The Inhibitory Effects of the Herbals Secondary Metabolites (7α-acetoxyroyleanone, Curzerene, Incensole, Harmaline, and Cannabidiol) on COVID-19: A Molecular Docking Study.

BACKGROUND: Since the COVID-19 outbreak in early 2020, researchers and studies are continuing to find drugs and/or vaccines against the disease. As shown before, medicinal plants can be very good sources against viruses because of their secondary compounds which may cure diseases and help in survival of patients. There is a growing trend in the filed patents in this field. AIMS: In the present study, we test and suggest the inhibitory potential of five herbal based extracts including 7α-acetoxyroyleanone, Curzerene, Incensole, Harmaline, and Cannabidiol with antivirus activity on the models of the significant antiviral targets for COVID-19 like spike glycoprotein, Papain-like protease (PLpro), non-structural protein 15 (NSP15), RNA-dependent RNA polymerase and core protease by molecular docking study. METHODS: The Salvia rythida root was extracted, dried, and pulverized by a milling machine. The aqueous phase and the dichloromethane phase of the root extractive were separated by two-phase extraction using a separatory funnel. The separation was performed using the column chromatography method. The model of the important antivirus drug target of COVID-19 was obtained from the Protein Data Bank (PDB) and modified. TO study the binding difference between the studied molecules, the docking study was performed. RESULTS: These herbal compounds are extracted from Salvia rhytidea, Curcuma zeodaria, Frankincense, Peganum harmala, and Cannabis herbs, respectively. The binding energies of all compounds on COVID-19 main targets are located in the limited area of 2.22-5.30 kcal/mol. This range of binding energies can support our hypothesis for the presence of the inhibitory effects of the secondary metabolites of mentioned structures on COVID-19. Generally, among the investigated herbal structures, Cannabidiol and 7α- acetoxyroyleanone compounds with the highest binding energy have the most inhibitory potential. The least inhibitory effects are related to the Curzerene and Incensole structures by the lowest binding affinity. CONCLUSION: The general arrangement of the basis of the potential barrier of binding energies is in the order below: Cannabidiol > 7α-acetoxyroyleanone > Harmaline> Incensole > Curzerene. Finally, the range of docking scores for investigated herbal compounds on the mentioned targets indicates that the probably inhibitory effects on these targets obey the following order: main protease> RNA-dependent RNA polymerase> PLpro> NSP15> spike glycoprotein.

Design, synthesis, computational study and cytotoxic evaluation of some new quinazoline derivatives containing pyrimidine moiety.

Quinazoline derivatives, as an important category of heterocyclic compounds, have received much attention for the design and development of new drugs due to their various pharmacological properties. Besides, there is a great deal of evidence showing pyrimidine analogs as anticancer agents. Thus, in the present study, for the design of new target compounds with cytotoxic activity, we focused on various quinazolinone and pyrimidine hybrids. A new series of quinazoline-pyrimidine hybrid derivatives (6a-6n) have been designed and synthesized as novel antiproliferative agents. All the synthesized compounds characterized based on their IR, NMR and Mass spectroscopic data. Antiproliferative activities of the new compounds were evaluated against three human cancer cell lines (MCF-7, A549, SW-480). The compounds were found to have appropriate potential with IC50 values ranging from 2.3 ± 5.91 to 176.5 ± 0.7 µM against the tested cell lines. Compound 6n exerted the highest antiproliferative activity with IC50 values of 5.9 ± 1.69 µM, 2.3 ± 5.91 µM and 5.65 ± 2.33 µM against A549, SW-480 and MCF-7 respectively. The results indicated that 6n could induce apoptosis in A549 cell line in a dose dependent manner and arrest in the S phase of cell cycle. Docking studies were also done to investigate the detailed binding pattern of the synthesized compounds against EGFR. Furthermore, molecular dynamic simulation and binding free energy calculation have been done to rescore initial docking pose of the synthesized compounds using ensemble-based MMGB/PBSA free energy method. According to the results, free energy calculation confirmed biological activity of compounds and also, Arg 817 and Lys 721 residues had the pivotal role in the high potency of 6n. Finally, the drug likeness and in silico ADME study were also predicted.

Olanzapine manipulates neuroactive signals and may onset metabolic disturbances.

Olanzapine is one of the most prescribed atypical antipsychotics to treat psychiatric illness and is associated with weight gain and metabolic disturbance. The present study investigated the olanzapine-regulated metabolic pathways using functional enrichent analysis including binding affinity with G-protein-coupled receptors (GPCRs). Proteins modulated by olanzapine were retrieved from SwissTargetPrediction, DIGEP-Pred, and BindingDB and then enriched in Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) to assess molecular function, biological process, and cellular components including Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. We used homology modeling to improve the 3D structure for GPCR synapse proteins including dopamine, serotonin, muscarinic, and histamine receptors which were then optimized using molecular dynamics (MD) simulations. The protein-olanzapine binding mechanisms for different GPCR binders were evaluated using molecular docking; later refined by MD simulations. Binding mechanism of olanzapine with D2, 5HT1A, 5HT2A, 5HT2B, 5HT2C, M1, and M2 receptors were created using homology modeling and optimized using MD simulations. In target identification, it was observed that olanzapine majority targeted G-protein coupled receptors. Further, enrichment analysis identified around 76% of the total genes regulated in molecular function, biological process, and cellular components were common including KEGG pathways. Moreover, it was observed that olanzapine had a major potency over the neurotransmitter synapse including neuroactive signals . Olanzapine-induced weight gain and metabolic alterations could be due to the deregulation of multiple synapses like dopamine, serotonin, muscarinic, and histamine at the feeding center followed by cGMP-PKG, cAMP, and PI3K-Akt signaling pathways. HIGHLIGHTSOlanzapine is used in the management of psychiatric illnesses.Olanzapine causes disturbance in lipids and glucosehomeostasis and manipulates energy expenditure.Olanzapine-induced weight gain may occur due to the deregulation of the multiple synapse and cGMP-PKG, cAMP, and PI3K-Akt signaling pathwayCommunicated by Ramaswamy H. Sarma.

Study of tyramine-binding mechanism and insecticidal activity of oil extracted from Eucalyptus against Sitophilus oryzae.

The rice weevil, Sitophilus oryzae (L.), is a major pest of stored grains throughout the world, which causes quantitative and qualitative losses of food commodities. Eucalyptus essential oils (EOs) possess insecticidal and repellent properties, which make them a potential option for insect control in stored grains with environmentally friendly properties. In the current study, the binding mechanism of tyramine (TA) as a control compound has been investigated by funnel metadynamics (FM) simulation toward the homology model of tyramine1 receptor (TyrR) to explore its binding mode and key residues involved in the binding mechanism. EO compounds have been extracted from the leaf and flower part of Eucalyptus camaldulensis and characterized by GC/MS, and their effectiveness has been evaluated by molecular docking and conventional molecular dynamic (CMD) simulation toward the TyrR model. The FM results suggested that Asp114 followed by Asp80, Asn91, and Asn427 are crucial residues in the binding and the functioning of TA toward TyrR in Sitophilus Oryzae. The GC/MS analysis confirmed a total of 54 and 31 constituents in leaf and flower, respectively, where most of the components (29) are common in both groups. This analysis also revealed the significant concentration of Eucalyptus and α-pinene in leaves and flower EOs. The docking followed by CMD was performed to find the most effective compound in Eucalyptus EOs. In this regard, butanoic acid, 3-methyl-, 3-methyl butyl ester (B12) and 2-Octen-1-ol, 3,7-dimethyl- (B23) from leaf and trans- ß-Ocimene (G04) from flower showed the maximum dock score and binding free energy, making them the leading candidates to replace tyramine in TyrR. The MM-PB/GBSA and MD analysis proved that the B12 structure is the most effective compound in inhibition of TyrR.

Metamorphosis of prostate specific membrane antigen (PSMA) inhibitors.

Prostate-specific membrane antigen (PSMA), also called glutamate carboxypeptidase II (GCP(II)), is a Zn-dependent metalloprotease that is known as a well prostate cancer indication and a potential targeting towards anti-cancer medicines and drug delivery. Because of its centrality in the diagnostics and treatment of prostate cancer, several types of inhibitors are designed with particular scaffolds. In this study, important groups of related inhibitors as well as reported experimental and computational studies are being reviewed, in which we examined three functional groups on each group of structures. The importance of computational biochemistry and the necessity of extensive research in this area on PSMA and its effective ligands are recommended.

Novel Cytotoxic Phenanthro-triazine-3-thiol Derivatives as Potential DNA Intercalators and Bcl-2 Inhibitors.

Novel phenanthro-triazine-3-thiol derivatives were designed as potential DNA intercalators and Bcl-2 inhibitors. After being synthesized, the compounds were evaluated for their cytotoxic activity against MOLT-4 (human acute lymphoblastic leukemia) and MCF-7 (human breast adenocarcinoma) cells by MTT assay. P1 (bearing hydrogen substitution) was the most potent derivative against MOLT-4 with an IC50 value of 7.1 ± 1.1 µM, whereas P11 (bearing phenyl substitution) demonstrated considerable cytotoxicity against MCF-7 with an IC50 value of 15.4 ± 2.9 µM. Compounds P7, P8, P14 and P15 exhibited moderate cytotoxic effects. Furthermore, to confirm the potential DNA intercalation and Bcl-2 inhibitory activities of phenanthro-triazine scaffolds, molecular docking analysis was performed. Molecular docking studies indicated that these compounds not only bind to DNA by intercalation mainly through stacking interactions but also are well accommodated in the active site of Bcl-2. Therefore, P1 and P11 having phenanthro-triazine-3-thiol scaffold could be presented as cytotoxic agents with dual DNA intercalation and Bcl-2 inhibitory activities.

Integration of System Biology Tools to Investigate Huperzine A as an Anti-Alzheimer Agent.

Aim: The present study aimed to investigate huperzine A as an anti-Alzheimer agent based on the principle that a single compound can regulate multiple proteins and associated pathways, using system biology tools. Methodology: The simplified molecular-input line-entry system of huperzine A was retrieved from the PubChem database, and its targets were predicted using SwissTargetPrediction. These targets were matched with the proteins deposited in DisGeNET for Alzheimer disease and enriched in STRING to identify the probably regulated pathways, cellular components, biological processes, and molecular function. Furthermore, huperzine A was docked against acetylcholinesterase using AutoDock Vina, and simulations were performed with the Gromacs package to take into account the dynamics of the system and its effect on the stability and function of the ligands. Results: A total of 100 targets were predicted to be targeted by huperzine A, of which 42 were regulated at a minimum probability of 0.05. Similarly, 101 Kyoto Encyclopedia of Genes and Genomes pathways were triggered, in which neuroactive ligand-receptor interactions scored the least false discovery rate. Also, huperzine A was predicted to modulate 54 cellular components, 120 molecular functions, and 873 biological processes. Furthermore, huperzine A possessed a binding affinity of -8.7 kcal/mol with AChE and interacted within the active site of AChE via H-bonds and hydrophobic interactions.

Simulation, In Vitro, and In Vivo Cytotoxicity Assessments of Methotrexate-Loaded pH-Responsive Nanocarriers.

In this study, pH-responsive niosomal methotrexate (MTX) modified with ergosterol was prepared for potential anticancer application. The prepared formulation had a size of 176.7 ± 3.4 nm, zeta potential of -31.5 ± 2.6 mV, EE% of 76.9 ± 2.5%, and a pH-responsive behavior in two different pHs (5.4 and 7.4). In-silico evaluations showed that MTX intended to make a strong hydrogen bond with Span 60 compartments involving N2 and O4 atoms in glutamic acid and N7 atom in pteridine ring moieties, respectively. The cytotoxic effects of free and pH-MTX/Nio were assessed against MCF7 and HUVECs. Compared with free MTX, we found significantly lower IC50s when MCF7 cells were treated with niosomal MTX (84.03 vs. 9.464 µg/mL after 48 h, respectively). Moreover, lower cell killing activity was observed for this formulation in normal cells. The pH-MTX/Nio exhibited a set of morphological changes in MCF7 cells observed during cell death. In-vivo results demonstrated that intraperitoneal administration of free MTX (2 mg/kg) after six weeks caused a significant increase in serum blood urea nitrogen (BUN), serum creatinine, and serum malondialdehyde (MDA) levels of rats compared to the normal control rats. Treatment with 2 and 4 mg/kg doses of pH-MTX/Nio significantly increased serum BUN, serum creatinine, and serum lipid peroxidation. Still, the safety profile of such formulations in healthy cells/tissues should be further investigated.

Preparation of pH-Responsive Vesicular Deferasirox: Evidence from In Silico, In Vitro, and In Vivo Evaluations.

pH-sensitive nanocarriers can effectively deliver anticancer drugs to tumors and reduce the adverse effects of conventional chemotherapy. In this light, we prepared a novel pH-responsive deferasirox (DFX)-loaded vesicle and comprehensively performed in silico, in vitro, and in vivo studies to examine the properties of the newly synthesized formulation. Physiochemical assessment of the developed formulations showed that they have an average size (107 ± 2 nm), negative zeta potential (-29.1 ± 1.5 mV), high encapsulation efficiency (84.2 ± 2.6%), and a pH-responsive release. Using the molecular dynamics simulation, the structural and dynamic properties of ergosterol-containing niosomes (ST60/Ergo) in the presence of DFX molecules were analyzed and showed a good interaction between DFX and vesicle components. Cytotoxic assessment showed that niosomal DFX exhibited a greater cytotoxic effect than free DFX in both human cancer cells (MCF-breast cancer and Hela cervical cancer) and induced evident morphological features of apoptotic cell death. No marked difference between the ability of free and niosomal DFX was found in activating caspase-3 in Hela cells. Eight weeks of intraperitoneal administrations of free DFX at three doses caused a significant increase in serum biochemical parameters and liver lipid peroxidation. Treatment with 5 mg/kg dose of niosomal DFX caused a significant increase in serum creatinine (P < 0.05); however, other parameters remained unchanged. On the other hand, administration of niosomal DFX at the highest dose (10 mg/kg) significantly increased serum creatinine (P < 0.05), BUN, and serum liver enzymes compared to the control rats (P < 0.001). Based on the results, the application of pH-responsive DFX-loaded niosomes, as a novel drug delivery platform, may yield promising results in cancer treatment.

8-Alkylmercaptocaffeine derivatives: antioxidant, molecular docking, and in-vitro cytotoxicity studies.

Due to their unique pharmacological characteristics, methylxanthines are known as therapeutic agents in a fascinating range of medicinal scopes. In this report, we aimed to examine some biological effects of previously synthesized 8-alkylmercaptocaffeine derivatives. Cytotoxic and antioxidative activity of 8-alkylmercaptocaffeine derivatives were measured in malignant A549, MCF7, and C152 cell lines. Assessment of cGMP levels and caspase-3 activity were carried out using a colorimetric competitive ELISA kit. Computational approaches were employed to discover the inhibitory mechanism of synthesized compounds. Among the twelve synthesized derivatives, three compounds (C1, C5, and C7) bearing propyl, heptyl, and 3-methyl-butyl moieties showed higher and more desirable cytotoxic activity against all the studied cell lines (IC50 < 100 µM). Furthermore, C5 synergistically enhanced cisplatin-induced cytotoxicity in MCF-7 cells (CI < 1). Both C5 and C7 significantly increased caspase-3 activity and intracellular cGMP levels at specific time intervals in all studied cell lines (P < 0.05). However, these derivatives did not elevate LDH leakage (P > 0.05) and exhibited no marked ameliorating effects on oxidative damage (P > 0.05). Computational studies showed that H-bond formation between the nitrogen atom in pyrazolo[4,3-D] pyrimidine moiety with Gln817 and creating a hydrophobic cavity result in the stability of the alkyl group in the PDE5A active site. We found that synthesized 8-alkylmercaptocaffeine derivatives induced cell death in different cancer cells through the cGMP pathway. These findings will help us to get a deeper insight into the role of methylxanthines as useful alternatives to conventional cancer therapeutics.

Flavonoids as potent allosteric inhibitors of protein tyrosine phosphatase 1B: molecular dynamics simulation and free energy calculation.

Protein tyrosine phosphatase 1B (PTP1B) is a member of the PTP superfamily which is considered to be a negative regulator of insulin receptor (IR) signaling pathway. PTP1B is a promising drug target for the treatment of type 2 diabetes, obesity, and cancer. The existence of allosteric site in PTP1B has turned the researcher's attention to an alternate strategy for inhibition of this enzyme. Herein, the molecular interactions between the allosteric site of PTP1B with three non-competitive flavonoids, (MOR), (MOK), and (DPO) have been investigated. Three ligands were docked into allosteric site of the enzyme. The resulting protein-ligand complexes were used for molecular dynamics studies. Principal component and free-energy landscape (FEL) as well as cluster analyses were used to investigate the conformational and dynamical properties of the protein and identify representative enzyme substrates bounded to the inhibitors. Per residue energy decomposition analysis attributed dissimilar affinities of three inhibitors to the several hydrogen bonds and non-bonded interactions. In conclusion, our results exhibited an inhibitory pattern of the ligands against PTP1B.

Molecular dynamics simulation and molecular docking studies of 1,4-Dihydropyridines as P-glycoprotein's allosteric inhibitors.

P-glycoprotein (P-gp) is a main factor contributing to multidrug resistance. The effect of this transporter protein on limiting the effectiveness of chemotherapy has been shown by various studies. In a previous report, we synthesized some 14-dihydropyridine (DHP) derivatives as inhibitors of human P-gp. In the present study, a computational approach has been exploited to reveal the main interactions between DHPs and P-gp. In order to do this, homology modeling was performed to obtain a model of the protein. Then, molecular dynamics simulation was used to refine the constructed model of P-gp in the presence of the lipids bilayer. Model validation was performed with several tools. Finally, molecular docking followed by MD simulation of ligand-protein complex was employed to elucidate the binding mode and the dynamical changes of protein with/without DHPs bound. The results emphasized that interaction of the residues Gln912, Ser909, Arg905, Ser474, Val472 with DHPs play a crucial role in the inhibitory of these ligands and this was in a relatively good accordance with the results reported in the experimental studies.

Novel 5-oxo-hexahydroquinoline derivatives: design, synthesis, in vitro P-glycoprotein-mediated multidrug resistance reversal profile and molecular dynamics simulation study.

Overexpression of the efflux pump P-glycoprotein (P-gp) is one of the important mechanisms of multidrug resistance (MDR) in many tumor cells. In this study, 26 novel 5-oxo-hexahydroquinoline derivatives containing different nitrophenyl moieties at C4 and various carboxamide substituents at C3 were designed, synthesized and evaluated for their ability to inhibit P-gp by measuring the amount of rhodamine 123 (Rh123) accumulation in uterine sarcoma cells that overexpress P-gp (MES-SA/Dx5) using flow cytometry. The effect of compounds with highest MDR reversal activities was further evaluated by measuring the alterations of MES-SA/Dx5 cells' sensitivity to doxorubicin (DXR) using MTT assay. The results of both biological assays indicated that compounds bearing 2-nitrophenyl at C4 position and compounds with 4-chlorophenyl carboxamide at C3 demonstrated the highest activities in resistant cells, while they were devoid of any effect in parental nonresistant MES-SA cells. One of the active derivatives, 5c, significantly increased intracellular Rh123 at 100 µM, and it also significantly reduced the IC50 of DXR by 70.1% and 88.7% at 10 and 25 µM, respectively, in MES-SA/Dx5 cells. The toxicity of synthesized compounds against HEK293 as a noncancer cell line was also investigated. All tested derivatives except for 2c compound showed no cytotoxicity. A molecular dynamics simulation study was also performed to investigate the possible binding site of 5c in complex with human P-gp, which showed that this compound formed 11 average H-bonds with Ser909, Thr911, Arg547, Arg543 and Ser474 residues of P-gp. A good agreement was found between the results of the computational and experimental studies. The findings of this study show that some 5-oxo-hexahydroquinoline derivatives could serve as promising candidates for the discovery of new agents for P-gp-mediated MDR reversal.