Letters in Drug Design & Discovery - Volume 21, Issue 9, 2024

A five-membered heterocyclic compound known as 1,2,4-oxadiazole has one oxygen, two carbon, and two nitrogen atoms within a ring. Numerous studies have shown that 1,2,4-oxadiazole has the potential to be an essential moiety in many harmful pharmacological conditions. 1,2,4-oxadiazole and its derivatives have been used as an antiviral, cough suppressant, vasodilator, anxiolytic, etc. To synthesize a single molecule with potent pharmacological action, two or more pharmacophores are combined currently. This enhances pharmacological effects, facilitates interaction possible with many targets, and reduces the adverse effects related to them. It has been reported that synthesis of 1,2,4-oxadiazole and its analog is possible using a variety of methods. In this present review, we emphasized recently accepted synthetic methods for 1,2,4-oxadiazole and its analogs synthesis. Additionally, the structure-activity relationship concerning several pharmacological effects, interactions with various targets, and the utility of different techniques for the analysis and purification has been described. On the behalf of the above study, the researchers can use this review study to better understand their 1,2,4-oxadiazole research in the future.

Biostimulants are one of the most important substancesfor improving productivity, growth and yield of plants as well as heavy metal detoxification, and stimulating natural toxins, controlling pests and diseases and boosting both water and nutrient efficiency. Google Scholar, Science Direct, CAB Direct, Springer Link, Scopus, Web of Science, Taylor and Francis, and Wiley Online Library have been checked. The search was done to all manuscript sections according to the terms "Salicylic acid," "Humic acid," "Fulvic acid," "Biostimulants" and "Plant growth promotion." On the basis of the initial check, Titles and Abstracts were screened on the basis of online literature, and then articles were read carefully. Salicylic acid may have important roles in abiotic stresses such as salinity, drought, cold, heavy metal and heat stresses, and it has been considered an important environmentally-sound agent with tremendous economical benefits and rapid responses. The positive effects of the application of salicylic acid have been reported in crops such as ajwain, alfalfa, anthurium, artemisia, artichoke, barley, bean, black mustard, broad bean, chickpea, chicory, canola, coriander, corn, cotton, cucumber, cumin, fennel, fenugreek, goji, longan, milk thistle, millet, onion, pea, pepper, pistachio, radish, rice, rosemary, rye, safflower, saffron, savory, sorghum, soybean, spinach, strawberry, sugar beet, tomato, wheat, etc. Humic acid can improve and stimulate plant growth and yield, suppress diseases and promote more resistance to stresses. Fulvic acid can increase root system and promote seed germination, growth rate and final yield. The present manuscript highlights the most important impacts of salicylic acid, humic acid, and fulvic acid ,emphasizing their roles in modern sustainable crop production.

Background: Inflammation is a common and intractable disease for humans. Current antiinflammatory drugs have a lot of side effects, which cause irreversible damage to the body. Objective: We predict the activity of the N-acylethanolamine-hydrolyzing acid amidase (NAAA) inhibitor to find more effective compounds. Methods: we established a quantitative structure-activity relationship (QSAR) model by gene expression programming to predict the IC50 values of natural compounds. The NAAA inhibitor, as a cysteine enzyme, plays an important role in the therapy of pain, anti-inflammatory effects and application of other diseases. A total of 36 NAAA inhibitors were optimized by the heuristic method in the CODESSA program to build a linear model. The 27 compounds and 9 compounds were in train and test sets. On this basis, we selected three descriptors and used them to build nonlinear models in gene expression programming. Results: The best model in the gene expression programming method was found, the square of correlation coefficients of R2 and mean square error for the training set were 0.79 and 0.14, testing set was 0.78 and 0.20, respectively. Conclusion: From this method, the activity of molecules could be predicted, and the best method was found. Therefore, this model has a stronger predictive ability to develop NAAA inhibitors.

Background: Microorganisms can infect wounds and disrupt healing by causing inflammation and tissue injury. Objective: Simvastatin (SIM) is reported to have antibacterial activity; therefore, this research is designed to evaluate the efficacy of simvastatin emulgel in wound healing. Methods: The simvastatin emulgel was assessed for physical appearance, rheological behaviour, spreadability, pH, ex vivo drug release and in vivo activity. The wound-healing activity was assessed by percent wound contraction, hydroxyproline estimation and histopathological evidence in wound-induced albino rats. Results: The simvastatin emulgel exhibited viscosity and spreadability of 6875 ± 531.21 mPa.s and 10.15 ± 0.31 g.cm/sec, respectively. The simvastatin emulgel exhibited wound contraction in wound healing studies compared to the reference product (p < 0.05). This activity was statistically significant (p < 0.05) in comparison to the control. The hydroxyproline content supported the wound-healing promoting effect of simvastatin emulgel, and marked improvements in the skin histological architecture were seen in the histopathological study. Conclusion: The study manifested the promising potential of simvastatin emulgel in speeding the healing of rat wounds with epithelization. Therefore, the designed simvastatin emulgel can be used as an option for the conventional topical dosage form.

Introduction: Sudden SARS-CoV-2 pandemic disrupted global public health; hence, searching for more effective treatments is urgently needed. Objective: Recently, a new host protein LRRC15 has been identified, facilitating viral attachment and cellular invasion and hence can be a good target against SARS-CoV-2. In this study, design some potential inhibitors against LRRC15. Methods: Here, we explored three strategies to find potential inhibitors against LRRC15, including the repurposing of ACE2 inhibitors, structure-based de novo drug generation, and virtual screening of three chemical libraries (ZINC Trial, ZINC Fragments, and Enamine HTSC). Results: Based on binding affinity Benazepril (-7.7 kcal/mol) was chosen as a final repurpose drug candidate, and ten de novodrugs (-8.9 to -8.0 kcal/mol) and 100 virtually screened drugs (-11.5 to -10.7 kcal/mol) were elected for further ADMET and drug likeliness investigation. After filtering, Z131403838 and Z295568380 were chosen as final drug candidates, and de novo drugs were further optimized. Optimization, re-docking, and pharmacokinetic analysis confirmed L-2 and L-36 as the best hit de novo drug candidates. Furthermore, all five final drugs demonstrated stable receptor-drug complex stability in molecular dynamics simulation. Conclusion: Effective treatment options are necessary to combat the SARS-CoV-2 epidemics. All the compounds presented in this study appeared to be promising inhibitorpromising inhibitors against LRRC15, though the future clinical investigation is needed toensure the biological effectiveness.

Background: Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb). It is one of the leading causes of death of 1.5 million people each year. TB can be treated by directly observed treatment short course (DOTS), but due to multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis, consequences can be devastating if the single DOTS dose is missed by the patient. MDR and XDR-TB require much more attention and time to control the infection. The longer period of tuberculosis treatment has side effects and it is expensive. Objectives: This alarming condition demands the development of novel processes to diagnose the disease in its early stage as well as to produce more promising antimicrobial chemotherapeutics. The current study aimed to explore molecular mechanisms involving docking simulation-based quantitative structureamino acid relationship (QSAAR) in order to have a better understanding of the interactions between the fluoroquinolones and MtbDNA gyrase. Methods: In this study, 24 fluoroquinolone (FQ) compounds present in the literature were selected and docked against the MtbDNA gyrase. Further, the relationship between the minimum inhibitory concentration of the compounds and interacting amino acids was assessed using QSAAR. Results: The study has established a novel method of formulating a quantitative structure-amino acid relationship. A significant correlation (R-value=0.829) between biological activity and the docked amino acid residues responsible for producing anti-tubercular activities has been obtained. Conclusion: The predicted residues captured in the developed model have been explored to report the Mtbvirulence.

Background: Psoriasis is recognized as an autoimmune dermatosis, and keratin 6 (KRT 6) is a hallmark of psoriasis. Gallic acid (GA) is a natural and small molecule with a series of biological activities. However, the effect of GA on psoriasis has not been clarified. Aims: This study aimed to investigate the anti-psoriatic activity of GA in psoriasis-like mice and in vitro. Methods: The transcriptions of the Homosapiens KRT6 gene, and Musmusculus KRT6 gene, were identified using a quantitative real-time reverse transcriptase PCR (qRT-PCR) assay. Expressions of KRT 6, STAT3, pSTAT3, Nrf2, and pNrf2 in HaCaT cells and skin biopsies were determined with a western blotting assay. The immunofluorescence (IF) assay was used to examine the expression of KRT6, pSTAT3, and pNrf2 in HaCaT cells. The expression of KRT 6, PCNA, Ki67, and CD3 was evaluated on the skin of psoriasis-like mice and quantified with histochemical scores (H scores). Results: GA significantly inhibited KRT 6 gene transcription and expression in psoriasis-like disease both in vitroand in vivo. It significantly inhibited the expression of keratinocyte proliferation markers (PCNA and Ki67), suppressed the expression of CD3 (a marker of T cells), and decreased the thickness of the folded skin, as well as improved the splenomegaly in imiquimod-induced mice similar to psoriasis. Furthermore, the suppressing effect of GA on KRT 6 was abolished by the continuous activation of Nrf2 rather than STAT3, although GA significantly inhibited Nrf2 and STAT3 activation in IL-17A-induced HaCaT cells. Conclusions: KRT 6 acts as a potential target for GA against psoriasis, and the anti-psoriatic effect of GA could be related to Nrf2 signaling.

Background: Lung cancer is the malignancy with the second highest diagnostic rate and the leading cause of cancer-related death. Objective: This study aims to investigate the potential mechanism and molecular targets of Panax notoginseng saponins (PNS) in inhibiting lung cancer through network pharmacology. Methods: Pharmacodynamic targets of each compound of PNS were searched from TargetNet, SwissTargetPrediction, and BatMan-TCM databases. Next, the differential expression genes (DEGs) in lung cancer were obtained from the Gene Expression Omnibus (GEO) database and screened by R package. Later, the STRING 11.0 database was utilized to analyze the protein-protein interaction (PPI) network of common targets of PNS-lung cancer, clusterProfiler to perform gene ontology (GO) annotation, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis for the common targets, and Cytoscape 3.8.0 to construct and analyze the "ingredient-target" network for the common targets of PNS-lung cancer. Results: A total of 154 potential pharmacodynamic targets of PNS, 2399 DEGs of lung cancer-related diseases, and 21 common targets of PNS-lung cancer were obtained by database search and screening. The 21 common targets were mainly involved in biological processes (such as small molecule metabolism and cytokine production) and were major components of cellular structures (such as neuronal cell bodies and membrane rafts). Besides, these targets could function as carboxylic ester hydrolases, G protein-coupled amine receptors, and oxidoreductase. They were mainly enriched in 14 signaling pathways, like neuroactive ligand-receptor interaction, regulation of lipolysis in adipocytes, and calcium signaling pathway. Furthermore, the molecular docking results revealed that aldo-keto reductase family 1 member C3 (AKR1C3) and melanin metabolic enzyme (MME) may be direct targets of ginsenoside Rg1 and notoginsenoside R2. Conclusion: Our study showed that ginsenosides inhibit the progression of lung cancer through multiple targets and pathways. More importantly, PNS may treat lung cancer by directly inhibiting AKR1C3.

Background: Non-small cell lung cancer is one of the most common cancers worldwide, and targeted chemotherapy has become a kind of the main treatment. Gefitinib, the most widely studied targeted agent in non-small cell lung cancer, is an orally active tyrosine kinase inhibitor. However, gefitinib inevitably generates acquired drug resistance, leading to treatment failure. Objective: A new class of compounds containing 4-anilinoquinazoline lead structure was designed and synthesized by modifying the structure of gefitinib. These compounds are expected to exert better anticancer activity and better binding to the EGFR-TK domain, enrich the structure of 4-anilinoquinazoline derivatives and inspire further structural modifications. Methods: The antiproliferative activity of nine derivatives was determined in three cancer cell lines (A549, PC9, and HepG2) using the MTT method. The ADMET profile of all compounds was predicted, and the binding affinity of the compounds (5 and 6) to EGFR was predicted by Schrödinger. In addition, the effect of these compounds (3-6) in inducing apoptosis in HepG2 cells was also studied. Results: Four (3, 5, 6 and 9) of the newly synthesized derivatives exhibited superior antiproliferative activity against A549 to gefitinib (IC⁵⁰ = 12.64 ± 3.59 μM), with compound 5 having the best activity (IC⁵⁰ = 7.39 ± 1.24 μM). Moreover, the ability of compounds (3-6) to induce HepG2 cell apoptosis was significantly better than that of gefitinib. Conclusion: Nine structures (compounds 2-10) were synthesized and characterized, and compound 5 had the best antiproliferative activity. Compound 3 possessed the best ability to induce HepG2 apoptosis. Also, ADMET calculations were performed in silico, and the results revealed that compound 3 has more suitable characteristics as a potential drug candidate.

Background: Breast cancer is the most prevalent malignant tumour in women of all races and is the second largest cause of cancer-related death in the majority of races. Based on the pattern of gene expression, five intrinsic or molecular classifications for breast tumours are frequently used. Our research, which is presently being utilized to treat breast cancer and has the potential to significantly change the course of the illness, is focused on two of them: luminal B breast cancer and triplenegative/ basal-like breast cancer. Methods: Screening a database containing millions of drug molecules or phytochemicals has become rapid and simple due to computer-aided drug design (CADD) techniques. In the current work, nine natural compounds were screened for ambrox from a sperm whale using docking research. Results: Following docking studies, nine substances were discovered to interact with basal-like and luminal B breast cancer proteins. All nine metabolites, however, adhered to Lipinski's rule of five and had sufficient oral bioavailability. The greatest binding affinities were demonstrated by 13,14,15,16-tetranorlabdane-3-oxo-8,12-diol, 6-β-hydroxy ambrox, 1-α-hydroxy-3-oxoambrox, and 2-α-3-β-dihydroxy ambrox. Conclusion: Therefore, it can be concluded that research on molecular docking and pharmacological mimics may hasten the discovery of new medications. The use of ambrox metabolites in the treatment of breast cancer also requires future perspectives on their therapeutic use.

Background: Pre-eclampsia (PE) is a pregnancy-related complication that has a global prevalence of 3-5% among pregnant women. Objective: The objective of this study is to examine the molecular mechanism underlying the therapeutic effects of Astragalus membranaceus(AE) in the treatment of PE through the application of network pharmacology and molecular docking. Methods: The databases, including TCMSP, Uniprot, Genecards, STRING, and DAVID, and software, including jvenn, Cytoscape, and AutoDock Vina, were used to do the analysis. Results: Sixteen AE-related active ingredients were screened, involving 127 targets, among which the main active ingredients included kaempferol, quercetin, and jaranol, etc. The primary targets of AE for the management of PE encompassed AKT1, CASP3, EGFR, IL1B, IL6, MMP9, PTGS2, TNF, TP53, and VEGFA. The outcomes of the enrichment analysis revealed that AE was predominantly implicated in pathways such as the IL-17 signaling pathway and PI3K-Akt signaling pathway, among others. The molecular docking findings confirmed that the principal active constituents exhibit favorable binding to their central targets. Specifically, the molecular docking results evinced that the primary active ingredients evince robust binding activity towards the core targets. Conclusion: AE has the potential to act synergistically in the management of PE by engaging multiple components, targets, and pathways, thereby establishing a basis for further exploration of its material basis and mechanism of action.