Letters in Drug Design & Discovery - Volume 21, Issue 10, 2024

Introduction: Pesticides have lethal properties, capable of controlling or eliminating a living organism; they block the organisms' vital metabolic processes. They cause serious problems for human health, as they are highly toxic. The most used pesticides that are considered toxic are known as organophosphothioates (OP/P=S) in their commercialized form and organophosphates (OP/P=O) in their active form. These compounds have been the subject of studies on their metabolism and toxicology. According to research, these pesticides' toxicity is increased when oxidative metabolic desulfurization reactions occur, with the P=S bond being transformed into a P=O bond. This toxicity is due to the ability of OP/P=O species to inhibit the human acetylcholinesterase enzyme (HssAChE). Methods: To study the oxidative biotransformation of OP/P=S pesticides and the inhibition of the HssAChE enzyme by OP/P=S and OP/P=O using the molecular docking technique and QM/MM calculations. Results: The theoretical results showed that parathion is the compound with the greatest capacity to transform its P=S bonds into P=O bonds, thus forming the active paraoxon metabolite in the oxidative biotransformation process. In the HssAChE inhibition by OP/P=S and OP/P=O, our results showed that of all the compounds investigated, those with the highest inhibitory activities are parathion, paraoxon, malathion, diazoxon, chlorpyrifos and omethoate. Conclusion: This study was essential due to the lack of information in the literature about the oxidative biotransformation process of OP/P=S pesticides and the ability of these compounds to inhibit HssAChE. With this study, it was possible to observe that, in the oxidative biotransformation, chlorpyrifos and parathion have greater capacities to transform into their active metabolites and in the inhibition of the HssAChE enzyme, it was possible to observe that not all OF/P=O are the ones with the highest abilities to inhibit the HssAChE enzyme.

Introduction: Natural compounds obtained from marine algae, especially Rhodophyta are now being investigated for various biological activities. However, the antimicrobial activity and toxicity profile of compounds present in these algae isunderexplored. Objective: This study procured two compounds, Debilon and Phorbasterone-B, from Rhodophyta to analyze their in silico and in vitro potential against pathogenic bacterial strains and their acute toxicity. Methods: Debilon and Phorbasterone-B were extracted from Rhodophyta by a previously reported method and were further subsequently exploited computationally for their physicochemical properties, prediction of biological activity and molecular docking against bacterial proteins, toxicity, and experimentally for antibacterial potential against pathogenic strains of Vibrio cholera, Salmonella typhi, Escherichia coli, Enterococcus faecalis, Staphylococcus aureus, Bacillus subtilis, and Pseudomonas aeruginosa. Results: Docking studies proved that these molecules possess a chemical affinity for the bacterial proteins and can inhibit the growth of these microorganisms, as confirmed by antibacterial assay. Whereas the prediction analysis and toxicity studies showed that the friendliness of these molecules to the human body is enormous. Conclusion: From this study, it has been proved that DN and PB are perfect candidates for inhibiting these bacterial strains.

Background & Objectives: Heterocyclic pyrimidine and pyrazole rings have attracted the interest of medicinal chemists because of their pharmacological potential including antimicrobial activity. Based on molecular hybridization, new chalcones 6a-g and pyrimidines 7a-g based on a pyrazole scaffold were designed. Methods: The synthesis of these compounds involved mild condensation reactions between compound 4 and various aromatic aldehydes in a mixture of ethanol/NaOH (95:5 v/v) to give the corresponding chalcones 6a-g. These chalcones were further reacted with urea in the presence of a base in ethanol to produce the pyrimidine derivatives 7a-g. These new candidates were screened for their in vitro antimicrobial activities and molecular docking studies were evaluated. Results: The antibacterial and antifungal studies of all synthesized compounds against the strains tested showed that compounds 6c, d, and 7c, d exhibited the highest antibacterial and antifungal activities. In addition, the structure-activity relationship and docking studies are discussed. Conclusion: The synthesized compounds 6c, 6d, 7c, and 7d showed the highest antibacterial and antifungal activities against the tested strains.

Objective: The mechanism of Vaccaria segetalis (VS) seeds and Gleditsia sinensis Lam (GS) thorns in the treatment of prostate cancer (PC) was analyzed via network pharmacological analysis methods and molecular docking. Methods: The Traditional Chinese Medicine Systems Pharmacology Database Platform (TCMSP) was used to screen the PC’s effective components and targets; GeneCards and OMIM databases to search for targets related to PC. The intersection target was uploaded to the STRING database to obtain a proteinprotein interaction (PPI) network; and the key targets were screened from the PPI network via R language, CytoNCA, and CytoHubba tools. Gene Ontology (GO) and Kyoto encyclopedia of genes and genome (KEGG) pathway enrichment tools were used to analyze biological processes and molecular docking of key targets via AutoDock Vina software. Results: A total of 13 compounds, 229 nodes, 879 edges, and 20 key targets were obtained through the PPI network. Go and KEGG analysis showed that the intersection targets of VS and GS with PC were mainly involved in regulating cell promotion, cell apoptosis, cell cycle, and reversing epithelialmesenchymal transition (EMT) processing. Molecular docking revealed that the relevant targets of potential PC were characterized with stabilized affinity. Specifically, the targets with better affinity included estrogen receptor 1 (ESR1) with kaempferol, transcription factor p65 (RELA) with fisetin, kaempferol, quercetin, and mitogen-activated protein kinase 1 (MAPK1) with fisetin, and G1/S-specific cyclin-D1 (CCND1) with fisetin, kaempferol, and quercetin. Conclusion: In summary, this study reveals potential molecular therapeutic mechanisms of VS and GS in PC and provides a reference for the wide application of VS and GS in the clinical management of PC.

Aims: In silico Identification of Novel SphK1 Inhibitors. Background: A tumor is one of the major causes of death worldwide; the emergence of new targeted drugs has changed the mode of tumor treatment and opened up the era of targeted therapy. Sphingosine kinase 1 (SphK1) is a strictly conserved lipid checkpoint kinase, mainly located in the cytosol, and is overexpressed and enhances the development and progression of various type of tumors, such as melanoma, esophageal, gastric, and colon cancers. SphK1, consisting of 384 amino acid residues, has two domains: C-terminal (CTD) and N-terminal (NTD). SphK1 phosphorylates sphingosine to generate sphingosine-1-phosphate (S1P), which exists in high concentration in both the plasma and the lymph of cancer patients. S1P has 5 receptors (S1PRs) and controls 5 signal pathways, Ras/Raf/MEK1/2, PI3K/Akt, G-protein/PLC/PKC, Rho/Rock/NF-ĸB and PTEN; they are all related to cell growth, proliferation, differentiation, apoptosis, migration, and stress fiber formation. The sphK1/S1P signal pathway influences tumor cells' growth, proliferation, survival and angiogenesis, and SphK1 inhibitors can decrease Treg cell recruitment at tumor location. In T cells, SphK1/S1P signal way activates NF-ĸB and induces proliferator-activated receptor γ (PPARγ) transcription, which in turn regulates lipolysis in T cells. SphK1 can induce T cell failure through excessive S1P in extracellular vesicles of the tumor microenvironment. SphK1 inhibitors block S1P generation and inhibit cell growth, proliferation, differentiation, apoptosis, migration, and stress fiber formation, leading to increased CD8⁺T cells and decreased Treg cells in the tumor microenvironment. S1P also upregulates the expression of programmed cell death 1 ligand 1(PD-L1) through Early 2-factor transcription factor 1 (E2F1). Objective: The discovery of better Sphk1 inhibitors by pharmacophore model, ADMET, molecular docking, MM/GBSA, and MD simulation. Methods: Here, SphK1 pharmacophore was created; first, it was used for virtual screening, ADMET properties of screened-out molecules were predicted, and the obtained molecules were performed molecular docking and Molecular Mechanics Generalized Born Surface Area (MM/GBSA) calculation, then molecular dynamics (MD) simulation was performed, and Molecular Mechanics Poisson-Boltzmann Surface Area (MM/PBSA) were calculated. Results: Compounds 1, 2, and 3 were obtained through screening, and the binding energy of 1, 2, and 3 were better than that of the existing corresponding target inhibitors. Conclusion: The overexpression of Sphk1 is closely related to the occurrence, development, migration and drug resistance of tumors and has a good prospect of drug development. Given the important role of SphK1 inhibitors in treating tumors and the shortcomings of clinical application of SphK1 inhibitors, small molecule targeting inhibition SphK1 was screened to overcome the low efficiency. Firstly, establishing a pharmacophore model for virtual screening, and then ADMET prediction, sixty-seven molecules were selected. And then, molecular docking and MM/GBSA calculation obtain three compounds with lower Glide Score. In addition, they both have lower binding energy than PF-543. The docking result shows that Asp167, Asp264, and Thr282 of SphK1 with ligand more easily form H-bonds interaction. Next, in molecular dynamics simulation, compounds 1, 2, and 3 can stably bind with SphK1 and have a high activity of inhibiting SphK1, with more research potential. In conclusion, compounds 1, 2, and 3 inhibit SphK1 laying a foundation for further compound synthesis and activity evaluation. Compounds 1, 2 and 3 can stably bind to the receptor protein, which is valuable for further experimental research.