In response to the urgent need to control Coronavirus disease 19 (COVID-19), this study aims to explore potential anti-SARS-CoV-2 agents from natural sources. Moreover, cytokine immunological ...responses to the viral infection could lead to acute respiratory distress which is considered a critical and life-threatening complication associated with the infection. Therefore, the anti-viral and anti-inflammatory agents can be key to the management of patients with COVID-19. Four bioactive compounds, namely ferulic acid
, rutin
, gallic acid
, and chlorogenic acid
were isolated from the leaves of
(L.) Merr (ethyl acetate extract) and identified using spectroscopic evidence. Furthermore, molecular docking and dynamics simulations were performed for the isolated and identified compounds (
-
) against SARS-CoV-2 main protease (Mpro) as a proposed mechanism of action. Furthermore, all compounds were tested for their half-maximal cytotoxicity (CC
) and SARS-CoV-2 inhibitory concentrations (IC
). Additionally, lung toxicity was induced in rats by mercuric chloride and the effects of treatment with
aqueous extract, ferulic acid
, rutin
, gallic acid
, and chlorogenic acid
were recorded through measuring TNF-α, IL-1β, IL-2, IL-10, G-CSF, and genetic expression of miRNA 21-3P and miRNA-155 levels to assess their anti-inflammatory effects essential for COVID-19 patients. Interestingly, rutin
, gallic acid
, and chlorogenic acid
showed remarkable anti-SARS-CoV-2 activities with IC
values of 31 µg/mL, 108 μg/mL, and 360 µg/mL, respectively. Moreover, the anti-inflammatory effects were found to be better in ferulic acid
and rutin
treatments. Our results could be promising for more advanced preclinical and clinical studies especially on rutin
either alone or in combination with other isolates for COVID-19 management.
In continuation of our previous effort, different in silico selection methods were applied to 310 naturally isolated metabolites that exhibited antiviral potentialities before. The applied selection ...methods aimed to pick the most relevant inhibitor of SARS-CoV-2 nsp10. At first, a structural similarity study against the co-crystallized ligand, S-Adenosyl Methionine (SAM), of SARS-CoV-2 nonstructural protein (nsp10) (PDB ID: 6W4H) was carried out. The similarity analysis culled 30 candidates. Secondly, a fingerprint study against SAM preferred compounds 44, 48, 85, 102, 105, 182, 220, 221, 282, 284, 285, 301, and 302. The docking studies picked 48, 182, 220, 221, and 284. While the ADMET analysis expected the likeness of the five candidates to be drugs, the toxicity study preferred compounds 48 and 182. Finally, a density-functional theory (DFT) study suggested vidarabine (182) to be the most relevant SARS-Cov-2 nsp10 inhibitor.
A thiazolidine-2,4-dione nucleus was molecularly hybridised with the effective antitumor moieties; 2-oxo-1,2-dihydroquinoline and 2-oxoindoline to obtain new hybrids with potential activity against ...VEGFR-2. The cytotoxic effects of the synthesised derivatives against Caco-2, HepG-2, and MDA-MB-231 cell lines were investigated. Compound 12a was found to be the most potent candidate against the investigated cell lines with IC
50
values of 2, 10, and 40 µM, respectively. Furthermore, the synthesised derivatives were tested in vitro for their VEGFR-2 inhibitory activity showing strong inhibition. 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. Compound 12a was further investigated for its apoptotic behaviour by assessing the gene expression of four genes (Bcl2, Bcl-xl, TGF, and Survivin). Molecular dynamic simulations authenticated the high affinity, accurate binding, and perfect dynamics of compound 12a against VEGFR-2.
Papain-like protease is an essential enzyme in the proteolytic processing required for the replication of SARS-CoV-2. Accordingly, such an enzyme is an important target for the development of ...anti-SARS-CoV-2 agents which may reduce the mortality associated with outbreaks of SARS-CoV-2. A set of 69 semi-synthesized molecules that exhibited the structural features of SARS-CoV-2 papain-like protease inhibitors (PLPI) were docked against the coronavirus papain-like protease (PLpro) enzyme (PDB ID: (4OW0). Docking studies showed that derivatives
and
were better than the co-crystallized ligand while derivatives
,
,
,
,
,
,
,
, and
exhibited good binding modes and binding free energies. The pharmacokinetic profiling study was conducted according to the four principles of the Lipinski rules and excluded derivative 31. Furthermore, ADMET and toxicity studies showed that derivatives
,
, and
have the potential to be drugs and have been demonstrated as safe when assessed via seven toxicity models. Finally, comparing the molecular orbital energies and the molecular electrostatic potential maps of
,
, and
against the co-crystallized ligand in a DFT study indicated that
is the most promising candidate to interact with the target receptor (PLpro).
In continuation of our antecedent work against COVID-19, three natural compounds, namely, Luteoside C (130), Kahalalide E (184), and Streptovaricin B (278) were determined as the most promising ...SARS-CoV-2 main protease (Mpro) inhibitors among 310 naturally originated antiviral compounds. This was performed via a multi-step in silico method. At first, a molecular structure similarity study was done with PRD_002214, the co-crystallized ligand of Mpro (PDB ID: 6LU7), and favored thirty compounds. Subsequently, the fingerprint study performed with respect to PRD_002214 resulted in the election of sixteen compounds (7, 128, 130, 156, 157, 158, 180, 184, 203, 204, 210, 237, 264, 276, 277, and 278). Then, results of molecular docking versus Mpro PDB ID: 6LU7 favored eight compounds (128, 130, 156, 180, 184, 203, 204, and 278) based on their binding affinities. Then, in silico toxicity studies were performed for the promising compounds and revealed that all of them have good toxicity profiles. Finally, molecular dynamic (MD) simulation experiments were carried out for compounds 130, 184, and 278, which exhibited the best binding modes against Mpro. MD tests revealed that luteoside C (130) has the greatest potential to inhibit SARS-CoV-2 main protease.
Based on the pharmacophoric features of EGFR inhibitors, a new semisynthetic theobromine-derived compound was designed to interact with the catalytic pocket of EGFR. Molecular docking against wild ...(EGFRWT; PDB: 4HJO) and mutant (EGFRT790M; PDB: 3W2O) types of EGFR-TK indicated that the designed theobromine derivative had the potential to bind to that pocket as an antiangiogenic inhibitor. The MD and MM-GBSA experiments identified the exact binding with optimum energy and dynamics. Additionally, the DFT calculations studied electrostatic potential, stability, and total electron density of the designed theobromine derivative. Both in silico ADMET and toxicity analyses demonstrated its general likeness and safety. We synthesized the designed theobromine derivative (compound XI) which showed an IC50 value of 17.23 nM for EGFR inhibition besides IC50 values of 21.99 and 22.02 µM for its cytotoxicity against A549 and HCT-116 cell lines, respectively. Interestingly, compound XI expressed a weak cytotoxic potential against the healthy W138 cell line (IC50 = 49.44 µM, 1.6 times safer than erlotinib), exhibiting the high selectivity index of 2.2. Compound XI arrested the growth of A549 at the G2/M stage and increased the incidence of apoptosis.
A new semisynthetic derivative of the natural alkaloid, theobromine, has been designed as a lead antiangiogenic compound targeting the EGFR protein. The designed compound is an (m-tolyl)acetamide ...theobromine derivative, (T-1-MTA). Molecular Docking studies have shown a great potential for T-1-MTA to bind to EGFR. MD studies (100 ns) verified the proposed binding. By MM-GBSA analysis, the exact binding with optimal energy of T-1-MTA was also identified. Then, DFT calculations were performed to identify the stability, reactivity, electrostatic potential, and total electron density of T-1-MTA. Furthermore, ADMET analysis indicated the T-1-MTA's general likeness and safety. Accordingly, T-1-MTA has been synthesized to be examined in vitro. Intriguingly, T-1-MTA inhibited the EGFR protein with an IC50 value of 22.89 nM and demonstrated cytotoxic activities against the two cancer cell lines, A549, and HCT-116, with IC50 values of 22.49, and 24.97 μM, respectively. Interestingly, T-1-MTA's IC50 against the normal cell lines, WI-38, was very high (55.14 μM) indicating high selectivity degrees of 2.4 and 2.2, respectively. Furthermore, the flow cytometry analysis of A549 treated with T-1-MTA showed significantly increased ratios of early apoptosis (from 0.07% to 21.24%) as well as late apoptosis (from 0.73% to 37.97%).
This study describes the synthesis and biological activity of new imadazopyrazines as first-in-class CDK9 inhibitors. The inhibition of CDK9 is a well-established therapeutic target in cancer ...therapy. The new compounds were assessed using an in vitro kinase assay against CDK9. In this assay, compound
exhibited the highest CDK9 inhibition with an IC
of 0.18 µM. The cytotoxicity effect of the novel compounds was evaluated in three cancer cell lines: HCT116, K652, and MCF7. The results of this assay showed a correlation between the antiproliferative effect of the inhibitors and their CDK9 inhibitory effect in the biochemical assay. This suggests CDK9 inhibition as a mechanistic pathway for their anticancer effect. Several compounds demonstrated potent cytotoxic effects with single-digit micromolar IC
values yielded through an MTT assay. The compounds with the most promising data were further assessed for their antiviral activity against human Coronavirus 229E. The results showed that compound
showed the highest antiviral potency with an IC
of 63.28 µM and a selectivity index of 4.8. In silico target prediction data showed that
displayed a good affinity to proteases. The result of the docking studies of
with COVID-19 main protease revealed a high binding affinity, which confirmed the results obtained from in vitro study. The physiochemical and in silico pharmacokinetic parameters indicated reasonable drug-likeness properties of the new compounds, including solubility, lipophilicity, absorption, oral bioavailability, and metabolic stability. Further lead optimization of this novel scaffold could lead to a revolution of a new class of preclinical CDK9 agents.
To evaluate patterns of antiseizure medication (ASM) prescription in pregnancy and changes over a 16-year period: 2005–2020, and to investigate maternal complications in pregnant women with epilepsy ...(WWE).
Data of pregnant WWE was retrospectively reviewed at the King Faisal Specialist Hospital and Research Centre, Riyadh and Jeddah, Saudi Arabia.
Out of 162 pregnancies, 81.5% were prescribed ASMs. During the study period, the prescription rate increased from 68.8% to 93.5%. Between 2005 and 2020, the use of new ASMs increased from 15.4% to 75.5% (p < 0.0001). Furthermore, valproate use markedly decreased from 23.08% to 2.04%. The rate of maternal and delivery complications was 29.6%; the most frequent was gestational diabetes (5.6%), followed by bleeding during pregnancy (4.9%). Furthermore, preeclampsia and eclampsia were documented in 3.7% and 1.8%, respectively. ASMs use and other factors were not found to be associated with maternal complications (p > 0.05). However, first generation ASMs, i.e. carbamazepine (38.71%) and valproate (41.67%), were associated with higher maternal complication rates than new ASMs, i.e. levetiracetam (25%) and lamotrigine (20%), but the difference was not statistically significant (p = 0.4403).
ASM prescription in pregnancy is increasing as is the use of new ASMs. The rate of maternal and delivery complications was relatively low, particularly preeclampsia and eclampsia. ASMs use was not found to associated with these complications. However, exposure to first generation ASMs seemed to be a predictor of adverse pregnancy outcomes.
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.
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