Two rare 2-phenoxychromone derivatives, 6-demethoxy-4`-O-capillarsine (
) and tenuflorin C (
), were isolated from the areal parts of
and
respectively, for the first time. Being rare in nature, the ...inhibition potentialities of
and
against SARS-CoV-2 was investigated using multistage in silico techniques. At first, molecular similarity and fingerprint studies were conducted for
and
against co-crystallized ligands of eight different COVID-19 enzymes. The carried-out studies indicated the similarity of
and
with
, the co-crystallized ligand of COVID-19 Papain-Like Protease (PLP), (PDB ID: 3E9S). Therefore, molecular docking studies of
and
against the PLP were carried out and revealed correct binding inside the active site exhibiting binding energies of -18.86 and -18.37 Kcal/mol, respectively. Further, in silico ADMET in addition to toxicity evaluation of
and
against seven models indicated the general safety and the likeness of
and
to be drugs. Lastly, to authenticate the binding and to investigate the thermodynamic characters, molecular dynamics (MD) simulation studies were conducted on
and PLP.
Background
The COVID-19 pandemic has led to significant loss of life and economic disruption worldwide. Currently, there are limited effective treatments available for this disease. SARS-CoV-2 ...RNA-dependent RNA polymerase (SARS-CoV-2 RdRp) has been identified as a potential target for drug development against COVID-19. Natural products have been shown to possess antiviral properties, making them a promising source for developing drugs against SARS-CoV-2.
Objectives
The objective of this study is to identify the most effective natural inhibitors of SARS-CoV-2 RdRp among a set of 4924 African natural products using a multi-phase in silico approach.
Methods
The study utilized remdesivir (RTP), the co-crystallized ligand of RdRp, as a starting point to select compounds that have the most similar chemical structures among the examined set of compounds. Molecular fingerprints and structure similarity studies were carried out in the first part of the study. The second part of the study included molecular docking against SARS-CoV-2 RdRp (PDB ID: 7BV2) and Molecular Dynamics (MD) simulations including the calculation of RMSD, RMSF, Rg, SASA, hydrogen bonding, and PLIP. Moreover, the calculations of Molecular mechanics with generalised Born and surface area solvation (MM-GBSA) Lennard-Jones and Columbic electrostatic interaction energies have been conducted. Additionally, in silico ADMET and toxicity studies were performed to examine the drug likeness degrees of the selected compounds.
Results
Eight compounds were identified as the most effective natural inhibitors of SARS-CoV-2 RdRp. These compounds are kaempferol 3-galactoside, kaempferol 3-O-β-D-glucopyranoside, mangiferin methyl ether, luteolin 7-O-β-D-glucopyranoside, quercetin-O-β-D-3-glucopyranoside, 1-methoxy-3-indolylmethyl glucosinolate, naringenin, and asphodelin A 4’-O-β-D-glucopyranoside.
Conclusion
The results of this study provide valuable information for the development of natural product-based drugs against COVID-19. However, the elected compounds should be further studied in vitro and in vivo to confirm their efficacy in treating COVID-19.
In recent years, suppressing tubulin polymerization has been developed as a therapeutic approach for cancer treatment. Thus, new derivatives based on thiazol-5(4
H
)-ones have been designed and ...synthesized in an eco-friendly manner. The synthesized derivatives have the same essential pharmacophoric features of colchicine binding site inhibitors. The anti-proliferative activity of the new derivatives was evaluated on three human cancer cell lines (HCT-116, HepG-2, and MCF-7) using MTT assay procedure and colchicine was used as a positive control. Compounds
4f
,
5a
,
8f
,
8g
, and
8k
showed superior antiproliferative activities against the three tested cell lines with IC
50
values ranging from 2.89 to 9.29 μM. Further investigation for the most active cytotoxic agents as tubulin polymerization inhibitors was also performed in order to explore the mechanism of their anti-proliferative activity. Tubulin polymerization assay results were found to be comperable with the cytotoxicity results. Compounds
4f
and
5a
were the most potent tubulin polymerization inhibitors with an IC
50
value of 9.33 and 9.52 nM, respectively. Further studies revealed the ability of
5a
to induce apoptosis and arrest cell cycle growth at the G2/M phase. Molecular docking studies were also conducted to investigate possible binding interactions between the target compounds and the tubulin heterodimer active site. From these studies, it was concluded that inhibition of tubulin polymerization yields the reported cytotoxic activity.
In recent years, suppressing tubulin polymerization has been developed as a therapeutic approach for cancer treatment.
Display omitted
•Twenty compounds of novel quinazolin-4(3H)-ones bearing sulfonylurea derivatives were designed and synthesized.•Molecular docking, pharmacophore, QSAR and ADMET studies were carried ...out.•In vivo anti-hyperglycemic activity, in vitro PPARγ binding affinity and insulin-secreting ability were carried out.•Some of the synthesized compounds showed promising anti-hyperglycemic activities.
Peroxisome proliferator-activated receptor gamma (PPARγ) and sulfonylurea receptor (SUR) play crucial roles in management of type-2 diabetes mellitus. In this study, a series of novel quinazoline-4(3H)-one-sulfonylurea hybrids were designed and synthesized as dual PPARγ and SUR agonists. The synthesized compounds were evaluated for their in vivo anti-hyperglycemic activities against STZ-induced hyperglycemic rats. Four compounds (19a, 19d, 19f and 25g) demonstrated potent activities with reduction in blood glucose levels of 40.43, 46.42, 41.23 and 42.50 %, respectively. The most active ten compounds were further evaluated in vitro for their PPARγ binding affinities and insulin-secreting abilities. Compounds 19b, 19d, 19f, 25f and 25g exhibited the highest affinities against PPARγ with IC50 values of 0.371, 0.350, 0.369, 0.408 and 0.353µM, respectively. In addition, compounds 19d, 19f, and 25d showed the highest insulin-secreting activities with EC50 values of 0.97, 1.01 and 1.15µM, respectively. Furthermore, molecular docking and pharmacophore generation techniques were carried out to investigate binding patterns and fit values of the designed compounds with PPARγ and SUR, respectively. Also, two QSAR models were generated to explore the structural requirements controlling the different biological activities of the synthesized compounds against PPARγ and SUR.
Four new nicotinamide-based derivatives were designed as antiangiogenic VEGFR-2 inhibitors. The congeners were synthesized possessing the pharmacophoric essential features to bind correctly with the ...VEGFR-2 active pocket. All members were evaluated for their cytotoxic and VEGFR-2 inhibitory potentialities. Compound 6 was the most potent showingIC50 values of 9.3 ± 0.02 and 7.8 ± 0.025 µM against HCT-116 and HepG-2 cells, respectively, and IC50 of 60.83 nM regarding VEGFR-2 enzyme inhibition. Compound 6 arrested the growth of HCT-116 cells at the pre-G1 and G2-M phases. Further, it induced both early and late apoptosis. Additionally, compound 6 caused a significant decrease in TNF-α and IL6 by 66.42% and 57.34%, respectively. The considered compounds had similar docking performances to that of sorafenib against the VEGFR-2 (PDB ID: 2OH4). The correct binding of compound 6 with VEGFR-2 was validated using MD simulations, and MM-GPSA calculations.
This work is one of our efforts to discover potent anticancer agents. We modified the most promising derivative of our previous work concerned with the development of VEGFR-2 inhibitor candidates. ...Thirteen new compounds based on benzoxazole moiety were synthesized and evaluated against three human cancer cell lines, namely, breast cancer (MCF-7), colorectal carcinoma (HCT116), and hepatocellular carcinoma (HepG2). The synthesized compounds were also evaluated against VEGFR-2 kinase activity. The biological testing fallouts showed that compound 8d was more potent than standard sorafenib. Such compound showed IC50 values of 3.43, 2.79, and 2.43 µM against the aforementioned cancer cell lines, respectively, compared to IC50 values of 4.21, 5.30, and 3.40 µM reported for sorafenib. Compound 8d also was found to exert exceptional VEGFR-2 inhibition activity with an IC50 value of 0.0554 μM compared to sorafenib (0.0782 μM). In addition, compound 8h revealed excellent cytotoxic effects with IC50 values of 3.53, 2.94, and 2.76 µM against experienced cell lines, respectively. Furthermore, compounds 8a and 8e were found to inhibit VEGFR-2 kinase activity with IC50 values of 0.0579 and 0.0741 μM, exceeding that of sorafenib. Compound 8d showed a significant apoptotic effect and arrested the HepG2 cells at the pre-G1 phase. In addition, it exerted a significant inhibition for TNF-α (90.54%) and of IL-6 (92.19%) compared to dexamethasone (93.15%). The molecular docking studies showed that the binding pattern of the new compounds to VEGFR-2 kinase was similar to that of sorafenib.
In the designed compounds, a new linker was inserted in the form of fragments with verified VEGFR‐2 inhibitory potential, including an α,β‐unsaturated ketonic fragment, pyrazole, and pyrimidine. ...Also, new distal hydrophobic moieties were attached to these linkers that are expected to increase the hydrophobic interaction with VEGFR‐2 and, consequently, the affinity. These structural optimizations have led us to identify the novel dihydropyrazole derivative 6e as a promising hit molecule. All the new derivatives were evaluated to assess their anticancer activity against three human cancer cell lines, including HepG2, HCT‐116, and MCF‐7. The results of the in vitro anticancer evaluation study revealed the moderate to excellent cytotoxicity of 6c, 6e, 6g, and 7b, with IC50 values in the low micromolar range. The inhibitory activity of VEGFR‐2 was investigated for 16 of the designed compounds. The enzyme assay results of the new compounds were compared with those of sorafenib as a reference VEGFR‐2 inhibitor. The obtained results demonstrated that our derivatives are potent VEGFR‐2 inhibitors. The most potent derivatives 6c, 6e, 6g, and 7b showed IC50 values in the range of 0.11–0.22 µM. Molecular docking and pharmacokinetic studies were also conducted to rationalize the VEGFR‐2 inhibitory activity and to evaluate the ability of the most potent derivatives to be developed as good drug candidates.
Compounds with a new linker inserted in the form of fragments with verified VEGFR‐2 inhibitory potentials were designed, and new distal hydrophobic moieties were attached to these linkers. Testing of these new compounds for anticancer activity and VEGFR‐2 inhibition revealed compounds 6c, 6e, 6g, and 7b as the most potent derivatives. Molecular docking and pharmacokinetic studies were conducted to evaluate their potency as drug candidates.
New quinoline and isatin derivatives having the main characteristics of VEGFR-2 inhibitors was synthesised. The antiproliferative effects of these compounds were estimated against A549, Caco-2, ...HepG2, and MDA-MB-231. Compounds 13 and 14 showed comparable activities with doxorubicin against the Caco-2 cells. These compounds strongly inhibited VEGFR-2 kinase activity. The cytotoxic activities were evaluated against Vero cells. Compound 7 showed the highest value of safety and selectivity. Cell migration assay displayed the ability of compound 7 to prevent healing and migration abilities in the cancer cells. Furthermore, compound 7 induced apoptosis in Caco-2 through the expressive down-regulation of the apoptotic genes, Bcl2, Bcl-xl, and Survivin, and the upregulation of the TGF gene. Molecular docking against VEGFR-2 emerged the interactions of the synthesised compounds in a similar way to sorafenib. Additionally, seven molecular dynamics simulations studies were applied and confirmed the stability of compound 13 in the active pocket of VEGFR-2 over 100 ns.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Sofosbuvir is the first approved direct-acting antiviral (DAA) agent that inhibits the HCV NS5B polymerase, resulting in chain termination. The molecular models of the 2′-dihalo ribonucleotides used ...were based on experimental biological studies of HCV polymerase inhibitors. They were modeled within HCV GT1a and GT1b to understand the structure–activity relationship (SAR) and the binding interaction of the halogen atoms at the active site of NS5B polymerase using different computational approaches. The outputs of the molecular docking studies indicated the correct binding mode of the tested compounds against the active sites in target receptors, exhibiting good binding free energies. Interestingly, the change in the substitution at the ribose sugar was found to produce a mild effect on the binding mode. In detail, increasing the hydrophobicity of the substituted moieties resulted in a better binding affinity. Furthermore, in silico ADMET investigation implied the general drug likeness of the examined derivatives. Specifically, good oral absorptions, no BBB penetration, and no CYP4502D6 inhibitions were expected. Likely, the in silico toxicity studies against several animal models showed no carcinogenicity and high predicted TD50 values. The DFT studies exhibited a bioisosteric effect between the substituents at the 2′-position and the possible steric clash between 2′-substituted nucleoside analogs and the active site in the target enzyme. Finally, compound 6 was subjected to several molecular dynamics (MD) simulations and MM-PBSA studies to examine the protein-ligand dynamic and energetic stability.
Cancer is still a dangerous disease with a high mortality rate all over the world. In our attempt to develop potential anticancer candidates, new quinazoline and phthalazine based compounds were ...designed and synthesized. The new derivatives were built in line with the pharmacophoric features of thalidomide. The new derivatives as well as thalidomide were examined against three cancer cell lines, namely: hepatocellular carcinoma (HepG-2), breast cancer (MCF-7) and prostate cancer (PC3). Then the effects on the expression levels of caspase-8, VEGF, NF-κB P65, and TNF-α in HepG-2 cells were evaluated. The biological data revealed the high importance of phthalazine based compounds (
24a-c
), which were far better than thalidomide with regard to the antiproliferative activity.
24b
showed IC
50
of 2.51, 5.80 and 4.11 μg mL
−1
compared to 11.26, 14.58, and 16.87 μg mL
−1
for thalidomide against the three cell lines respectively.
24b
raised caspase-8 level by about 7 folds, compared to 8 folds reported for thalidomide. Also, VEGF level in HepG-2 cells treated with
24b
was 185.3 pg mL
−1
, compared to 432.5 pg mL
−1
in control cells. Furthermore, the immunomodulatory properties were proven to
24b
, which reduced TNF-α level by approximately half. At the same time, NF-κB P65 level in HepG-2 cells treated with
24b
was 76.5 pg mL
−1
compared to 278.1 and 110.5 pg mL
−1
measured for control cells and thalidomide treated HepG-2 cells respectively. Moreover, an
in vitro
viability study against Vero non-cancerous cell line was investigated and the results reflected a high safety profile of all tested compounds. This work suggests
24b
as a promising lead compound for development of new immunomodulatory anticancer agents.
Cancer is still a dangerous disease with a high mortality rate all over the world.
PDF
