Combinatorial Chemistry & High Throughput Screening - Volume 22, Issue 6, 2019

The glycation of proteins is non-physiological post-translational incorporation of carbohydrates onto the free amines or guanidines of proteins and some lipids. Although the existence of glycated proteins has been known for forty years, a full understanding of their pathogenic nature has been slow in accruing. In recent years, however, glycation has gained widespread acceptance as a contributing factor in numerous metabolic, autoimmune, and neurological disorders, tying together several confounding aspects of disease etiology. From diabetes, arthritis, and lupus, to multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer’s, and Parkinson’s diseases, an emerging glycation/inflammation paradigm now offers significant new insight into a physiologically important toxicological phenomenon. It exposes novel drug targets and treatment options, and may even lay foundations for long-awaited breakthroughs. This ‘current frontier’ article briefly profiles current knowledge regarding the underlying causes of glycation, the structural biology implications of such modifications, and their pathological consequences. Although several emerging therapeutic strategies for addressing glycation pathologies are introduced, the primary purpose of this mini-review is to raise awareness of the challenges and opportunities inherent in this emerging new medicinal target area.

Background: Molecular docking has often been used before to calculate in silico affinity of drugs towards their molecular target, but not to estimate leading CYP isoform responsible for metabolism of studied compounds. Objective: The aim of this study is to present molecular docking as a valid alternative for costly in vitro studies resulting in estimation of leading CYP isoform. Methods: In vitro part was based on incubations of studied compounds with isolated CYP3A4 isoform followed by LC-MS analysis. The in silico stage consisted of docking three-dimensional models of the studied compounds with a three-dimensional model of the leading metabolizing isoform (CYP3A4), which was designated during the in vitro part of the study. XenoSite P450 metabolism prediction was also used to predict sites of metabolism and calculate probability values. Results: The calculated affinities showed a clear similarity when the in vitro results were compared with the calculated in silico affinity values. XenoSite CYP3A4 metabolism probability values also confirm significant participation of CYP3A4 in metabolism of studied compounds. Conclusion: Both molecular docking and XenoSite P450 metabolism prediction provide data that stands in agreement with in vitro studies, granting a more detailed spectrum on predicting CYP3A4 metabolism, and presenting molecular docking as a promising tool to cut costs and increase effectiveness in early drug development stages.

Aim and Objective: Flap endonuclease-1 (FEN1) plays a central role in DNA replication and DNA damage repair process. In mammals, FEN1 functional sites variation is related to cancer and chronic inflammation, and supports the role of FEN1 as a tumor suppressor. However, FEN1 is overexpressed in multiple types of cancer cells and is associated with drug resistance, supporting its role as an oncogene. Hence, it is vital to explore the multi-functions of FEN1 in normal cell metabolic process. This study was undertaken to examine how the gene expression profile changes when FEN1 is downregulated in 293T cells. Materials and Methods: Using the RNA sequencing and real-time PCR approaches, the transcript expression profile of FEN1 knockdown HEK293T cells have been detected for the next step evaluation, analyzation, and validation. Results: Our results confirmed that FEN1 is important for cell viability. We showed that when FEN1 downregulation led to the interruption of nucleic acids related metabolisms, cell cycle related metabolisms are significantly interrupted. FEN1 may also participate in non-coding RNA processing, ribosome RNA processing, transfer RNA processing, ribosome biogenesis, virus infection and cell morphogenesis. Conclusion: These findings provide insight into how FEN1 nuclease might regulate a wide variety of biological processes, and laid the foundation for understanding the role of other RAD2 family nucleases in cell growth and metabolism.

Aim and Objective: A Quantitative Structure-Activity Relationship (QSAR) has been widely developed to derive a correlation between chemical structures of molecules to their known activities. In the present investigation, QSAR models have been carried out on 76 Camptothecin (CPT) derivatives as anticancer drugs to develop a robust model for the prediction of physicochemical properties. Materials and Methods: A training set of 60 structurally diverse CPT derivatives was used to construct QSAR models for the prediction of physiochemical parameters such as Van der Waals surface area (SvdW), Van der Waals Volume (VvdW), Molar Refractivity (MR) and Polarizability (α). The QSAR models were optimized using Multiple Linear Regression (MLR) analysis. A test set of 16 compounds was evaluated using the defined models. The Genetic Algorithm And Multiple Linear Regression Analysis (GA-MLR) were used to select the descriptors derived from the Dragon software to generate the correlation models that relate the structural features to the studied properties. Results: QSAR models were used to delineate the important descriptors responsible for the properties of the CPT derivatives. The statistically significant QSAR models derived by GA-MLR analysis were validated by Leave-One-Out Cross-Validation (LOOCV) and test set validation methods. The multicollinearity and autocorrelation properties of the descriptors contributed in the models were tested by calculating the Variance Inflation Factor (VIF) and the Durbin–Watson (DW) statistics. Conclusion: The predictive ability of the models was found to be satisfactory. Thus, QSAR models derived from this study may be helpful for modeling and designing some new CPT derivatives and for predicting their activity.

Introduction: A variety of organic compounds has been reported to have antibacterial activity. However, antimicrobial resistance is one of the main problems of current anti-infective therapy, and the development of novel antibacterials is one of the main challenges of current drug discovery. Methods: Using our previously developed dual-reporter High-Throughput Screening (HTS) platform, we identified a series of furanocoumarins as having high antibacterial activity. The construction of the reporter system allows us to differentiate three mechanisms of action for the active compounds: inhibition of protein synthesis (induction of Katushka2S), DNA damaging (induction of RFP) or other (inhibition of bacterial growth without reporter induction). Results: Two primary hit-molecules of furanocoumarin series demonstrated relatively low MIC values comparable to that observed for Erythromycin (Ery) against E. coli and weakly induced both reporters. Dose-dependent translation inhibition was shown using in vitro luciferase assay, however it was not confirmed using C14-test. A series of close structure analogs of the identified hits was obtained and investigated using the same screening platform. Compound 19 was found to have slightly lower MIC value (15.18 μM) and higher induction of Katushka2S reporter in contrast to the parent structures. Moreover, translation blockage was clearly identified using both in vitro luciferase assay and C14 test. The standard cytotoxicity test revealed a relatively low cytotoxicity of the most active molecules. Conclusion: High antibacterial activity in combination with low cytotoxicity was demonstrated for a series of furanocoumarins. Further optimization of the described structures may result in novel and attractive lead compounds with promising antibacterial efficiency.

Aim and Objective: Cardiovascular disease is a serious threat to human health because of its high mortality and morbidity rates. At present, there is no effective treatment. In Southeast Asia, traditional Chinese medicine is widely used in the treatment of cardiovascular diseases. Quercetin is a flavonoid extract of Ginkgo biloba leaves. Basic experiments and clinical studies have shown that quercetin has a significant effect on the treatment of cardiovascular diseases. However, its precise mechanism is still unclear. Therefore, it is necessary to exploit the network pharmacological potential effects of quercetin on cardiovascular disease. Materials and Methods: In the present study, a novel network pharmacology strategy based on pharmacokinetic filtering, target fishing, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, compound-target-pathway network structured was performed to explore the anti- cardiovascular disease mechanism of quercetin. Results: The outcomes showed that quercetin possesses favorable pharmacokinetic profiles, which have interactions with 47 cardiovascular disease-related targets and 12 KEGG signaling pathways to provide potential synergistic therapeutic effects. Following the construction of Compound-Target-Pathway (C-T-P) network, and the network topological feature calculation, we obtained top 10 core genes in this network which were AKT1, IL1B, TNF, IL6, JUN, CCL2, FOS, VEGFA, CXCL8, and ICAM1. KEGG pathway enrichment analysis. These indicated that quercetin produced the therapeutic effects against cardiovascular disease by systemically and holistically regulating many signaling pathways, including Fluid shear stress and atherosclerosis, AGE-RAGE signaling pathway in diabetic complications, TNF signaling pathway, MAPK signaling pathway, IL-17 signaling pathway and PI3K-Akt signaling pathway.

Aim and Objective: The aim of this paper is to introduce HSBM as a green and environmentally friendly technique for the synthesis of thiochromeno[4,3-b]pyran and benzo[h]thiazolo[2,3-b]quinazoline derivatives over ZnAl2O4 nanopowders as an efficient catalyst. Materials and Methods: ZnAl2O4 nanopowders were synthesized via a co-precipitation of Zn(NO3)2 and Al(NO3)3 salts and were characterized by XRD, FE-SEM, TEM and DLS techniques. The as-prepared ZnAl2O4 nano-powders have been used as a catalyst on the synthesis of pyran nucleus using high-speed ball milling (HSBM) technique. The structure of products was confirmed with NMR analysis. Results: ZnAl2O4 exhibits a cubic crystal structure (Space group: Fd-3m) with the average crystallite size of 41 nm. The average particle size of ZnAl2O4 nano-powders determined by DLS technique is 55 nm. The catalytic activity of nano-powders was examined on the synthesis of 2- amino-4,5-dihydro-4-arylthiochromeno[4,3-b]pyran-3-carbonitriles, (8Z)-2-amino-8-arylidene-4,5, 7,8-tetrahydro-4-arylthiopyrano[4,3-b]pyran-3-carbonitriles, 4-aryl-3,4,5,6-tetrahydrobenzo[h]quinazoline- 2(1H)-thiones and 4-aryl-1,3,4,5-tetrahydro-2H-thiochromeno[4,3-d]pyrimidine-2-thione derivatives. All products were obtained in high yields with short reaction times. Conclusion: ZnAl2O4 nanopowders were prepared via a cost-effective co-precipitation method and showed good potential for the synthesis of 4H-pyran analogous in good yields. The salient advantages of HSBM technique include environmentally friendly with reduced solvents, is a simple technique and has low energy costs.

Background: Lipemia can influence laboratory test results by different mechanisms. Although the liquid chromatography–tandem mass spectrometry (LC-MS/MS) is considered the reference method for 25(OH)D3, some compounds (carbohydrate, lipids, proteins, etc.) in the blood may cause a false result indicating a negative or positive deviation rate from the correct blood level of the test. Case Report: In this paper, we report a case of D vitamin intoxication due to a false negative result caused by lipemia. A young woman with a complaint of pain in multiple joints applied to the physical therapy clinic and was found to have some cystic bone lesions. She was eventually diagnosed with DM tip 1, familial hyperlipidemia, and nephrolithiasis. Although she had D vitamin replacement therapy, low levels of blood 25(OH)D3 concentration, measured by an LC-MS/MS device, were detected. After blood dilution, a high level of 25(OH)D3 and blood intoxication due to lipid interference were indicated. Conclusion: From this case, we can conclude that analytical errors caused by the ingredients of a blood sample may lead to unnecessary treatment and intoxication. While evaluating the blood 25(OH)D3 levels, clinicians should guard against false-negative results due to interference in patients with familial hyperlipidemia.