The novel anti-cancer feature of Brazzein through activating of hTLR5 by integration of biological evaluation: molecular docking and molecular dynamics simulation.

Many of plant proteins exhibit the properties similar to the antitumor proteins although the anticancer activity of Brazzein on modulating the autophagy signaling pathway has not been determined so far. The present study aimed to develop a simplified system to enable the rational design of the activating extracellular domain of human Toll-like receptor 5 (hTLR5). To identify the anticancer effect of Brazzein, HADDOCK program and molecular dynamics (MD) simulation were applied to examine the binding of the wild type (WT) and p.A19K mutant of Brazzein to the TLR5. The expression of MAP1S and TNF-α genes was estimated based on real-time PCR. The results clearly confirmed that the WT of Brazzein activated hTLR5 in the MCF-7 cell line since the genes were more and significantly less expressed in the cells treated with the WT and p.A19K mutant than the control, respectively. The snapshots of MD simulation exhibit the consistent close interactions of hTLR5 with the two helices of Brazzein on its lateral side. The results of per residue-free energy decomposition analysis substantiate those of intermolecular contact analysis perfectly one. We propose that the WT of Brazzein can act as an antitumor drug candidate.

Synthesis, molecular docking, and cytotoxicity of quinazolinone and dihydroquinazolinone derivatives as cytotoxic agents.

BACKGROUND: Cancer is the most cause of morbidity and mortality, and a major public health problem worldwide. In this context, two series of quinazolinone 5a-e and dihydroquinazolinone 10a-f compounds were designed, synthesized as cytotoxic agents. METHODOLOGY: All derivatives (5a-e and 10a-f) were synthesized via straightforward pathways and elucidated by FTIR, 1H-NMR, CHNS elemental analysis, as well as the melting point. All the compounds were evaluated for their in vitro cytotoxicity effects using the MTT assay against two human cancer cell lines (MCF-7 and HCT-116) using doxorubicin as the standard drug. The test derivatives were additionally docked into the PARP10 active site using Gold software. RESULTS AND DISCUSSION: Most of the synthesized compounds, especially 5a and 10f were found to be highly potent against both cell lines. Synthesized compounds demonstrated IC50 in the range of 4.87-205.9 µM against HCT-116 cell line and 14.70-98.45 µM against MCF-7 cell line compared with doxorubicin with IC50 values of 1.20 and 1.08 µM after 72 h, respectively, indicated the plausible activities of the synthesized compounds. CONCLUSION: The compounds quinazolinone 5a-e and dihydroquinazolinone 10a-f showed potential activity against cancer cell lines which can lead to rational drug designing of the cytotoxic agents.

Indole alkaloids as potential candidates against COVID-19: an in silico study.

COVID-19 has recently grown to be pandemic all around the world. Therefore, efforts to find effective drugs for the treatment of COVID-19 are needed to improve humans' life quality and survival. Since the main protease (Mpro) of SARS-CoV-2 plays a crucial role in viral replication and transcription, the inhibition of this enzyme could be a promising and challenging therapeutic target to fight COVID-19. The present study aims to identify alkaloid compounds as new potential inhibitors for SARS-CoV-2 Mpro by the hybrid modeling analyses. The docking-based virtual screening method assessed a collection of alkaloids extracted from over 500 medicinal plants and sponges. In order to validate the docking process, classical molecular dynamic simulations were applied on selected ligands, and the calculation of binding free energy was performed. Based on the proper interactions with the active site of the SARS-CoV-2 Mpro, low binding energy, few side effects, and the availability in the medicinal market, two indole alkaloids were found to be potential lead compounds that may serve as therapeutic options to treat COVID-19. This study paves the way for developing natural alkaloids as stronger potent antiviral agents against the SARS-CoV-2.

Novel N-substituted indole hydrazones as potential antiplatelet agents: synthesis, biological evaluations, and molecular docking studies.

BACKGROUND AND PURPOSE: Antiplatelet agents can diminish the chance of coronary heart diseases due to the prevention of unusual clotting in the arteries by inhibiting platelet aggregation and avoiding the formation of a blood clot. This mechanism can help to prevent ischemic stroke likewise. To improve the activity of these drugs and reduce their side effects, further studies are required. EXPERIMENTAL APPROACH: Based on the previous studies representing the promising antiplatelet activity of indole hydrazones, a series of their homologs containing twenty-one compounds were prepared in two steps. First, alkylation reaction on the nitrogen of the indole ring, and second, chiff base formation by condensation of a primary amine and N-substituted indole-3 carbaldehyde. Consequently, their platelet anti-aggregation activity was evaluated based on the Born turbidimetric method. FINDINGS/RESULTS: Most of the compounds exhibited noticeable activity against platelet aggregation induced by arachidonic acid. Amongst them, two compounds 2e and 2f showed higher activity with IC50 values that made comparable to indomethacin and acetylsalicylic acid as standard drugs and had no toxicity on platelets. CONCLUSION AND IMPLICATIONS: The synthesized compounds exhibited promising activity against arachidonic acid-induced aggregation; however, none of them showed noticeable antiplatelet activity induced by adenosine di-phosphate. Chemical structure comparison of the prepared derivatives indicated the existence of a lipophilic medium-sized group on the phenyl ring increased their activity. In addition, the docking studies confirmed this hydrophobic interaction in the lipophilic pocket of cyclooxygenase-1 enzyme suggesting that hydrophobicity of this region plays a pivotal role in the anti-platelet activity of these compounds. To prove this finding, the enzymatic evaluation with the target enzyme is required.

Investigation of corona discharge ionization of barbituric acid using ion mobility spectrometry along with quantum chemical calculations.

This study aimed at examining atmospheric-pressure chemical ionization of barbituric acid through the corona discharge ion mobility spectrometry (CD-IMS) and the quantum chemical calculations. The results indicated two product ion peaks in the IMS spectrum of barbituric acid. The thermal decomposition of the barbituric acid sample was investigated by scanning the temperature of the injection port and analyzing the temporal evolution of the IMS peaks over elapsed time. It was found that the barbituric acid sample was not thermally decomposed in the injection port of the instrument. Experimental evidences were collected by changing the reactant ions, concentration of barbituric acid sample, and IMS cell temperature. The two observed peaks were then assigned to cationic form and oxygen protonated isomers of barbituric acid. The positions of the product ion peaks were explicated considering the dipole moments of the product ions.

Evaluation of angiotensin converting enzyme inhibitors by SPR biosensor and theoretical studies.

Surface plasmon resonance (SPR) biosensor has been utilized for monitoring analyte-ligand interactions in modern drug discovery processes. SPR biosensors measure the change in refractive indexes over the course of analyte molecules' binding to a specific immobilized ligand on sensor chip. This effort highlights a comprehensive SPR study besides enzymatic assay for discovery of new Angiotensin Converting Enzyme (ACE) inhibitors via screening of medicinal plants. At first, five medicinal plants were selected as potential sources for developing new ACE inhibitors through hydrolyzing hippuryl-L-histidyl-L-leucine (HHL) assay. The interaction of selected extracts with immobilized ACE on the sensor chip (500D) confirmed that the Onopordum acanthium L. had the greatest ACE inhibition activity among the set of compounds and its active compound (onopordia) was isolated. SPR biosensor used to evaluate binding affinity of onopordia and ACE. Equilibrium constant (KD), and changes in Gibb's free energy of the binding (ΔGbinding) values for the interaction of onopordia with ACE were found to be 10.24 µM and -28.48 kJ/mol, respectively. Computational analysis supported the binding of onopordia to the ACE active site. Kinetic and thermodynamic parameters of binding revealed that onopordia is an acceptable ACE inhibitor and could treat hypertension. SPR biosensor can be used to improve the drug discovery process for many important classes of drug targets due to its great sensitivity.

Room-Temperature Synthesis of 2-Arylbenzothiazoles using Sulfuric Acid Immobilized on Silica as a Reusable Catalyst under Heterogeneous Condition.

Application of sulfuric acid immobilized on silica gel as an efficient and benign catalyst has been explored in the synthesis of 2-arylbenzothiazoles via condensation reaction of aldehydes with 2-aminothiophenol. The reactions proceed under heterogeneous and mild conditions in ethanol at room temperature to provide 2-arylbenzothiazoles in high yields.