Current Drug Discovery Technologies - Volume 20, Issue 4, 2023

Background: Tuberculosis (TB) is one of the leading causes of death in the post-COVID- 19 era. It has been observed that there is a devastating condition with a 25-30% increase in TB patients. DNA gyrase B isoform has proved its high potential to be a therapeutically effective target for developing newer and safer anti-TB agents. Objective: This study aims to identify minimum structural requirements for the optimization of thiazolopyridine derivatives having DNA gyrase inhibitory activities. Moreover, developed QSAR models could be used to design new thiazolopyridine derivatives and predict their DNA gyrase B inhibitory activity before synthesis. Methods: 3D-QSAR and Group-based QSAR (G-QSAR) methodologies were adopted to develop accurate, reliable, and predictive QSAR models. Statistical methods such as kNN-MFA SW-FB and MLR SW-FB were used to correlate dependent parameters with descriptors. Both models were thoroughly validated for internal and external predictive abilities. Results: The 3D-QSAR model significantly correlated steric and electrostatic descriptors with q² 0.7491 and predicted r² 0.7792. The G-QSAR model showed that parameters such as SsOHE-index, slogP, ChiV5chain, and T_C_C_3 were crucial for optimizing thiazolopyridine derivatives as DNA gyrase inhibitors. The 3D-QSAR model was interpreted extensively with respect to 3D field points, and the pattern of fragmentation was studied in the G-QSAR model. Conclusion: The 3D-QSAR and G-QSAR models were found to be highly predictive. These models could be useful for designing potent DNA gyrase B inhibitors before their synthesis.

Background: One of the most important principles in disease control is the health of livestock and poultry feed. Given the natural growth of Th. eriocalyx in Lorestan province, its essential oil can be added to the livestock and poultry feed and prevent the growth of the dominant filamentous fungi. Objective: Therefore, this study aimed to identify the dominant moldy fungal agents of livestock and poultry feed, examine phytochemical compounds and analyze antifungal effects, anti-oxidant properties, as well as cytotoxicity against human white blood cells in Th. eriocalyx. Methods: Sixty samples were collected in 2016. The PCR test was used to amplify ITS1 and ASP1 regions. The analysis of essential oil was conducted by gas chromatography and gas chromatographymass spectrometry devices. MIC and MFC were performed using the broth micro-dilution method. For the analysis of DDPH activity, DDPH was used. Cytotoxicity effect on healthy human lymphocytes was carried out by the MTT method. Results: In this study, A. niger, F. verticilloides and F. circinatum, P. oxalicum, and P. chrysogenum were the most resistant species, and A. oryzae and A. fumigatus, F. prolifratum and F. eqiseti, P. janthnellum were the most susceptible ones. IC50 value of T. daenensis Celak was 41.33 μg/ml, and 100 μl/ml of the essential oil caused slight cell lysis. Conclusion: Considering our results, compared with drugs and chemical additives, essential oils can be added to livestock and poultry feed to prevent the growth of filamentous fungi in the livestock and poultry feed.

Objective: This study aimed to evaluate the possible effects of chlorpyrifos on the rat hippocampus and evaluate whether these effects can be decreased with chrysin co-administration in an animal model. Methods: Male Wistar rats were randomly divided into 5 groups; Control (C), Chlorpyrifos (CPF), Chlorpyrifos + Chrysin (12.5 mg/kg) (CPF + CH1), Chlorpyrifos + Chrysin (25 mg/kg) (CPF + CH2), Chlorpyrifos + Chrysin (50 mg/kg) (CPF + CH3). After 45 days, hippocampus tissues were evaluated by biochemical and histopathological tests. Results: Biochemical findings indicated that CPF and CPF plus CH administration could not significantly change SOD activity, and MAD, GSH, and NO levels in the hippocampus tissue of animals versus controls. Histopathological findings of the toxic effects of CPF on hippocampus tissue as evidenced by inflammatory cell infiltration, degeneration/necrosis, and mild hyperemia. CH could ameliorate these histopathological changes in a dose-dependent manner. Conclusion: In conclusion, CH was effective against histopathological damage induced by CPF in the hippocampus through modulating inflammation and apoptosis.

Objective: Increased quinolinic acid (QA) accumulation has been found in many neurodegenerative diseases. Artemisia absinthium (A. absinthium) has been reported to have neuroprotective and antioxidant activities. This study was designed to evaluate the effect of A. absinthium in QAinduced neurotoxicity in OLN-93 Cells. Methods: OLN-93 cells were cultured in a DMEM medium containing 10% (v/v) fetal bovine serum, 100 units/ml penicillin, and 100 μg/ml streptomycin. The cells were pretreated with concentrations of A. absinthium extract for two h and then exposed to QA for 24 h. After 24 h cell viability, the level of malondialdehyde (MDA), reactive oxygen species (ROS), and apoptotic cells were quantitated in OLN-93 Cells. Results: Pretreatment with A. absinthium extract prevented the loss of cell viability in OLN-93 cells. ROS generation, lipid peroxidation, and apoptosis in QA-injured OLN-93 cells were reduced following A. absinthium extract pretreatment. Conclusion: A. absinthium extract exerts its neuroprotective effect against QA-induced neurotoxicity via oxidative stress and apoptosis modulation.

Background: The frequency of observed invasive Aspergillosis has increased in recent years. Infection with other molds happens but does not lead to a large proportion of invasive infections. The present study aims to isolate Bacillus amyloliquefaciens M13-RW0 from soil and evaluate its antifungal effects against some saprophytic fungi, such as Aspergillus niger, Aspergillus flavus, and Mucor hiemalis. Materials and Methods: In this research, a total of 150 samples (from the soil, air, and surfaces) were prepared from different parts of Isfahan, Iran. Isolation and purification of growing bacteria were conducted using the nutrient agar medium. The inhibitory effects of 100 isolated bacteria were evaluated against the growth of A. niger, A. flavus, and M. hiemalis, 4 bacteria were isolated with inhibitory effects against the selected fungi, and consequently, one of the bacteria isolated from the soil samples was found to show the highest inhibition of fungal growth. Quantitative evaluation of the growth inhibitory effect was performed using linear culturing of fungal suspension (10⁴ spore/ml) at distances of 5, 10, 15, 20, 25, and 30mm from bacterial isolate (0.5 McFarland) on Sabouraud Dextrose Agar (SDA) medium. Results were checked 24, 48, 72, and 96 hours later. The bacterial isolate with the most inhibitory effect was identified by phenotypic and molecular tests. Results: According to the results, among the 4 inhibitory bacterial isolates, Bacillus amyloliquefaciens strain M13-RW01, isolated from the soil samples, was identified as the bacterium with the most significant potential antifungal activity. The strong inhibitory effect was revealed after 48 hours for all distances of 15mm and more between the fungi and the bacterium. Conclusion: The identified bacterium could not only be considered an inhibitor bacterium against saprophytic fungi but could also be put forward to help produce new antifungal drugs for controlling fungal diseases.

Introduction: Recently, the coronavirus disease 2019 (COVID-19) infection, with a vast spectrum of clinical and paraclinical symptoms has been a major health concern worldwide. Therapeutical management of COVID-19 includes antiviral and anti-inflammatory drugs. NSAIDs, as the second-line therapy, are often prescribed to relieve the symptoms of COVID-19. The a-L-guluronic acid (G2013) is a non-steroidal patented (PCT/EP2017/067920) agent with immunomodulatory properties. This study investigated the effect of G2013 on the outcome of COVID-19 in moderate to severe patients. Methods: The disease’s symptoms were followed up during hospitalization and for 4 weeks postdischarge in G2013 and control groups. Paraclinical indices were tested at the time of admission and discharge. Statistical analysis was performed on clinical and paraclinical parameters and ICU admission and death rate. Results: The primary and secondary outcomes indicated the efficiency of G2013 on COVID-19 patients’ management. There were significant differences in the duration of improvement of fever, coughing, fatigue/malaise. Also, a comparison of paraclinical indices at the time of admission and discharge showed significant change in prothrombin, D-dimer, and platelet. As the main findings of this study, G2013 significantly decreased the percentage of ICU admission (control:17 patients, G2013:1 patient) and death (control: 7 cases, G2013:0). Conclusion: These results conclude that G2013 has sufficient potential to be considered for moderate to severe COVID-19 patients, can significantly reduce the clinical and physical complications of this disease, has a positive effect on modulating the coagulopathy process, and aids in saving lives.

Aim: The prenyl-binding protein, phosphodiesterase-δ (PDEδ), is essential for the localization of prenylated KRas to the plasma membrane for its signaling in cancer. Introduction: The general objective of this work was to develop virtually new potential inhibitors of the PDEδ protein that prevent Ras enrichment at the plasma membrane. Methods: All computational molecular modeling studies were performed by Molecular Operating Environment (MOE). In this study, sixteen crystal structures of PDEδ in complex with fifteen different fragment inhibitors were used in the protein-ligand interaction fingerprints (PLIF) study to identify the chemical features responsible for the inhibition of the PDEδ protein. Based on these chemical characteristics, a pharmacophore with representative characteristics was obtained for screening the BindingDB database. Compounds that matched the pharmacophore model were filtered by the Lipinski filter. The ADMET properties of the compounds that passed the Lipinski filter were predicted by the Swiss ADME webserver and by the ProTox-II-Prediction of Toxicity of Chemicals web server. The selected compounds were subjected to a molecular docking study. Results: In the PLIF study, it was shown that the fifteen inhibitors formed interactions with residues Met20, Trp32, Ile53, Cys56, Lys57, Arg61, Gln78, Val80, Glu88, Ile109, Ala11, Met117, Met118, Ile129, Thr131, and Tyr149 of the prenyl-binding pocket of PDEδ. Based on these chemical features, a pharmacophore with representative characteristics was composed of three bond acceptors, two hydrophobic elements, and one hydrogen bond donor. When the pharmacophore model was used in the virtual screening of the Binding DB database, 2532 compounds were selected. Then, the 2532 compounds were screened by the Lipinski rule filter. Among the 2532 compounds, two compounds met the Lipinski's rule. Subsequently, a comparison of the ADMET properties and the drug properties of the two compounds was performed. Finally, compound 2 was selected for molecular docking analysis and as a potential inhibitor against PDEδ. Conclusion: The hit found by the combination of structure-based pharmacophore generation, pharmacophore- based virtual screening, and molecular docking showed interaction with key amino acids in the hydrophobic pocket of PDEδ, leading to the discovery of a novel scaffold as a potential inhibitor of PDEδ.

Background: Mycobacterium avium sp. paratuberculosis (MAP) is a pathogen, which causes paratuberculosis in animals; it has also been found to be associated with a number of autoimmune disorders in humans. The emergence of drug resistance has also been found in this bacillus during disease management. Objective: The present study’s focus was to identify potential therapeutic targets for the therapeutic management of Mycobacterium avium sp. paratuberculosis infection by in silico analysis. Methods: Differentially-expressed genes (DEGs) can be good drug targets, which can be identified from microarray studies. We used gene expression profile GSE43645 to identify differentiallyexpressed genes. An integrated network of upregulated DEGs was constructed with the STRING database and the constructed network was analyzed and visualized by Cytoscape. Clusters in the proteinprotein interaction (PPI) network were identified by the Cytoscape app ClusterViz. MAP proteins predicted in clusters were analyzed for their non-homology with the human proteins, and homologous proteins were excluded. Essential proteins and cellular localization analysis and the physicochemical characteristics prediction were also done. Finally, the druggability of the target proteins and drugs that can block the targets was predicted using the DrugBank database and confirmed by molecular docking. Structural prediction and verification of drug target proteins were also carried out. Results: Two drug targets, MAP_1210 (inhA) and MAP_3961 (aceA), encoding enoyl acyl carrier protein reductase and isocitrate lyase enzymes, respectively, were finally predicted as potential drug targets. Conclusion: Both of these proteins have been predicted as drug targets in other mycobacterial species also, supporting our results. However, further experiments are required to confirm these results.