High-throughput computational screening and in vitro evaluation identifies 5-(4-oxo-4H-3,1-benzoxazin-2-yl)-2-[3-(4-oxo-4H-3,1-benzoxazin-2-yl) phenyl]-1H-isoindole-1,3(2H)-dione (C3), as a novel EGFR-HER2 dual inhibitor in gastric tumors.

Gastric cancers are caused primarily due to the activation and amplification of the EGFR or HER2 kinases resulting in cell proliferation, adhesion, angiogenesis, and metastasis. Conventional therapies are ineffective due to the intra-tumoral heterogeneity and concomitant genetic mutations. Hence, dual inhibition strategies are recommended to increase potency and reduce cytotoxicity. In this study, we have conducted computational high-throughput screening of the ChemBridge library followed by in vitro assays and identified novel selective inhibitors that have a dual impediment of EGFR/HER2 kinase activities. Diversity-based High-throughput Virtual Screening (D-HTVS) was used to screen the whole ChemBridge small molecular library against EGFR and HER2. The atomistic molecular dynamic simulation was conducted to understand the dynamics and stability of the protein-ligand complexes. EGFR/HER2 kinase enzymes, KATOIII, and Snu-5 cells were used for in vitro validations. The atomistic Molecular Dynamics simulations followed by solvent-based Gibbs binding free energy calculation of top molecules, identified compound C3 (5-(4-oxo-4H-3,1-benzoxazin-2-yl)-2-[3-(4-oxo-4H-3,1-benzoxazin-2-yl) phenyl]-1H-isoindole-1,3(2H)-dione) to have a good affinity for both EGFR and HER2. The predicted compound, C3, was promising with better binding energy, good binding pose, and optimum interactions with the EGFR and HER2 residues. C3 inhibited EGFR and HER2 kinases with IC50 values of 37.24 and 45.83 nM, respectively. The GI50 values of C3 to inhibit KATOIII and Snu-5 cells were 84.76 and 48.26 nM, respectively. Based on these findings, we conclude that the identified compound C3 showed a conceivable dual inhibitory activity on EGFR/HER2 kinase, and therefore can be considered as a plausible lead-like molecule for treating gastric cancers with minimal side effects, though testing in higher models with pharmacokinetic approach is required.

Assessing the potential impact of COVID-19 Omicron variant: Insight through a fractional piecewise model.

We consider a new mathematical model for the COVID-19 disease with Omicron variant mutation. We formulate in details the modeling of the problem with omicron variant in classical differential equations. We use the definition of the Atangana-Baleanu derivative and obtain the extended fractional version of the omicron model. We study mathematical results for the fractional model and show the local asymptotical stability of the model for infection-free case if R 0 < 1 . We show the global asymptotically stable of the model for the disease free case when R 0 ≤ 1 . We show the existence and uniqueness of solution of the fractional model. We further extend the fractional order model into piecewise differential equation system and give a numerical algorithm for their numerical simulation. We consider the real cases of COVID-19 in South Africa of the third wave March 2021-Sep 2021 and estimate the model parameters and get R 0 ≈ 1 . 4004 . The real parameters values are used to show the graphical results for the fractional and piecewise model.

Identification of New Mycobacterium tuberculosis Proteasome Inhibitors Using a Knowledge-Based Computational Screening Approach.

Mycobacterium tuberculosis (Mtb) is a deadly tuberculosis (TB)-causing pathogen. The proteasome is vital to the survival of Mtb and is therefore validated as a potential target for anti-TB therapy. Mtb resistance to existing antibacterial agents has enhanced drastically, becoming a worldwide health issue. Therefore, new potential therapeutic agents need to be developed that can overcome the complications of TB. With this purpose, in the present study, 224,205 natural compounds from the ZINC database have been screened against the catalytic site of Mtb proteasome by the computational approach. The best scoring hits, ZINC3875469, ZINC4076131, and ZINC1883067, demonstrated robust interaction with Mtb proteasome with binding energy values of -7.19, -7.95, and -7.21 kcal/mol for the monomer (K-chain) and -8.05, -9.10, and -7.07 kcal/mol for the dimer (both K and L chains) of the beta subunit, which is relatively higher than that of reference compound HT1171 (-5.83 kcal/mol (monomer) and -5.97 kcal/mol (dimer)). In-depth molecular docking of top-scoring compounds with Mtb proteasome reveals that amino acid residues Thr1, Arg19, Ser20, Thr21, Gln22, Gly23, Asn24, Lys33, Gly47, Asp124, Ala126, Trp129, and Ala180 are crucial in binding. Furthermore, a molecular dynamics study showed steady-state interaction of hit compounds with Mtb proteasome. Computational prediction of physicochemical property assessment showed that these hits are non-toxic and possess good drug-likeness properties. This study proposed that these compounds could be utilized as potential inhibitors of Mtb proteasome to combat TB infection. However, there is a need for further bench work experiments for their validation as inhibitors of Mtb proteasome.

Synergistic efficacies of thymoquinone and standard antibiotics against multi-drug resistant isolates.

OBJECTIVES: To explore the antibacterial activity of thymoquinone (TQ), a quinone extracted from Nigella sativa. METHODS: This study was conducted from May 2019 to March 2020 at the Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia. The antimicrobial activity, minimum inhibitory concentration (MIC), and minimum bactericidal concentration (MBC) of TQ were determined using an agar well diffusion method and broth microdilution assays, and the synergistic effect was evaluated using antibiotics in parallel. The disruptive effect of TQ on bacterial cell membranes was determined using scanning electron microscopy. The antivirulence properties of TQ, which include adherence and biofilm formation, were also investigated using adherence and biofilm formation assays, respectively. RESULTS: Thymoquinone demonstrated bactericidal efficacy against 4/14 bacterial strains, with MIC range of 1.04-8.3 µg/mL and and MBC range of 10.41-66.66 µg/mL. Thymoquinone showed synergism against Klebsiella pneumoniae, Staphylococcus epidermidis (American Type Culture Collection 12228), Staphylococcus aureus, and Staphylococcus epidermidis in combination with the tested antibiotics. Thymoquinone inhibited bacterial adhesion by 39%-54%, 48%-68%, and 61%-81% at 0.5 × MIC, 1 × MIC, and 2 × MIC, respectively. The tested bacterial strains significantly inhibited biofilm formation after treatment with various concentrations of TQ for 24 and 48 hours. CONCLUSION: The combinatory effect of TQ with antimicrobials should be considered when developing new antimicrobial therapy regimens to overcome multidrug-resistant.

Anticancer efficacy of 3-(4-isopropyl) benzylidene-8-ethoxy, 6-methyl, chroman-4-one (SBL-060), a novel, dual, estrogen receptor-Akt kinase inhibitor in acute myeloid leukemia cells.

Estrogen receptor (ER) α is expressed in a subset of patient-derived acute myeloid leukemia (AML) cells, whereas Akt is predominantly expressed in most types of AML. Targeting AML with dual inhibitors is a novel approach to combat the disease. Herein, we examined a novel small molecule, 3-(4-isopropyl) benzylidene-8-ethoxy,6-methyl, chroman-4-one (SBL-060), capable of targeting AML cells by inhibiting ERα and Akt kinase. The chemical properties of SBL-060 were identified by proton nuclear magnetic resonance (1H-NMR), 13C-NMR, and mass spectroscopy. In silico docking was performed using an automated protocol with AutoDock-VINA. THP-1 and HL-60 cell lines were differentiated using phorbol 12-myristate 13-acetate. ERα inhibition was assessed using ELISA. The MTT assay assessed cell viability. Flow cytometry was performed for cell cycle, apoptosis, and p-Akt analyses. Chemical analysis identified the compound as 3-(4-isopropyl) benzylidene-8-ethoxy,6-methyl, chroman-4-one, which showed high binding efficacy toward ER, with a ΔGbinding score of -7.4 kcal/mol. SBL-060 inhibited ERα, exhibiting IC50 values of 448 and 374.3 nM in THP-1 and HL-60 cells, respectively. Regarding inhibited cell proliferation, GI50 values of SBL-060 were 244.1 and 189.9 nM for THP-1 and HL-60 cells, respectively. In addition, a dose-dependent increase in sub G0/G1 phase cell cycle arrest and total apoptosis was observed after treatment with SBL-060 in both cell types. SBL-060 also dose-dependently increased the p-Akt-positive populations in both THP-1 and HL-60 cells. Our results indicate that SBL-060 has excellent efficacy against differentiated AML cell types by inhibiting ER and Akt kinase, warranting further preclinical evaluations.