Letters in Drug Design & Discovery - Volume 20, Issue 11, 2023

ATP dependent MurC-F ligases are essential for the biosynthesis of peptidoglycan, an essential bacterial cell wall component that is required for bacterial cell survival. Last, in the series, MurF catalyzes the ATP-dependent addition of D-Ala-D-Ala dipeptide to UDP-N-acetylmuramyl-tripeptide to form the UDP-N-acetylmuramy-pentapeptide monomeric precursor of peptidoglycan. Owing to its critical essentiality in peptidoglycan biosynthesis and absence in eukaryotic counterparts, MurF is considered a promising target for the design and development of potent antibacterial agents. Several MurF inhibitors have been designed and evaluated for their MurF inhibitory and antibacterial activity. These include aminoalkylphosphinates, sulfonamides, diarylquinolones, hydroxylamines, phosphorylated hydroxylamines, thiazolylaminopyrimidines, 2,4,6-trisubstituted 1,3,5-triazines, etc. However, most of the inhibitors developed till date lack potent antibacterial activity against both Gram-positive and Gram-negative bacteria. In the present review, an updated status of MurF ligase inhibitors is presented that may provide a useful source for the design of novel MurF inhibitors with potent and broad-spectrum antibacterial activity.

The world needs a paradigm change from the current views on many plants to secure future food and nutrition. Many neglected and underutilized plants, specially medicinal and aromatic plants, are nutrient dense, appropriate in diversifying diets, provide enough vitamins and micronutrients for people, high resistant to diseases and pests, and can be adapted in many regions and of course with tremendous pharmaceutical benefits. Many of the medicinal plant species which were common in traditional medicine are still neglected and underutilized, especially in developing and under-developing countries. Lack of attention to these plants means their potential medicinal properties are under exploited and underestimated. The searches focused on publications from 1980 to July 2021 using PubMed, Google Scholar, Science Direct, and Scopus databases. Review of the literature was carried out using the following keywords, "medicinal plants", "neglected plants", "underutilized plants", "aromatic plants", "traditional medicine science", and "South America". In this review article, the authors have focused on medicinal values of Schinusterebinthifolius, Uncaria tomentosa, Phyllanthusamarus, Astrocaryum aculeatum, Croton cajucara, Arrabidaea chica, Bauhinia forticata, Copaifera langsdorffii, Cordia verbenacea, Caesalpinia ferrea, Salix alba L., Casearia sylvestris, Carapa guianensis, Costus spicatus, and Eugenia uniflora L., in both modern and traditional science. Although many studies have evaluated the biological characteristics of these plants, little has been done to identify and characterize its chemical components, which is certainly a niche that requires to be further explored.

The review aims to summarize the major and dominant natural antioxidants and their resources from medicinal and herbal plants with antiviral, anti-inflammation and antimicrobial activities. For this review manuscript, online databases, including Web of Science, Scopus, PubMed, and Science Direct, were searched for papers published from 1960 to November, 2021. Search terms consisted of “medicinal plants”, “traditional Iranian medicine”, “traditional Persian medicine”, “pharmaceutical properties”, “antioxidant activity”, “antiviral activity”, “anti-inflammation”, “antimicrobial” and “antibacterial activities”. (-)-Epicatechin, Caffeic acid, Gallic acid, Hydroxytyrosol, Kaempferol, and Resveratrol are some of the most important chemical compounds with antioxidant properties. Rosmarinic acid, Caffeic acid, Carnosol, P-Coumaric acid, Carnosic acid, Luteolin, Apigenin, and Kaempferol are the major chemical compounds with antiviral properties. Curcumin, Colchicine, Resveratrol, Capsaicin, (-)-Epigallocatechin, Quercetin, Myristicin, and Elmicin are the principal chemical compounds with anti-inflammatory properties. Isoeugenol, Coumarin, Piperonal, Scoparone, Spathulenol, D-Limonene, and Myrcene are the principal chemical compounds with antibacterial properties in traditional Iranian medicine. Persian traditional medicine, or Iranian traditional medicine, is one of the main ancient forms of traditional medicine, which has influenced knowledge regarding other medicinal plants in various countries. It has also been considered one of the most well-known traditional and holistic systems of medicine.

Background: Curcumin, a polyphenolic compound present in the turmeric plant (Curcuma longa) is well known for its anti-aging, anti-tumor, anti-inflammatory, anti-mutagenic and antioxidative properties due to which turmeric has been used as a medicinal plant from ages. Objective: Our current study aims at finding the most potent targets of curcumin displaying efficient binding by using various systems biology tools. Around 560 genes related to wound healing are extracted from PubMed using the combination of words like wound healing, curcumin, Homo sapiens, etc. Methods: For the investigation of the mechanism of curcumin interference at the system level, proteinprotein interaction network (PPIN) of the proteins involved in the wound healing process was generated using the STRING database. The noise of the data generated in PPIN was removed by modulation of the network with the help of Molecular Complex Detection (MCODE) and finding the seed proteins. GO enrichment analysis along with network topology analysis and molecular docking will help in pinpointing the most important and efficient curcumin binding proteins. Results: The findings of this study shows that besides SCR, PPARG and MAPK3, AKT3 is one of the novel targets for wound healing as the binding affinity of AKT3 is -4.53 Kcal/mol, which is close to SRC with the highest binding affinity with binding energy of -6.6 Kcal/mol. The binding energy of PPARG was -6.2 Kcal/mol and for MAPK3 the binding energy was -5.95 Kcal/mol. Besides AKT3, FLT4 and RPS6KB1 were also the novel targets of curcumin with binding affinities of -4.13 Kcal/mol and -4.04 Kcal/mol. In network analysis, we obtained PIK3R1 as a connector node which acted as a hub node with highest betweenness score. Conclusion: From the results obtained, we can say that curcumin finds its role in all four stages of wound healing and it also prevents the healing cells from turning into tumors.

Background: A large scale experimental validation conducted at the National Center for Advancing Translational Sciences (NCATS/NIH, USA) confirmed the predictions of our 3D-SDAR model of hERG blockage and phospholipidosis induction. It was demonstrated that both hERG blockage and phospholipidosis induction are driven by a common three-center toxicophore composed of two aromatic rings and an amino group. This work extends our earlier efforts by predicting the hERG blocking potential of pharmaceuticals from two additional datasets: i) one comprised of 106 drugs with reported clinical signs of cardiotoxicity from the AZCERT database and ii) a dataset of 54 FDA-approved tyrosine kinase inhibitors (TKIs). Methods: A bagging-like 3D-SDAR algorithm aggregating predictions from 100 randomized models was used to predict the hERG blocking potential of all 160 drugs. All 106 drugs from the AZCERT dataset were further evaluated for their hERG inhibition at NCATS using a thallium flux assay. Results: Comparison of the predicted hERG class against the results of the thallium flux qHTS assay resulted in an overall predictive accuracy of 0.736 and the area under the ROC curve of 0.780. Factors such as the generation of false negatives by the thallium flux assay, proximity to the cut-off, use of conformations that may differ from the biologically relevant ones, and the lack of structurally similar compounds in the modeling set could explain the somewhat reduced predictive performance compared to that of the original model. The original 3D-SDAR model was also used to evaluate the TKIs ability to block hERG. Comparing our predictions to class assignments based on IC50 values with a 30 μM cut-off, an accuracy of 0.850, sensitivity of 0.906, and specificity of 0.625 were achieved. Conclusion: 3D-SDAR provides a reliable platform for the prediction of hERG blockage. Particular attention should be paid to all investigational new drugs containing our three-center hERG toxicophore, especially those having highly flexible molecules. Particular scrutiny should be given to the tyrosine kinase inhibitors, which represent a therapeutic class possessing all structural characteristics previously associated with an increased potential to block hERG.

Background: Lycopene, a natural antioxidant from carotenoids, is produced by plants and microorganisms. It has been investigated in many studies in relation with potential health effects. Objective: Due to the high lipid-solubility of lycopene, its skin penetration is challenged. Therefore, in the present study, lycopene was loaded into lipid nanoparticles to improve penetration and pharmacological properties. Methods: Solid lipid nanoparticles (SLNs) containing lycopene were prepared and anti-tyrosinase properties were studied in the present study. The formulation was investigated in terms of drug release and antityrosinase properties. Determination of encapsulation efficiency was performed directly. Electron microscopy was used to examine the shape of the nanoparticles. Subsequently, the rate of drug release was investigated by the cell diffusion method. The present study applied cytotoxicity tests, cellular tyrosinase inhibition, melanin content, and free radical level to evaluate the effect of formulations on melanogenesis inhibition, and western blot assay was used to determine tyrosinase and MITF levels. Results: The results from particle size investigation for LYC-SLNs were 151.1 ± 2.3, and exploring the data of electron microscopy showed that the shapes of nanoparticles were spherical, and the encapsulation efficiency was 85.76 ± 2.75%. In determining the anti-tyrosinase effects of LYC-SLNs, a significant reduction in cellular tyrosinase activity and melanin and ROS levels were observed; It is also worth noting that LYC-SLNs reduced melanin production with minimal toxicity against melanoma cells. Conclusion: In general, the results confirm that SLNs can be an efficient delivery platform for the topical delivery of lycopene as a natural anti-oxidant and anti-melanogenic agent.

Background: Sustained release of synthetic polymeric microparticles has gained more attention as drug delivery carriers because of their properties such as good stability, low toxicity, dosing frequency, and simple and mild preparation method. The present work was envisaged to reduce the dosing frequency by preparing drug loaded biodegradable microspheres by the O/O emulsion solvent evaporation technique. Objective: The objective behind microspheres’ preparation is to sustain the metformin release by using ethyl cellulose as a synthetic polymer. The model drug metformin having a low biological half-life (1.5-3 hours) is selected. Methods: As the metformin is highly water soluble in nature, the oil-in-oil solvent evaporation techniques are used and span 80 is utilized as surfactant. The effect of stirring rate and surfactant concentration on the characteristics of encapsulation efficiency and drug release from the microsphere are investigated. Results: The results show that the drug-polymer (1:1) ratio gives better sustained release results. The obtained microparticles are characterized by X-RD analysis and Fe-SEM, and release behavior is checked for release patterns. A 3² full factorial design is employed for the responses. The free-flowing spherical microspheres show high drug entrapment efficiency. Conclusion: The data obtained suggest that microspheres can be successfully designed with sustained release for diabetic treatment.

Background: Inhibition of cholinesterase enzyme has been recognized as an important target in the symptomatic treatment of Alzheimer’s disease. Objective: In the current work, a series of new N-(4-(imidazo[1,2-a]pyridin-2-yl)phenyl)cinnamamide derivatives were synthesized and their inhibitory activities against acetyl cholinesterase, butrylcholinesterase, and Lipoxygenase were evaluated. Methods: The target compounds were synthesized as the literature reported with some modifications. The AChE, BChE, and LOX inhibitory activities of the synthesized compounds were evaluated using in vitro methods. The docking and kinetic studies were performed for the most potent compounds to evaluate the inhibition mechanism. Results: The structural elucidation of the synthesized imidazo-pyridine derivatives was performed by different spectroscopic techniques including IR, NMR, and Mass. Most of the synthesized compounds demonstrated good AChE, BChE, and LOX inhibitory activities. The most active AChE, BChE, and sLOX-1 inhibitors were found for compounds 4a, 4g, and 4l, respectively. The docking study also revealed that the three compounds, 4a, 4g, and 4l, have important binding interactions with the AChE, BChE, and sLOX-1 enzyme active sites, respectively. Conclusion: The results of current study shows imidazo[1,2-a]pyridine derivatives have potential for development of novel drug candidate for AD as AChE, BChE and sLOX-1 inhibitors.

Background: Diabetes mellitus (DM) is a metabolic disorder in which blood sugar levels are elevated over a prolonged period of time. SGLT2 inhibitors have recently demonstrated positive effects on diabetes care by minimizing hyperglycemia through decreased glucosuria. Objective: The aim was to carry out molecular docking and ADMET studies of 1,2,4 triazole and 1,2,4 oxadiazole scaffolds as SGLT2 inhibitors. Methods: Structures of newer molecules of two series of 1,2,4 triazoles and 1,2,4 oxadiazoles were drawn by using Chem Draw Ultra 8.0 software. The AutoDock Vina 1.5.6 software was used for the molecular docking studies. In silico ADMET properties were calculated online using admetSAR and pkCSM predictors. Results: We have designed 1563 different 1,2,4 triazoles and 1,2,4 oxadiazoles as SGLT2 inhibitors. A total of 14 compounds from both the triazole and oxadiazole series were shown to have better binding affinity to the SGLT2 protein than canagliflozin. Among them, SSN 10 and SSON 7 showed the highest docking score and binding affinity of -10.7 kcal/mol and -10.5 kcal/mol, respectively. In silico ADMET properties were also calculated in order to determine physiochemical properties, pharmacokinetics and toxicity of best binding molecules. In addition, these molecules were predicted to be non-carcinogens, showing good oral bioavailability and physiochemical characteristics safer with optimal partition coefficient (LogP = 2.07-5.24). Conclusion: Novel SGLT2 inhibitors were designed based on the scaffold of 1,2,4 triazoles and 1,2,4 oxadiazoles resulting in a new lead molecule with a maximum binding affinity; these molecules were also estimated to be noncarcinogenic with low LogP.

Background: Bronchopulmonary dysplasia (BPD) is a common chronic lung disease in the respiratory system of premature infants. Gm15886, as a lncRNA, is highly expressed in lung tissue of BPD newborn mice. Aims: This study aimed to clarify the roles of the Gm15886 gene in the pathogenesis of BPD mice by determining the expression of Gm15886 and Hipk1 in lung tissues. Methods: Sequence and localization of the Gm15886 gene and the related information of its adjacent genes were obtained using the UCSC browsing tool. The targeting gene of the Gm15886 was predicted using the Ensemble database and double luciferase assay. Neonatal C57BL/6J mice were exposed to 95% hyperoxia for 7 days to generate the hyperoxia-induced BPD mouse model. RT-PCR assay was used to detect Gm15886, Hipk1, and VEGF gene transcriptions in lung tissues in the development process of BPD (0, 3, 5, and 7 days). The pathological changes in lung tissues and Hipk1/VEGF gene transcription in lung tissues were detected in the Gm15886 gene silenced BPD mice. Results: Gm15886 gene transcription in lung tissues was significantly increased in mice of the hyperoxia model group compared to that in the air control group (p<0.05). Gm15886 gene could completely bind and interact with the base sequence within the second exon of the Hipk1 gene. Hipk1 was a targeting gene for Gm15886. Gene transcription and expression of Hipk1 were remarkably enhanced in mice of the hyperoxia model group compared to that in the air control group (p<0.05). The silencing of the Gm15886 gene improved alveolar morphology and markedly downregulated Hipk1 and upregulated VEGF gene transcription compared to those in the Blank vector BPD group (p<0.05). Conclusion: Gm15886-Hipk1 signaling pathway plays a critical role in the pathogenesis of BPD through modulating Hipk1 and VEGF gene transcription. This study might provide a theoretical basis for the treatment of BPD.

Background: Argan oil is one of the products used for antidiabetic purposes in Morocco. Objective: This work aims to study the acute and subchronic effect treatment of the roasted (Roil) and unroasted (UnRoil) Argan oils on oral glucose tolerance test (OGTT) and body weight in normal and diabetic rats, evaluate the effect of these oils on glucose absorption by the diaphragm and determine total polyphenol, flavonoids, tannins, chlorophyll and carotenoids amounts. Methods: The anti-hyperglycemic effect of Roil and UnRoil was investigated in normal and alloxanediabetic rats by treating the animals orally with 2 mLKg^-1/day of oils for 1 day (Acute treatment) and 4 weeks (Subchronic treatment). Then, OGTT was carried out at the end of each treatment, and the body weight was checked for each week. Besides, these oils (1 gL^-1) were tested on glucose absorption by the diaphragm isolated from Wistar rats in vitro. Results: This work shows that Roil and UnRoil significantly decrease the postprandial glycemic level in acute and subchronic treatments in normal and diabetic rats. Besides, the intake of these oils in diabetic rats significantly attenuates the postprandial glycemia compared to the acute-treated group. In vitro glucose uptake by the hemidiaphragm study shows that Argan oils promote glucose consumption by the muscles. Conclusion: Argan oils showed a very important anti-hyperglycemic effect, which could be explained by promoting peripheral glucose uptake. UnRoil shows a better effect than Roil on glucose consumption, meaning that the roasting process influences the phytoconstituent responsible for this activity.

Background: Diabetic neuropathic pain seriously affects the quality of a patient’s life. To predict molecular mechanism based on network pharmacology and verify the interaction between the active ingredient of Astragalus membranaceus and Panax notoginseng coupled-herbs (AP) and target genes related to Diabetic neuropathic pain (DNP) molecular docking assay was performed. AP and their target genes related to DNP were analyzed based on network pharmacology followed by experimental validation. Methods: TCMSP, PubMed and CNKI websites were used to acquire active components in AP. OMIM, DrugBank database and DisGeNET database were used to collect and analyze target genes related to DNP. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and gene ontology (GO) analysis were conducted in the DAVID database. The protein-protein interaction (PPI) network model was constructed by introducing the selected components-disease common target into the string database. Auto- Dock Vina 1.1.2 was used to dock receptor proteins with small ligand molecules. VonFrey’s statement was used to detect mechanical allodynia of DNP rats. Potential targets were detected by Western blot assay. Results: We decided that 22 and 9 chemical compositions possessed the fair ability of absorption, distribution, metabolism and excretion in Astragalus membranaceus and Panax notoginseng, respectively. These active compositions act on 70 target genes related to DNP. The core gene in the protein-protein interaction network are CAT, ESR1, HMOX1, IL1β, IL6, NFE2L2, NOS2, PPARG, PTGS2 and TNF, etc. Furthermore, GO, and KEGG pathway enrichment analyses indicated that DNP related target genes regulated by AP exist in multiple signaling pathways, including insulin resistance, PI3K-Akt signaling, HIF-1 signaling pathway, Fluid shear stress and atherosclerosis, and AGE-RAGE signaling pathway etc. AP inhibited mechanical hyperalgesia and reduced SERPINE1, FN1, IL1β, and IL6 expression of diabetic neuropathic rats in a dose-dependent manner. Conclusion: We first confirm that AP possess an anti-DNP effect through multiple signaling pathways based on network pharmacology. These results provide a theoretical basis for us to further research on the molecular mechanism of AP in the treatment of DNP.

Background: The COVID-19 outbreak is a serious concern and has caused a great loss to the global economy. Therefore, COVID-19 has become an urgent public health problem. Although new vaccines and small molecule drugs are now available, these prevention and treatment methods cannot completely control the epidemic due to the constant mutation of SARS-CoV-2. Targeting 3CLpro/RdRp is expected to develop drugs that are not susceptible to the mutation of SARS-COV-2, and it will also have a certain effect on the coronavirus that may appear in the future. Objective: This study aimed to find small molecules against SARS-CoV-2 with research potential and provide relevant data for the rational development of anti-SARS-COV-2 drugs. Methods: Targeting 3CLpro/RdRp, using Shards database (120,000 natural small molecule compounds) in the ZINC database, adopting a step-by-step screening strategy, and taking Lopinavir, Indinavir, and Molnupiravir as screening criteria was done. Moreover, the top scoring compounds were screened using rigid docking, and molecular dynamics simulation and ADME prediction were performed. Finally, the molecules with better scores were screened out. Results: After molecular docking with 3CLpro as the target, 3207 compounds meeting the screening criteria were obtained. After applying Lipinski's rule of five for drug property screening, 1825 compounds that met the criteria were obtained. After molecular docking with RdRp as the target, ZINC04259665 has a good docking score. According to molecular dynamics simulation results, ZINC04259665 is stable in combination with 3CLpro/RdRp. ADME prediction shows that ZINC04259665 has good druggability. Conclusion: Using 3CLpro/RdRp targets and then using a step-by-step strategy to screen the compound with the highest score through molecular dynamics simulation and ADME prediction, it was found that ZINC04259665 has good development potential and can be used as a follow-up hit compound for research. In addition, the data obtained provide relevant information for the rational development of anti- SARS-COV-2 drugs.

Background: Many contagious diseases have been caused by a variety of nontuberculous mycobacteria, opportunistic pathogens that can cause disseminated or localized diseases, particularly pulmonary, skin, and soft tissue infections. Objective: In this study fifty-five substituted 4-N-alkylated-2-trifluoromethylquinolines were evaluated against five species of nontuberculous mycobacteria: Mycobacterium fortuitum, Mycobacterium chelonae, Mycobacterium abscessus, Mycobacterium kansasii, and Mycobacterium avium. Methods: The antimycobacterial activities of all tested compounds were assessed using the microplate procedure with broth microdilution assay. The most actives were selected for their potential cytotoxic activity against Vero cells. Results: Most of the compounds displayed some activity against M. kansaii, of which 12, 15, 34, 37 and 48 were the most active at 3.12 μg/mL. The derivative 8 was the most active against M. fortuitum at 6.25 μg/mL and the most active against M. chelonae at 3.12 μg/mL. The derivative 2 was the most active against M. avium at 12.5 μg/mL, and 9 the most active against M. abscessus at 12.5 μg/mL. All the most active compounds showed MIC values similar to the references drugs used against these species. Conclusion: 47 compounds displayed some activity against some of the species analyzed, highlighting derivatives 12, 15, 34, 37, and 48, which presented the lower MIC values. Compounds 34 and 37 displayed the highest activity and did not show cytotoxicity against Vero cells. These findings have opened new perspectives for the research of new drugs against these mycobacterial species based on the quinoline nucleus.

Background: Heterocyclic sulfone-bearing small molecules are particularly important objects in medicinal chemistry. Structure-diversified pyridinyloxy-substituted imidazo[2,1-b][1,3]thiazines are characterized by satisfactory drug-like parameters and possess significant anti-inflammatory effects in in vivo studies. Objective: Oxidation of a series of 6-(2-pyridinyloxy) imidazo[2,1-b][1,3]thiazines under the action of m-chloroperbenzoic acid with a view to anti-inflammatory activity enhancement and structure optimization. Methods: A series of appropriate sulfones was synthesized by the action of m-chloroperbenzoic acid on 6-[(pyridin-2-yl)oxy]-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazines. The structure of the synthesized products was confirmed by ¹H, ¹³C NMR, and LC-MS spectra. In vivo anti-inflammatory activity was studied using carrageenin model of inflammatory oedema on white rats. ADMET parameters of compounds were evaluated in silico using AdmetSAR. For the most active compounds, docking studies to COX-1,2, 5-LOX and FLAP were performed. Results: It was found that transformation to sulfones could be achieved by soft oxidation at room temperature for 48 h using the 3-fold excess of oxidant in the presence of sodium hydrogen phosphate. Antiinflammatory activity screening results revealed that all synthesized sulfones showed significant antiexudative action with inflammation inhibition index in the range of 37.7 - 48.1%. The compound 2i was found to be the most active in the experiment, and its activity was equal to the reference drug effect; it also possesses satisfactory ADMET parameters and high energy of binding to 5-LOX and FLAP. Conclusion: The synthesized sulfone 2i is of interest for in-depth studies and further design of new potential non-steroidal anti-inflammatory agents.