In silico anti-alzheimer study of phytochemicals from Lamiaceae family through GSK3-ß inhibition.

Glycogen synthase kinase 3-beta (GSK3-ß) is a serine-threonine protease expressed in the brain, and its hyperactivity is considered the underlying cause of Alzheimer's disease. This enzyme requires an ATP molecule in its N-terminal lobe to phosphorylate its substrates, with the most important substrate being the Tau protein. This study focuses on the inhibitory mechanism of four naturally occurring compounds-apigenin, luteolin, rosmarinic acid, and salvianolic acid-from the Laminaceae family against GSK3-ß. The orientation of the ligands within the ATP-binding pocket of GSK3-ß and their binding energy were determined through molecular docking. Additionally, molecular dynamics simulations was conducted to study the conformational changes induced by the ligands in the protein structure. The results showed that apigenin and salvianolic acid achieved deeper parts of the cavity compared to luteolin and rosmarinic acid and formed stable complexes with the enzyme. In the rosmarinic acid complex, the enzyme exhibited the most exposed conformation. On the other hand, luteolin binding caused a small closure of the opening, suggesting a potentially ATP-competitive role. Our results suggest these compounds as lead candidates for the design of GSK3-ß inhibitors.

Various concentrations of hesperetin induce different types of programmed cell death in human breast cancerous and normal cell lines in a ROS-dependent manner.

The polyphenolic component of citrus fruits, hesperetin (Hst), is a metabolite of hesperidin. In this study, we examined the effect of varying doses and exposure times of hesperetin on MCF-7 and MDA-MB-231 cancer cells, as well as MCF-10A normal cells. By using MTT assay, real-time PCR, western blot, and flow cytometry, we determined the effects of Hst on cell viability, ROS levels, and markers of cell death. Furthermore, molecular docking was used to identify Hst targets that might be involved in ROS-dependent cell death. According to the results, different concentrations of Hst induced different modes of cell death at specific ROS levels. Paraptosis occurred in all cell lines at concentration ranges of IC35 to IC60, and apoptosis occurred at concentrations greater than IC65. In addition, MDA-MB-231 cells were subjected to senescence at sub-toxic doses when treated for a long period of time. When Hst levels were higher, N-acetylcysteine (NAC)'s effect on neutralizing ROS was more pronounced. According to the docking results, Hst may interact with several proteins involved in the regulation of ROS. As an example, the interaction of CCS (Copper chaperone for superoxide dismutase) with Hst might interfere with its chaperone function in folding SOD-1 (superoxide dismutase enzyme), contributing to an increase in cytoplasmic ROS levels. Finally, depending on the ROS level, Hst induces various modes of cell death.

Computational design of fusion proteins against ErbB2-amplified tumors inspired by ricin toxin.

Although the anti-cancer activity of ricin is well-known, its non-specific targeting challenges the development of ricin-derived medicines. In the present study, novel potential ribosome-inactivating fusion proteins (RIPs) were computationally engineered by incorporation of an ErbB2-dependant penetrating peptide (KCCYSL, MARAKE, WYSWLL, MARSGL, MSRTMS, and WYAWML), a linker (either EAAAK or GGGGS) and chain A of ricin which is responsible for the ribosome inactivation. Molecular dynamics simulations assisted in making sure that the least change is made in conformation and dynamic behavior of ricin chain A in selected chimeric protein (CP). Moreover, the potential affinity of the selected CPs against the ligand-uptaking ErbB2 domain was explored by molecular docking. The results showed that two CPs (CP2 and 10) could bind the receptor with the greatest affinity.

Design of novel disturbing peptides against ACE2 SARS-CoV-2 spike-binding region by computational approaches.

The SARS-CoV-2, the virus which is responsible for COVID-19 disease, employs its spike protein to recognize its receptor, angiotensin-converting enzyme 2 (ACE2), and subsequently enters the host cell. In this process, the receptor-binding domain (RBD) of the spike has an interface with the α1-helix of the peptidase domain (PD) of ACE2. This study focuses on the disruption of the protein-protein interaction (PPI) of RBD-ACE2. Among the residues in the template (which was extracted from the ACE2), those with unfavorable energies were selected for substitution by mutagenesis. As a result, a library of 140 peptide candidates was constructed and the binding affinity of each candidate was evaluated by molecular docking and molecular dynamics simulations against the α1-helix of ACE2. Finally, the most potent peptides P23 (GFNNYFPHQSYGFMPTNGVGY), P28 (GFNQYFPHQSYGFPPTNGVGY), and P31 (GFNRYFPHQSYGFCPTNGVGY) were selected and their dynamic behaviors were studied. The results showed peptide inhibitors increased the radius, surface accessible area, and overall mobility of residues of the protein. However, no significant alteration was seen in the key residues in the active site. Meanwhile, they can be proposed as promising agents against COVID-19 by suppressing the viral attachment and curbing the infection at its early stage. The designed peptides showed potency against beta, gamma, delta, and omicron variants of SARS-CoV-2.

Inhibition of SARS-CoV-2 pathogenesis by potent peptides designed by the mutation of ACE2 binding region.

The outbreak of COVID-19 has resulted in millions of deaths. Despite all attempts that have been made to combat the pandemic, the re-emergence of new variants complicated SARS-CoV-2 eradication. The ongoing global spread of COVID-19 demands the incessant development of novel agents in vaccination, diagnosis, and therapeutics. Targeting receptor-binding domain (RBD) of spike protein by which the virus identifies host receptor, angiotensin-converting enzyme (ACE2), is a promising strategy for curbing viral infection. This study aims to discover novel peptide inhibitors against SARS-CoV-2 entry using computational approaches. The RBD binding domain of ACE2 was extracted and docked against the RBD. MMPBSA calculations revealed the binding energies of each residue in the template. The residues with unfavorable binding energies were considered as mutation spots by OSPREY. Binding energies of the residues in RBD-ACE2 interface was determined by molecular docking. Peptide inhibitors were designed by the mutation of RBD residues in the virus-receptors complex which had unfavorable energies. Peptide tendency for RBD binding, safety, and allergenicity were the criteria based on which the final hits were screened among the initial library. Molecular dynamics simulations also provided information on the mechanisms of inhibitory action in peptides. The results were finally validated by molecular docking simulations to make sure the peptides are capable of hindering virus-host interaction. Our results introduce three peptides P7 (RAWTFLDKFNHEAEDLRYQSSLASWN), P13 (RASTFLDKFNHEAEDLRYQSSLASWN), and P19 (RADTFLDKFNHEAEDLRYQSSLASWN) as potential effective inhibitors of SARS-CoV-2 entry which could be considered in drug development for COVID-19 treatment.

Rapid review and meta-analysis of adverse events associated with molnupiravir in patients with COVID-19.

AIMS: The aim of this study was to evaluate the safety profile of molnupiravir in COVID-19 patients. METHODS: PubMed, Cochrane Library, medRxive and Google Scholar were searched for articles published up to April 25, 2022. Meta-analysis was performed using Comprehensive Meta-Analysis software. RESULTS: Four trials involving 2241 patients met the inclusion criteria. No significant difference was observed between molnupiravir at 200, 400 and 800 mg compared with placebo (200 mg: risk ratio [RR] = 0.97; 95% confidence interval [CI]: 0.78-1.20; P = .80; 400 mg: RR = 0.81; 95% CI: 0.64-1.02; P = .07; 800 mg: RR = 0.94; 95% CI: 0.83-1.06; P = .36) for any adverse events (AEs); at 200, 400 and 800 mg compared with placebo (200 mg: RR = 0.81; 95% CI: 0.41-1.63; P = .57; 400 mg: RR = 0.82; 95% CI: 0.41-1.61; P = .56; 800 mg: RR = 0.80; 95% CI: 0.59-1.08; P = .15) for serious adverse events; at 200, 400 and 800 mg compared with placebo (200 mg: RR = 1.74; 95% CI: 0.48-6.30; P = .39; 400 mg: RR = 1.07; 95% CI: 0.28-4.09; P = .91; 800 mg: RR = 0.47; 95% CI: 0.17-1.28; P = .14) for AEs leading to death; and at 200, 400 and 800 mg compared with placebo (200 mg: RR = 1.50; 95% CI: 0.26-8.55; P = .64; 400 mg: RR = 0.99; 95% CI: 0.17-5.68; P = .99; 800 mg: RR = 0.61; 95% CI: 0.31-1.23; P = .17) for treatment discontinuation due to AEs. CONCLUSION: This meta-analysis showed that the use of three doses of molnupiravir (200, 400 and 800 mg) is safe for COVID-19 patients. Further research is needed to confirm the present findings.

Artesunate, imatinib, and infliximab in COVID-19: A rapid review and meta-analysis of current evidence.

BACKGROUND AND OBJECTIVE: Despite the pervasive vaccination program against coronavirus disease 2019 (COVID-19), fully vaccinated people are still being infected by severe acute respiratory syndrome coronavirus 2, making an effective and safe therapeutic intervention a crucial need for the patients' survival. The purpose of the present study is to seek available evidence for the efficacy and safety of three promising medications artesunate, imatinib, and infliximab against COVID-19. METHODS: A literature search was conducted in PubMed, Cochrane Library, medRxive, and Google Scholar up to January 2022. Furthermore, the clinical trial databases were screened to find more citations. The Cochrane Collaboration tool and Newcastle-Ottawa scale were used to assess the included studies. Meta-analysis was performed using RevMan 5.4.1. RESULTS: Five published studies were identified as eligible. Meta-analysis showed that there was no significant difference between the infliximab and control groups in terms of mortality rate (risk ratio [RR]: 0.65; 95% confidence interval [CI]: 0.40-1.07; p = 0.09). However, a significant difference was observed between the two groups for the hospital discharge (RR: 1.37; 95% CI: 1.04-1.80; p = 0.03). No remarkable clinical benefit was observed in favor of using imatinib for COVID-19 patients. Artesunate showed significant improvement in patients with COVID-19. CONCLUSION: In the present, limited evidence exists for the efficacy and safety of artesunate, imatinib, and infliximab in patients with COVID-19. The findings of WHO's Solidarity international trial will provide further information regarding these therapeutic interventions.

Efficacy and safety of arbidol (umifenovir) in patients with COVID-19: A systematic review and meta-analysis.

OBJECTIVE: To provide the latest evidence for the efficacy and safety of arbidol (umifenovir) in COVID-19 treatment. METHODS: A literature systematic search was carried out in PubMed, Cochrane Library, Embase, and medRxiv up to May 2021. The Cochrane risk of bias tool and Newcastle-Ottawa scale were used to assess the quality of included studies. Meta-analysis was performed using RevMan 5.3. RESULTS: Sixteen studies were met the inclusion criteria. No significant difference was observed between arbidol and non-antiviral treatment groups neither for primary outcomes, including the negative rate of PCR (NR-PCR) on Day 7 (risk ratio [RR]: 0.94; 95% confidence interval (CI): 0.78-1.14) and Day 14 (RR: 1.10; 95% CI: 0.96-1.25), and PCR negative conversion time (PCR-NCT; mean difference [MD]: 0.74; 95% CI: -0.87 to 2.34), nor secondary outcomes (p > .05). However, arbidol was associated with higher adverse events (RR: 2.24; 95% CI: 1.06-4.73). Compared with lopinavir/ritonavir, arbidol showed better efficacy for primary outcomes (p < .05). Adding arbidol to lopinavir/ritonavir also led to better efficacy in terms of NR-PCR on Day 7 and PCR-NCT (p < .05). There was no significant difference between arbidol and chloroquine in primary outcomes (p > .05). No remarkable therapeutic effect was observed between arbidol and other agents (p > .05). CONCLUSION: The present meta-analysis showed no significant benefit of using arbidol compared with non-antiviral treatment or other therapeutic agents against COVID-19 disease. High-quality studies are needed to establish the efficacy and safety of arbidol for COVID-19.

Discovery of direct inhibitor of KRAS oncogenic protein by natural products: a combination of pharmacophore search, molecular docking, and molecular dynamic studies.

BACKGROUND AND PURPOSE: Aberrant signaling by oncogenic RAS proteins occurs in almost all human tumors. One of the promising strategies to overcome such cancers is the inhibition of KRAS protein, a subtype of RAS family involved in cell growth, differentiation, and apoptosis, through preventing its effector, SOS1, from being attached to the protein. EXPERIMNTAL APPROACH: Herein, a virtual screening process was performed using pharmacophore search, molecular docking, and molecular dynamic simulations. A pharmacophore model was created to indicate essential features for a KRAS inhibitor and used for screening the National Cancer Institution (NCI) database to retrieve similar compounds to the pharmacophore model with more than 70% similarity. Chosen compounds were then docked into KRAS and four compounds were selected based on the highest binding scores. Next, a similarity search was done in the whole PubChem database to increase the number of potential inhibitors. The filtered compounds were docked again into KRAS and three of them were selected for molecular dynamic simulation. FINDINGS / RESULTS: Compounds 1a, 2d, and 3a can inhibit SOS-iKRASG12D interaction due to the higher number of interactions with the protein. Moreover, they achieved the equilibrium faster than the approved inhibitor. CONCLUSION AND IMPLICATIONS: Auriculasin, a polyphenol flavonoid, can be considered as a potential inhibitor of SOS1-KRAS interaction. This compound seems to be a stronger anticancer than 9LI, a known inhibitor of KRAS, due to its better docking scores. Moreover, this compound can be an appropriate candidate to be formulated as an oral drug.

Inhibition of liver alanine aminotransferase and aspartate aminotransferase by hesperidin and its aglycone hesperetin: An in vitro and in silico study.

AIMS: This study aimed to investigate the inhibitory effects of two natural flavonoids, hesperetin (HT) and hesperidin (HD), on two gluconeogenesis enzymes, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities and their possible mechanisms of action. MAIN METHODS: Rat liver incubated with different concentrations of HT and HD was used to measure enzyme activities spectrophotometrically, based on monitoring the oxidation of NADH to NAD+ at 340nm. Molecular docking simulation was also applied to reveal the molecular mechanism of the inhibition caused by HT and HD. KEY FINDINGS: Both flavonoids demonstrated inhibitory effects against the enzyme activities, with IC50 values of 153.9 and 68.88µM for HT-ALT and HD-ALT treatment respectively. Likewise, the IC50 values of 85.29µM for HT-AST and 110.3µM for HD-AST were obtained from spectrophotometric results. CONCLUSION: The docking simulation revealed that HT and HD block the enzyme entrance channel and prevent the substrates from accessing the enzyme active sites. Having prevented production of pyruvate, α-ketoglutarate, and the oxaloacetate, these two compounds inhibit hepatic gluconeogenesis and consequently, hinder the progression of diabetes. SIGNIFICANCE: This study suggests that HT and HD may be considered as leading compounds for designing safe and effective drugs in management of increased ALT and AST-related disorders specially diabetes.