Rankings 2022 annual report, approximately 12.4% of Mississippians have cardiovascular disease and 15.2% have diabetes, ranking Mississippi at 48th in the nation on both measures. Compared with the rest of the nation, Mississippians are themost likely to be born at a lowbirth weight (Mississippi: 11.8%; United States: 8.2% of infants weighing less than 2500 grams at birth; https://bit.ly/48sx9fh) and die a premature death (Mississippi: 13 781 years; United States: 8659 years of potential life lost before age 75 per 100 000 population annually; https://bit. ly/3tcXPR1). In addition, Mississippi had one of the highest rates of obesity, with 39.1% of the state categorized as obese.1 From health behaviors, like smoking and physical activity, to lack of health care access, Mississippians are burdened with excess disease, much of which is associated with factors that are preventable and modifiable. These poor health indicators are not confined to Mississippi's adults.
PDF
