Isolation and In Silico Anti-SARS-CoV-2 Papain-Like Protease Potentialities of Two Rare 2-Phenoxychromone Derivatives from Artemisia spp.

Two rare 2-phenoxychromone derivatives, 6-demethoxy-4`-O-capillarsine (1) and tenuflorin C (2), were isolated from the areal parts of Artemisia commutata and A. glauca, respectively, for the first time. Being rare in nature, the inhibition potentialities of 1 and 2 against SARS-CoV-2 was investigated using multistage in silico techniques. At first, molecular similarity and fingerprint studies were conducted for 1 and 2 against co-crystallized ligands of eight different COVID-19 enzymes. The carried-out studies indicated the similarity of 1 and 2 with TTT, the co-crystallized ligand of COVID-19 Papain-Like Protease (PLP), (PDB ID: 3E9S). Therefore, molecular docking studies of 1 and 2 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 1 and 2 against seven models indicated the general safety and the likeness of 1 and 2 to be drugs. Lastly, to authenticate the binding and to investigate the thermodynamic characters, molecular dynamics (MD) simulation studies were conducted on 1 and PLP.Peer Reviewe

Crystal structures and Hirshfeld surface analysis of 2-(adamantan-1-yl)-5-(4-fluorophenyl)-1,3,4-oxadiazole and 2-(adamantan-1-yl)-5-(4-chlorophenyl)-1,3,4-oxadiazole

The crystal structures of the title adamantane-oxadiazole hybrid compounds, C18H19FN2O (I) and C18H19ClN2O (II), are built up from an adamantane unit and a halogenophenyl ring, [X = F (I), Cl (Mb in position 5 on the central 1,3,4-oxadiazole unit. The molecular structures are very similar, only the relative orientation of the halogenophenyl ring in comparison with the central five membered ring differs slightly. In the crystals of both compounds, molecules are linked by pairs of C-H center dot center dot center dot N hydrogen bonds, forming inversion dimers with R-2(2)(12) ring motifs. In (I) the dimers are connected by C-H center dot center dot center dot F interactions, forming slabs lying parallel to the be plane. In (II), the dimers are linked by C-H center dot center dot center dot pi and offset pi-pi interactions [interplanar distance = 3.4039 (9) angstrom], forming layers parallel to (10 (1) over bar)

Synthesis and Biological Evaluation of Imadazo[1,2-a]pyrazines as Anticancer and Antiviral Agents through Inhibition of CDK9 and Human Coronavirus

In this work, novel imadazo[1,2-a]pyrazine derivatives were synthesized and evaluated as CDK9 inhibitors. The results of CDK9 assay showed that the derivatives with pyridin-4-yl in position 2 and benzyl in position 3 of imadazo[1,2-a]pyrazine 3c displayed the most potent CDK9 inhibitory activity with IC50 of 0.16 µM. The anti-proliferative effect of the new compounds was examined against breast cancer (MCF7), colorectal cancer (HCT116), and chronic myelogenous leukaemia (K652) cell lines. The data of MTT assay showed that the cytotoxic effect of the inhibitors is correlated to their inhibitory activity against CDK9. Compound 3c exhibited the most potent cytotoxicity effect with average IC50s of three cell lines of 6.66 µM. The drug likeness properties of 3c were predicated in silico and demonstrated that 3c have reasonable physiochemical and pharmacokinetic properties. Selected derivatives were assessed in antiviral assay against human coronavirus 229E. The results of this assay showed that the derivative with pyridin-4-yl in position 2 and cyclohexyl in position 3 of imadazo[1,2-a]pyrazine 3b exhibited the most potent anti-coronaviral activity with IC50 of 56.96 µM and selectivity index of 7.14. The target predication result revealed that 3b showed high affinity to protease enzyme. Docking studies of 3b with COVID-19 main protease was conducted and showed good binding affinity, which confirmed the in vitro assay data

Molecular Docking and Dynamic Simulation Revealed the Potential Inhibitory Activity of Opioid Compounds Targeting the Main Protease of SARS-CoV-2

Opioids are a class of chemicals, naturally occurring in the opium poppy plant, and act on the brain to cause a range of impacts, notably analgesic and anti-inflammatory actions. Moreover, an overview was taken in consideration for SARS-CoV-2 incidence and complications, as well as the medicinal uses of opioids were discussed being a safe analgesic and anti-inflammatory drug in a specific dose. Also, our article focused on utilization of opioids in the medication of SARS-CoV-2. Therefore, the major objective of this study was to investigate the antiviral effect of opioids throughout an in silico study by molecular docking study to fifteen opioid compounds against SARS-CoV-2 main protease (PDB ID 6LU7, Mpro). The docking results revealed that opioid complexes potentially inhibit the Mpro active site and exhibiting binding energy (-11.0 kcal/mol), which is comparably higher than the ligand. Furthermore, ADMET prediction indicated that all the tested compounds have good oral absorption and bioavailability and can transport via biological membranes. Finally, Mpro-pholcodine complex was subjected to five MD (RMSD, RMSF, SASA, Rg, and hydrogen bonding) and two MM-PBSA, and conformational change studies, for 100 ns, confirmed the stability of pholcodine, as a representative example, inside the active site of Mpro

Design, synthesis, antitumor evaluation, and molecular docking of novel pyrrolo[2,3-d]pyrimidine as multi-kinase inhibitors

In the last twenty years, protein kinases have been identified as important targets for cancer therapy. In order to prevent unexpected toxicity, medicinal chemists have always focused on discovering selective protein kinase inhibitors. However, cancer is a multifactorial process and its formation and progression depend on different stimuli. Therefore, it is imperative to develop anticancer therapy that targets multiple kinases associated cancer progression. In this research a series of hybrid compounds was designed and synthesized successfully with the aim of producing anticancer activity through the induction of multiple protein kinase inhibition. The designed derivatives comprise isatin and pyrrolo[2,3-d]pyrimidine scaffolds in their structures with a hydrazine linking the two pharmacophores. Antiproliferative and kinase inhibition assays revealed promising anticancer and multi-kinase inhibitory effects of compound 7 with comparable results with the reference standards. Moreover, compound 7 suppressed cell cycle progression and induced apoptosis in HepG2 cells. Finally, molecular docking simulation was performed to investigate the potential types of interactions between the protein kinase enzymes and the designed hybrid compounds. The results of this research indicated the promising anticancer effect of compound 7 through the inhibition of a number of protein kinase receptors and the suppression of cell cycle and the induction of apoptosis

The Discovery of Potential SARS-CoV-2 Natural Inhibitors among 4924 African Metabolites Targeting the Papain-like Protease: A Multi-Phase In Silico Approach

Four compounds, hippacine, 4,2′-dihydroxy-4′-methoxychalcone, 2′,5′-dihydroxy-4-methoxychalcone, and wighteone, were selected from 4924 African natural metabolites as potential inhibitors against SARS-CoV-2 papain-like protease (PLpro, PDB ID: 3E9S). A multi-phased in silico approach was employed to select the most similar metabolites to the co-crystallized ligand (TTT) of the PLpro through molecular fingerprints and structural similarity studies. Followingly, to examine the binding of the selected metabolites with the PLpro (molecular docking. Further, to confirm this binding through molecular dynamics simulations. Finally, in silico ADMET and toxicity studies were carried out to prefer the most convenient compounds and their drug-likeness. The obtained results could be a weapon in the battle against COVID-19 via more in vitro and in vivo studies

Molecular docking, Hirshfeld surface analysis and spectroscopic investigations of 1-(adamantan-1-yl)-3-(4-fluorophenyl)thiourea: A potential bioactive agent

SERT, YUSUF/0000-0001-8836-8667WOS: 000489698800014In this study, the optimized molecular structure, Hirshfeld surface analysis, vibrational frequencies and corresponding vibrational modes of a potential bioactive agent namely; 1-(adamantan-1-yl)-3-(4-fluorophenyl)thiourea were studied experimentally and theoretically. The theoretical calculations of the title compound were carried out using the density functional theory (DFT/B3LYP and DFT/M06-2X) quantum mechanical method with 6-311 + + G(d,p) basis set and Gaussian 09W program. The vibrational assignments of the title compound were obtained using VEDA 4 program by %10 precision with the help of potential energy distributions (PED). The experimental (FT-IR and Laser-Raman) spectra were recorded in solid phase at 4000-400 cm(-1) (FT-IR) and 4000-100 cm(-1) (Laser-Raman). Additionally, the experimental and theoretical H-1 and C-13 NMR chemical shifts in DMSO-d(6) and UV-Vis. Spectral analysis in DMF were studied theoretically and experimentally. The highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) analyses were performed. The molecular docking studies of the title compound revealed that it may exhibit antibacterial activity via inhibition of bacterial DNA gyrase PDB: 3U2D enzyme.Deanship of Scientific Research at Princess Nourah bint Abdulrahman University through the Research Group Program [RGP-1438-0010]This work was funded by the Deanship of Scientific Research at Princess Nourah bint Abdulrahman University through the Research Group Program (Grant No. RGP-1438-0010)

A New Anticancer Semisynthetic Theobromine Derivative Targeting EGFR Protein: CADDD Study

A new lead compound has been designed as an antiangiogenic EGFR inhibitor that has the pharmacophoric characteristics to bind with the catalytic pocket of EGFR protein. The designed lead compound is a (para-chloro)acetamide derivative of the alkaloid, theobromine, (T-1-PCPA). At first, we started with deep density functional theory (DFT) calculations for T-1-PCPA to confirm and optimize its 3D structure. Additionally, the DFT studies identified the electrostatic potential, global reactive indices and total density of states expecting a high level of reactivity for T-1-PCPA. Secondly, the affinity of T-1-PCPA to bind and inhibit the EGFR protein was studied and confirmed through detailed structure-based computational studies including the molecular docking against EGFRWT and EGFRT790M, Molecular dynamics (MD) over 100 ns, MM-GPSA and PLIP experiments. Before the preparation, the computational ADME and toxicity profiles of T-1-PCPA have been investigated and its safety and the general drug-likeness predicted. Accordingly, T-1-PCPA was semi-synthesized to scrutinize the proposed design and the obtained in silico results. Interestingly, T-1-PCPA inhibited in vitro EGFRWT with an IC50 value of 25.35 nM, comparing that of erlotinib (5.90 nM). Additionally, T-1-PCPA inhibited the growth of A549 and HCT-116 malignant cell lines with IC50 values of 31.74 and 20.40 µM, respectively, comparing erlotinib that expressed IC50 values of 6.73 and 16.35 µM, respectively

Discovery of Potential SARS-CoV-2 Papain-like Protease Natural Inhibitors Employing a Multi-Phase In Silico Approach

As an extension of our research against COVID-19, a multiphase in silico approach was applied in the selection of the three most common inhibitors (Glycyrrhizoflavone (76), Arctigenin (94), and Thiangazole (298)) against papain-like protease, PLpro (PDB ID: 4OW0), among 310 metabolites of natural origin. All compounds of the exam set were reported as antivirals. The structural similarity between the examined compound set and S88, the co-crystallized ligand of PLpro, was examined through structural similarity and fingerprint studies. The two experiments pointed to Brevicollin (28), Cryptopleurine (41), Columbamine (46), Palmatine (47), Glycyrrhizoflavone (76), Licochalcone A (87), Arctigenin (94), Termilignan (98), Anolignan B (99), 4,5-dihydroxy-6″-deoxybromotopsentin (192), Dercitin (193), Tryptanthrin (200), 6-Cyano-5-methoxy-12-methylindolo [2, 3A] carbazole (211), Thiangazole (298), and Phenoxan (300). The binding ability against PLpro was screened through molecular docking, disclosing the favorable binding modes of six metabolites. ADMET studies expected molecules 28, 76, 94, 200, and 298 as the most favorable metabolites. Then, molecules 76, 94, and 298 were chosen through in silico toxicity studies. Finally, DFT studies were carried out on glycyrrhizoflavone (76) and indicated a high level of similarity in the molecular orbital analysis. The obtained data can be used in further in vitro and in vivo studies to examine and confirm the inhibitory effect of the filtered metabolites against PLpro and SARS-CoV-2