Exploring the potential of phytochemicals as inhibitors of 3'-phosphoadenosine 5'-phosphosulfate synthase 1 targeting cancer therapy.

3'-phosphoadenosine 5'-phosphosulfate synthase 1 (PAPSS1) is an enzyme that critically synthesises the biologically active form of sulfate (PAPS) for all sulfation reactions. The discovery of PAPSS1 as a possible drug target for cancer therapy, specifically in non-small cell lung cancer, has prompted us to investigate potential small-molecule inhibitors of PAPSS1. Here, a structure-based virtual screening method was used to search for phytochemicals in the IMPPAT database to find potential inhibitors of PAPSS1. The primary hits were selected based on their physicochemical, ADMET, and drug-like properties. Then, the binding affinities were calculated and analyzed the interactions to identify safer and more effective hits. The research identified two phytochemicals, Guggulsterone and Corylin, that exhibited significant affinity and specific interaction with the ATP-binding pocket of PAPSS1. Structural observations made by molecular docking were further accompanied by molecular dynamics (MD) simulations and principal component analysis (PCA) to examine the conformational changes and stability of PAPSS1 with the elucidated compounds Guggulsterone and Corylin. MD simulation results suggested that the binding of Guggulsterone and Corylin stabilizes the PAPSS1 structure, leading to fewer conformational changes. This implies that these compounds may be useful in developing PAPSS1 inhibitors for the therapeutic development against non-small cell lung cancer (NSCLC). This study highlights the potential of phytochemicals as PAPSS1 inhibitors and the utility of computational approaches in drug discovery.Communicated by Ramaswamy H. Sarma.

Discovering potential inhibitors of Raf proto-oncogene serine/threonine kinase 1: a virtual screening approach towards anticancer drug development.

Raf proto-oncogene serine/threonine kinase 1 (RAF1 or c-Raf) is a serine/threonine protein kinase crucial in regulating cell growth, differentiation, and survival. Any disruption or overexpression of RAF1 can result in neoplastic transformation and other disorders such as cardiomyopathy, Noonan syndrome, leopard syndrome, etc. RAF1 has been identified as a potential therapeutic target in drug development against various complex diseases, including cancer, due to its remarkable role in disease progression. Here, we carried out a multitier virtual screening study involving different in-silico approaches to discover potential inhibitors of RAF1. After applying the Lipinski rule of five, we retrieved all phytocompounds from the IMPPAT database based on their physicochemical properties. We performed a molecular docking-based virtual screening and got top hits with the best binding affinity and ligand efficiency. Then we screened out the selected hits using the PAINS filter, ADMET properties, and other druglike features. Eventually, PASS evaluation identifies two phytocompounds, Moracin C and Tectochrysin, with appreciable anti-cancerous properties. Finally, all-atom molecular dynamics simulation (MDS) followed by interaction analysis was performed on the elucidated compounds in complex with RAF1 for 200 ns to investigate their time-evolution dynamics and interaction mechanism. Molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) and Dynamical Cross-Correlation Matrix (DCCM) analyses then followed these results from the simulated trajectories. According to the results, the elucidated compounds stabilize the RAF1 structure and lead to fewer conformational alterations. The results of the current study indicated that Moracin C and Tectochrysin could serve as potential inhibitors of RAF1 after required validation.Communicated by Ramaswamy H. Sarma.

Impact of Hypnotic Drug Zolpidem Tartrate on the Development of Forensic Fly Sarcophaga ruficornis (Diptera: Sarcophagidae).

The flesh fly Sarcophaga ruficornis (Fabricius) is one of the fly species of significant medical and forensic importance since it is one of the most common flesh flies used in forensic investigations. Zolpidem tartrate is a sedative-hypnotic drug used for the short-term treatment of insomnia in adults and its use has been implicated in many suicide cases worldwide. Fresh chopped liver of buffalo Bubalus bubalis (Artiodactyla: Bovidae) containing different concentrations of Zolpidem tartrate was given to S. ruficornis larvae to evaluate the effect of Zolpidem tartrate on the developmental rate of the different stages, life cycle duration, and the morphological parameters. The findings have shown significant variation in the time required for the different developmental stages and total life cycle duration, which correlated positively with the Zolpidem tartrate concentration in different cultures. Compared to the control, the morphological parameters were negatively correlated with the concentration of Zolpidem tartrate in the treated cultures. The obtained results indicate that the Zolpidem tartrate retards larval development and alters the estimation of the total developmental duration. Thus, when Zolpidem tartrate may be the cause of death, the entomological evidence needs to be analyzed so it takes zolpidem-related changes to the mPMI into account.

Susceptibility of Culex quinquefasciatus (Say) Larvae to Methanolic Extracts of Annona reticulata.

<b>Background and Objective:</b> Environment pollution and resistance of many pests to the most frequently used chemical insecticides gave the rationale of altering to replace them with natural herbal extracts for pests and vector control. This study investigated the effect of methanolic extract of <i>Annona reticulata</i> on the mortality and development of larvae of <i>Culex quinquefasciatus</i>. <b>Materials and Methods:</b> Methanolic herbal extracts were analyzed using Reverse-Phase High-Performance Liquid Chromatography (RP-HPLC) to identify the phytochemical compounds in them. Ten mosquito larvae were used as replicates and exposed to each of the five concentrations of the plant extract (30, 100, 150, 200 and 250 mg mL¹) and ten larvae were exposed to double distilled water and considered as control. <b>Results:</b> Phytochemical analysis revealed the presence of phenols, steroids, quinones, tannins and saponins. Statistical analysis showed a significant strong correlation and regression between exposure to the different concentrations of the extract and mortality of <i>Culex quinquefasciatus</i> larvae where R² = 0.982, the Correlation value is 0.991099 (p<0.05). Results also showed that the extracts affect the development of larvae more than mortality. The effect of the extracts on the early larval stages was significantly high compared to the late stages of larvae. <b>Conclusion:</b> According to our knowledge results of this study has been reported for the first time in Saudi Arabia where <i>Annona reticulata</i> is neglected regionally and no study approved its efficacy as a botanical herbal extract against mosquitoes.

Target and non-target effects of Foeniculum vulgare and Matricaria chamomilla combined extract on Culex pipiens mosquitoes.

The present study focused on extracting green larvicides from extracts of the combination of Foeniculum vulgare and Matricaria chamomilla using different solvents of increasing polarity in a Soxhlet extractor and evaluating their ovicidal, larvicidal, and cytotoxic activities. The most promising among all tested extracts was hexane extract. The ovicidal activity of the hexane PH2 extract resulted in a significant (p < 0.05) decrease in egg hatchability from 95.00 ± 6.16% to 15 ± 9.04% at doses ranging from 62.5 to 500 µg/mL. The larval mortality with the hexane extract ranged from 13.33 ± 3.3% to 93.33 ± 3.3% at doses ranging from 31.25 to 250 µg/mL, respectively. The LC50 and LC90 values of the larvicidal activity of the hexane extract were estimated to be 148.3 and 242.17 µg/mL, respectively, after 24 h of exposure. Similarly, the LC50 values after 48 and 72 h of exposure were 124.93 and 100.3 µg/mL, respectively, against the third instar of Cx. pipiens. PH2 treatment of larvae resulted in histopathological changes such as degenerated epithelial cells and destruction of microvilli on the epithelial cells. The PH2 extract achieved a dose-dependent decrease in the rate of cell survival. The IC50 value of PH2-treated HUVECs was 192.07 µg/mL after 24 h of incubation. The cells showed changes in cellular and nuclear morphology. In conclusion, the hexane extract of PH2 could be used in mosquito management programs.

First record of West Nile Virus detection inside wild mosquitoes in Khartoum capital of Sudan using PCR.

This study aimed to explore the presence of West Nile Virus (WNV) inside four species of mosquitoes: Culex univittatus (Theobald), Culex quinquefasciatus (Say) Aedes vittatus (Bigot) and Aedes vexans (Meigen). Adult wild mosquitoes were collected from different sites: Soba West, Hellat Kuku, Shambat, and Khartoum North Central Live Stock Market (KCLM). Surveys were carried out at Khartoum State during two phases: pre to the rainy season and post to the rainy season. Mosquito specimens were identified using classical keys then preserved at -80 °C freezer for two weeks till the virus examination using polymerase chain reaction (PCR) were carried out. WNV has been detected inside the three species of mosquitoes: A. vexans, C. univittatus, and C. quinquefasciatus. The species were collected from Hellat Kuku, (Shambat and Hellat Kuku), and (Shambat and KCLM) respectively. Two species of mosquitoes were positive for the virus: C. quinquefasciatus and C. univittatus. Positive results for the virus during the first phase of the study; males of C. quinquefasciatus and C. univittatus collected during the second phase of the study were also tested for the existence of the virus and they were positive. For our knowledge this study represents first record of WNV inside wild mosquitoes in Sudan. PCR technique provided reliable information because specific primer-probe sets were used for the detection of the virus. Extra studies are required to incriminate these species of mosquitoes as potential vectors of WNV.

Evidence Based Efficacy of Selected Herbal Extracts Against Culex quinquefasciatus (Say) Larvae.

BACKGROUND AND OBJECTIVE: Chemical insecticides have some limitations in vectors control such as the emergence of resistance in vector mosquitoes to conventional synthetic insecticides. It aimed to evaluate the larvicidal efficacy and phytochemical potential of Azadirachta indica, Cymbopogon citratus and Allium sativum L. against ulex quinquefasciatus fourth instar larvae. MATERIAL AND METHODS: The plants were screened and evaluated for their phytochemical composition and larvicidal effects on . quinquefasciatus larvae. RESULTS: The bioassay results showed that the effects were dependent on time and concentration of the extract used. Results showed the least lethal dose value for ethanolic extract of . citrates (72 h exposure) and the highest value for aqueous extract of A. indica (24 h exposure). Chi-square values were significant at p<0.05. Phytochemical analysis showed phytochemicals such as alkaloids, flavonoids, cardiac glycosides and resins in all the three plants. However, tannins were absent in A. indica and A. sativum, while balsam was only present in A. indica. Saponins, balsam and phenols were not found in A. sativum. Phenols were also absent in . citratus. Terpenes, steroids and resins were absent A. indica. CONCLUSION: Findings of this study revealed that these herbal extracts constitute an effective eco-friendly approach for the control of . quinquefasciatus larvae.