A Multistage In Silico Study of Natural Potential Inhibitors Targeting SARS-CoV-2 Main Protease

Among a group of 310 natural antiviral natural metabolites, our team identified three compounds as the most potent natural inhibitors against the SARS-CoV-2 main protease (PDB ID: 5R84), Mpro. The identified compounds are sattazolin and caprolactin A and B. A validated multistage in silico study was conducted using several techniques. First, the molecular structures of the selected metabolites were compared with that of GWS, the co-crystallized ligand of Mpro, in a structural similarity study. The aim of this study was to determine the thirty most similar metabolites (10%) that may bind to the Mpro similar to GWS. Then, molecular docking against Mpro and pharmacophore studies led to the choice of five metabolites that exhibited good binding modes against the Mpro and good fit values against the generated pharmacophore model. Among them, three metabolites were chosen according to ADMET studies. The most promising Mpro inhibitor was determined by toxicity and DFT studies to be caprolactin A (292). Finally, molecular dynamics (MD) simulation studies were performed for caprolactin A to confirm the obtained results and understand the thermodynamic characteristics of the binding. It is hoped that the accomplished results could represent a positive step in the battle against COVID-19 through further in vitro and in vivo studies on the selected compounds

Design, Synthesis, In Silico and In Vitro Studies of New Immunomodulatory Anticancer Nicotinamide Derivatives Targeting VEGFR-2

VEGFR-2, the subtype receptor tyrosine kinase (RTK) responsible for angiogenesis, is expressed in various cancer cells. Thus, VEGFER-2 inhibition is an efficient approach for the discovery of new anticancer agents. Accordingly, a new set of nicotinamide derivatives were designed and synthesized to be VEGFR-2 inhibitors. The chemical structures were confirmed using IR, 1H-NMR, and 13C-NMR spectroscopy. The obtained compounds were examined for their anti-proliferative activities against the human cancer cell lines (HCT-116 and HepG2). VEGFR-2 inhibitory activities were determined for the titled compounds. Compound 8 exhibited the strongest anti-proliferative activities with IC50 values of 5.4 and 7.1 µM against HCT-116 and HepG2, respectively. Interestingly, compound 8 was the most potent VEGFR-2 inhibitor with an IC50 value of 77.02 nM (compare to sorafenib: IC50 = 53.65 nM). Treatment of HCT-116 cells with compound 8 produced arrest of the cell cycle at the G0–G1 phase and a total apoptosis increase from 3.05 to 19.82%—6.5-fold in comparison to the negative control. In addition, compound 8 caused significant increases in the expression levels of caspase-8 (9.4-fold) and Bax (9.2-fold), and a significant decrease in the Bcl-2 expression level (3-fold). The effects of compound 8 on the levels of the immunomodulatory proteins (TNF-α and IL-6) were examined. There was a marked decrease in the level of TNF-α (92.37%) compared to the control (82.47%) and a non-significant reduction in the level of IL-6. In silico docking, molecular dynamics simulations, and MM-PBSA studies revealed the high affinity, the correct binding, and the optimum dynamics of compound 8 inside the active site of VEGFR-2. Finally, in silico ADMET and toxicity studies indicated acceptable values of drug-likeness. In conclusion, compound 8 has emerged as a promising anti-proliferative agent targeting VEGFR-2 with significant apoptotic and immunomodulatory effects

Modified Benzoxazole-Based VEGFR-2 Inhibitors and Apoptosis Inducers: Design, Synthesis, and Anti-Proliferative Evaluation

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

Global economic burden of unmet surgical need for appendicitis

Background There is a substantial gap in provision of adequate surgical care in many low- and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially

Global economic burden of unmet surgical need for appendicitis

Background There is a substantial gap in provision of adequate surgical care in many low- and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially