Letters in Drug Design & Discovery - Volume 21, Issue 19, 2024

Multi-target drugs are gaining attention for treating chronic diseases. Phillygenin (C21H24O6), a compound in Forsythiae Fructus, demonstrates strong anti-inflammatory, antifibrotic, anticancer, antioxidant, and antimicrobial properties. Its polar functional groups allow for structural modifications, offering the potential for novel drug discovery and development.

This review provides an overview of Phillygenin as a scaffold for multi-target drug development against chronic disease and disorders. It examines the molecular mechanisms behind its therapeutic effects, focusing on targets like NF-κB, PI3K/AKT, MAPK, Nrf2-ARE, P2X7R/NLRP3, Ca²⁺-calcineurin-TFEB, JAK/STAT, Notch1, TGF-β/Smads, and AMPK/ERK/NF-κB.

A review of the literature on Phillygenin was conducted to explore its therapeutic applications. The study examined Phillygenin's molecular mechanisms and potential targets to highlight its multi-targeting capabilities.

Phillygenin shows promise in managing chronic diseases by targeting multiple cellular pathways, including NF-κB, PI3K/AKT, MAPK, Nrf2-ARE, P2X7R/NLRP3, Ca²⁺-calcineurin-TFEB, JAK/STAT, Notch1, TGF-β/Smads, and AMPK/ERK/NF-κB. Its versatility and natural origin make it a valuable scaffold for developing multi-target therapeutics.

Exploring Phillygenin as a framework for multi-target drugs offers the potential to boost efficacy and reduce side effects. Further research and clinical trials are needed to confirm Phillygenin's therapeutic potential.

For a long period, traditional medicine has held a crucial role in maintaining cardiovascular homeostasis. However, very few scientific studies have investigated and reported information on the mechanism by which these plants act through their active ingredients. Presently, there is consideration for utilizing computer-assisted methods to incorporate predictive and dependable data in addition to experimental findings.

The objective of this review article was to furnish information on medicinal plant extracts that have undergone experimental testing to assess their cardioprotective properties

Thus, eleven phytomolecules have been chosen based on their bioactivity scores and their belonging to medicinal plants frequently used in traditional medicine. Molecular docking analyses were carried out using Autodock Vina v1.5.7, and were performed to research the molecular pathway attributed to the effects of phytoconstituents extracted from medicinal plants known for their therapeutic effects against cardiovascular alterations. Computer ADME/toxicity studies were also performed to estimate the physiological and pharmacological signification of each phytomolecule.

The results showed that selected phytomolecules exert considerable therapeutic potential on different cardiovascular levels through activation, inhibition, and modulation of cellular factor's expressions, all leading to cardiac muscle protection against stressful attacks. ADMET analysis showed that all phytomolecules selected responded to drug-likeness according to Lipinski's rule of five and the possibility of developing medicines, taking into account the dose used for each phytoconstituent.

Our study demonstrated that various medicinal plants possess significant therapeutic potential at multiple cardiovascular levels through a series of vital processes, including activation, inhibition, and modulation of diverse cellular component expression.

Marine organisms are a rich source of metabolites that can be considered functional foods and produce new medicines against metabolic syndrome, including hypertension, dyslipidemia, hyperglycemia, obesity, insulin resistance, and hyperinsulinemia.

A total of 609 publications were searching results, 283 were screened entirely, and 43 duplications were removed.

These compounds, found in marine organisms such as algae, sponges, and mollusks, have vasodilatory properties, inhibit certain enzymes involved in blood pressure regulation, and exhibit anti-oxidant activity, making them promising candidates for developing hypertension treatments. Marine organisms showed an improvement in insulin sensitivity and blood glucose level regulation, suggesting their potential in developing novel therapies for diabetes management. Furthermore, some marine sources inhibit lipid accumulation, regulate metabolism, and suppress appetite, indicating their potential as therapeutic agents in combating obesity.

However, further studies on the pharmacological effects of marines should be performed to evaluate the potential of these compounds to produce novel drugs, but they hope this study paves and lights the way.

Eudragit L100, filled with miconazole and gelatinous polymeric eye drops, is designed to sustain the drug release and increase ocular effect.

The solvent diffusion technique was used to obtain the polymeric solution. The formulations developed were fully characterized and examined.

The optimized drug had a particle size of 71.15 2.3 nm, a zeta potential of approx. 2.57 to 0.76 mV, a polydispersity index of approx. 0.184 and a capture efficiency of 0.10% of 58.049. The prepared efforts showed a fungicidal effect on Candidiasis albicans cultures.

The polymeric solution containing the drug-filled with miconazole (MZ) showed an abrupt release in the first hours, followed by the pattern of sustained drug release. A higher cumulative corneal permeability was observed from MZ-containing polymeric solution, which prolonged MZ release in goat eyes. Mucoadhesive liners containing miconazole-loaded Eudragit L100 polymeric solution provide a promising approach to the ocular administration of miconazole (a fungicide) for the treatment of ocular infections requiring long-term drug administration.

The current use of Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2) inhibitors is often limited by low selectivity and adverse side effects, highlighting the urgent need for novel, highly selective agents targeting this receptor.

Based on existing VEGFR-2 inhibitors, we employed computer-aided drug design (CADD) techniques to develop a virtual compound library using active docking fragments. Molecular docking was performed using the configuration of VEGFR-2 as the receptor protein(PDB:4ASD). Comparative analysis and screening identified the most promising inhibitor, which was subsequently validated through molecular dynamics simulations.

From the virtual library, 10 potential highly active inhibitors were identified. In particular, Compound 9 demonstrated strong binding affinity with the protein configuration, forming four hydrogen bonds during docking. The calculated CODOCKER energy was 39.7315 kcal/mol, with an RMSD of 0.4634 nm and RMSF of 0.3234 nm. Compared to Sorafenib, Compound 9 exhibited superior docking selectivity and activity.

Computational analyses suggest that Compound 9 is a promising candidate as a highly selective VEGFR-2 inhibitor. Nonetheless, due to the inherent limitations of in silico docking studies, further chemical synthesis and experimental biological validation are required to confirm its potential.

Hepatocellular carcinoma (HCC) is a common hepatic malignant tumor severely affecting the life and health of people globally. Radix Sophorae Flavescentis (RSF) is a Chinese herbal medicine widely utilized in China. However, its main ingredients and mechanism have not been fully illustrated. The current study explored the potential mechanism of RSF treating HCC through network pharmacology, molecular docking, and molecular dynamics simulation.

The potential RSF active compounds and the corresponding targets were retrieved from TCMSP, TCMID, HERB, ETCM, and BATMAN-TCM databases. HCC-related target genes were primarily mined using GeneCards and OMIM databases. The intersection target genes of RSF and HCC were collected, and the protein-protein interaction (PPI) network was constructed to obtain the core target genes of RSF in HCC. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed on the core targets. The network analysis results were verified through molecular docking and molecular dynamics simulation using active compounds and core targets.

In this study, 23 potentially active ingredients of RSF and 203 corresponding targets of the active ingredients were mined, and 4594 HCC-related target genes were finally identified. Thereinto, quercetin, luteolin, formononetin, and 8-isopentenyl-kaempferol were predicted to be the core targets, and 61 core targets such as TP53, JUN, HSP90AA1, AKT1, MAPK1, RELA, TNF, and ESR1 were further screened through PPI network analysis. GO enrichment and KEGG pathway analysis revealed that the treatment of HCC with RSF mainly involved the receptor signaling pathway of vascular endothelial growth factor, cytoplasm, protein domain specific binding, and other biological processes. Signaling pathways included pathways in cancer, Hepatitis B, IL-17 signaling pathway, etc. Molecular docking and molecular dynamics simulations validated the above results.

This study elucidated the potential mechanism of RSF in the HCC treatment through network pharmacology, molecular docking, and molecular dynamics simulation, thereby offering valuable insights for future clinical investigations.

Diabetic nephropathy, a complex microvascular complication of diabetes, poses substantial health and economic challenges globally. ZWD, known for its multi-component composition, has demonstrated potential therapeutic effects in DN, yet its molecular mechanisms require further elucidation to support its clinical application.

This study aimed to comprehensively investigate the active components, target molecules, and molecular mechanisms of Zhenwu Decoction (ZWD), a Traditional Chinese Medicine (TCM) formula, in the treatment of diabetic nephropathy (DN), with a focus on its anti-inflammatory effects through the modulation of the PDE3A-mediated cAMP-PKA-NFκB axis.

The primary objective was to identify the active components of ZWD, their targets, and the underlying molecular pathways through which ZWD exerts its therapeutic effects on DN, specifically focusing on the modulation of inflammation in renal cells under high glucose conditions.

A combined approach of network pharmacology, single-cell transcriptomics, and molecular docking analyses was employed to investigate the active components, target molecules, and underlying mechanisms of ZWD in treating DN. A high-glucose-induced HK-2 cell model was established to simulate in vitro DN conditions. Cell viability was assessed using the CCK-8 assay, while quantitative real-time PCR (qPCR) and Western blotting were employed to quantify gene expression and protein levels, respectively.

Our analysis uncovered 141 active components in ZWD, which targeted 171 proteins involved in pathways related to hypoxia response, neuroactive ligand-receptor interaction, urotensin II signaling, and other pathways implicated in diabetes and vascular diseases. Among these, 75 overlapping genes were pinpointed as potential therapeutic targets of ZWD for DN. Protein-protein interaction networks revealed three functional clusters of targets potentially associated with oxidative stress responses, lipid metabolism, and hormonal regulation. Cell-type specific analyses showed differential expression of these targets in DN, particularly in proximal tubular epithelial cells. Notably, through molecular docking, we discovered a strong binding affinity between PDE3A and beta-sitosterol. In vitro experiments confirmed that ZWD extract modulated PDE3A expression, leading to the suppression of the PKA/AMPK/NF-κB axis and attenuation of high glucose-induced inflammation in HK-2 cells.

This study identified that Zhenwu Decoction (ZWD) suppressed high glucose-induced inflammation in renal cells by inhibiting the PDE3A-mediated cAMP-PKA-NFκB axis, highlighting the potential of ZWD as an effective adjunct therapy for diabetic nephropathy and paving the way for innovative anti-inflammatory treatments.

Patients with COVID-19 often have an impact on populations with underlying co-infection. METTL3 plays a crucial role in numerous infectious diseases, making the research on broad-spectrum anti-infective drugs targeting METTL3 both captivating and compelling.

The study aims to identify anti-infection potential compounds targeting METTL3 using a comprehensive virtual screening approach.

The approach involves ensemble docking and molecular dynamics simulations to predict and validate the potential of natural compounds. This was complemented by the application of deep learning, specifically CNN binary classification and regression models, to predict the anti-infection capabilities of the compounds identified through docking. Experimental validation through Surface Plasmon Resonance (SPR) further confirmed the computational predictions. Network and gene ontology analyses provided insights into the compounds' biological targets and pathways.

Ensemble docking approach achieved high prediction accuracy. We identified 17 natural compounds as potential METTL3 inhibitors, with Rosavin and Eriocitrin showing strong anti-infection potential against HIV-1, SARS-CoV-2, Mycobacterium tuberculosis, and Influenza A. Rosavin's low toxicity and strong METTL3 binding affinity were confirmed by SPR experiments and MD simulations. Network and gene ontology analyses suggest Rosavin may enhance immune responses by disrupting interferon degradation.

The multidimensional analysis identified Rosavin as a potent METTL3 inhibitor with significant anti-COVID-19 co-infection diseases potential.

The Nrf2-Keap1 pathway holds great significance in antioxidant defense mechanisms. This pathway has emerged as a pivotal clinical target for the development of highly potent therapeutic agents for neurodegenerative diseases. The Keap1-Nrf2 inhibitors covalently bind to the Keap1 protein, leading to modifications in cysteine residues. This computational study focused on the investigation of coumarin derivatives through in silico methods.

The aim of this study was to conduct an in silico exploration of coumarin derivatives as potential Keap1 inhibitors in the context of Alzheimer's disease.

Coumarin derivatives were obtained from the ZINC 15 database in the sdf (simple dimension file) format. The docking process utilized the crystal structure of the Keap1 protein (PDB ID: 4XMB), which was sourced from the RCSB Protein Data Bank (https://www.rcsb.org/). Molecular docking was conducted using the AutoDock Vina1.5.7 software. Following this, the top ten coumarin derivatives with the highest binding energy underwent an ADME study, SAR study, toxicity study, and medicinal chemistry score study. In the in silico study, resveratrol was employed as the standard drug.

We sourced ligand molecules from the ZINC 15 database in pdf format, while the Keap1 protein, identified by its PDB ID: 4XMB, was obtained from the RCSB website (https://www.rcsb.org/) in pdb format. We used resveratrol as the standard drug for the molecular docking analysis. The in silico molecular docking procedures were conducted using Autodock Vina 1.5.7 software.

Among the 75 coumarin derivatives assessed, 9 exhibited the most favourable binding energies towards Keap1. The top 9 derivatives of coumarin were further scrutinized in terms of their pharmacokinetic profiling and evaluation of bioactivity. Both compounds S1 and S2 exhibited noteworthy docking scores of -7.44 and -7.52 Kcal/mol, respectively. Our investigation revealed that all nine derivatives of coumarin exhibited properties characteristic of drug-like compounds. The investigation conducted suggested the potential development of coumarin derivatives as effective Keap1-Nrf2 inhibitors. Further validation of the computational findings requires both in vivo and in vitro studies.

Synthetic antibiotics are often much more potent than natural alternatives. They can effectively treat serious and life-threatening bacterial infections.

The chalcones were synthesized by Claisen-Schmidt condensation and characterized by FT-IR, 1HNMR, 13CNMR and MS methods. All the compounds underwent computational and in-vitro evaluations for antimicrobial and antioxidant properties.

The docking studies indicated that all the molecules displayed good binding energy with their selective targets, with 6g and 6h showing the best affinity among them. The antimicrobial test results showed that the MIC values ranged from 0.4 to 0.9 mg/ml, and compounds 6g and 6h demonstrated potential for gram-positive bacteria. At the same time, 6k and 6l displayed good inhibition activity against gram-negative bacteria. Compound 6k showed potential against Candida albicans, and compound 6l showed potential against Aspergillus Niger. However, compound 6b showed poor antimicrobial activity. Compounds 6g and 6f also exhibited ferrous ion chelating activity at 28.69 μg/ml and 29.94 μg/ml, respectively.

Based on the IC50 values, it was found that only compounds 6g and 6f had superior against oxidation, which was evaluated using EDTA as a reference. The ADMET properties were analyzed using SwissADME. Furthermore, the lead likeness results showed that 6g exhibited lead-like characteristics.

Significant research efforts have been directed towards developing systems for enhancing the intracellular delivery of phosphate-substituted compounds, such as biologically active peptides and nucleotides. Phosphoramidates (P-N) are organophosphorus structures containing a single covalent bond between the P(V) and N(III) atoms. Three types of phosphoroamidates are discovered. Organophosphorus compounds, defined as (RO)2P(O)NR’2 (R, R’ = H, alkyl, aryl, heteroaryl), is a stable phosphoryl bond (P=O). Novel phosphoramidate derivatives of hydroxy functional or amino functional compounds include peptides, peptidomimetics and nucleotide analogs. The compounds enable enhanced intracellular delivery of drugs as their corresponding phosphate esters or amides. phosphoramidates exhibit antiproliferative activity and could be used for the treatment of cancers. Phosphoramidates exhibit potential applications in the field of biomedicine as antiviral, anti-HIV, antimalarial and anticancer agents.

A computer-aided investigation compared these new compounds to Remdesivir, assessing potential pharmacological properties.

An efficient microwave method was used to synthesize novel N-arylphosphoramidates from commercially available nitroarenes using trialkyl phosphites.

Novel N-arylphosphoramidates are prepared with good yields and reduced reaction times. NMR spectroscopy (HH-COSY, HSQC, HMBC) elucidated their structures.

A practical reductive domino reaction involving a trialkyl phosphite under microwave irradiation has been developed to convert nitroarenes into dialkyl N-arylphosphoramidates. The comparative study conducted in this research effectively ranked compounds 5a-o concerning approved medications (Remdesivir), providing a solid foundation for further investigation. Molecular docking analysis of our 15 ligands and Remdesivir revealed several similarities. This indicates that Remdesivir, an approved drug, and our ligands have comparable binding affinities for the primary protease (PDB code 7BQY). Such insights encourage us for further exploration and optimization of their potential therapeutic applications as COVID-19 inhibitors. Molecular docking studies examined these compounds as COVID-19 inhibitors based on their interactions and binding affinities for the SARS-CoV-2 main protease (PDB code 7BQY).

Dermatophytosis is a significant global health issue that poses a serious risk to public well-being. This fungal infection occurs when dermatophytes invade the outer surfaces of both human and animal bodies. The use of common anti-dermatophyte medications has some limitations due to their side effects and drug resistance. Herbal remedies offer broad-spectrum antimicrobial effects low toxicity, and are widely used compared to traditional chemical fungicides. Recent studies have indicated that the ozone has antifungal activity due to its high oxidizing power and skin penetrating capacity.

This study examined the antifungal effects of ozonated olive oil in treating dermatophytosis caused by Trichophyton mentagrophytes through in vitro and in vivo tests on rats. The agar dilution method was used to establish the treatments' minimum inhibitory concentrations (MICs). For the in vivo study, thirty male Wistar albino rats from the Laboratory Animal Unit were prepared. The topical antifungals were then applied topically once daily for 7 days to the animals beginning 10 days after the appearance of symptoms. Five groups of animals were treated with virgin olive oil, ozonated olive oil (1.25, 2.5, or 5 mg/mL), and terbinafine (1.25 g/mL).

Following the therapy period, clinical and mycological efficacies were assessed. Ozonated olive oil and terbinafine were shown to have MIC of 2.5 µg/mL and 0.62 µg/mL against T. mentagrophytes, respectively. Ozonated olive oil showed antifungal effects and significantly reduced the clinical score by increasing hair growth and decreasing inflammation, similar to terbinafine.

Therefore, ozonated olive oil may serve as an alternative treatment for Trichophyton infections.

Breast cancer is the most common cancer in women. Tyrosine kinase inhibitors were developed to treat breast cancer. EGFR/ErbB1 inhibition has proved to be a promising target in breast carcinoma therapy. Drugs with benzimidazole nucleus have been approved by the FDA for cancer treatment.

To design and develop benzimidazole anticancer small molecules for EGFR inhibition for the treatment of breast cancer.

By 3D-QSAR-based virtual screening, molecular docking, molecular simulation and drug likeness study.

In this research, a 3D-QSAR pharmacophore was generated with four salient features. Namely H-bond acceptor (HBA), two ring aromatic (RA) and hydrophobic (HY) features. Its correlation-coefficient (r) is 0.8412, RMSD of 0 .96 and with 32.84 bits cost difference value. With virtual screening, 4 top hits were identified. Novel benzimidazole derivatives were designed (1a-ll) by using the features of hit molecules and the pharmacophore. The novel designed small molecules that were druggable as they passed the Lipinski and Veber rule. Novel ligands and EGFR protein interaction were good. 1a and 1i were found to be the best-designed molecules. They had -8.6 Kcal/mol and -8.4 Kcal/mol docking interaction energy, respectively, whereas Compound 4 (reference) scored -7.4 Kcal/mol. Both these molecules were stable inside the binding pocket of the EGFR protein. The molecular dynamic simulation study revealed that 1a attained equilibrium at 0.15nm.

In silicon novel benzimidazole small molecules were designed and developed as EGFR inhibitors to treat breast cancer.

Gastrointestinal (GI) disorders are a kind of common, but complicated disease that may be triggered by many factors. In Asia, many traditional Chinese herbs are prominent in treating GI disorders, but the pharmacological mechanism still remains vague or unknown due to the multiple-component characteristics of traditional Chinese medicine (TCM).

In order to investigate the therapy mechanism of traditional Chinese medicine (TCM) for Gastrointestinal (GI) diseases, a typical TCM prescription, Houpusanwu Decoction, for the treatment of ileus, a severe GI disease, is used as a probe presently.

We performed data mining on all components in Houpusanwu Decoction (HD), established a corresponding component database, and then conducted ADME screening of potentially active compounds in the database. Next, we identify potential targets of HD candidate compounds, followed by the establishment of a series of pharmacological networks. Finally, we conducted SP analysis and mechanism analysis.

Through pathway analysis, we found that HD treats ileus mainly through four pathways, i.e., GI motility-related Calcium, inflammation-related SCF/c-kit and p38/MAPK, and thrombosis and diabetes-related JAK2/STAT3 signaling pathways, which indicated that HD is a typical prescription with multichannel and multifunction of TCM characteristics.

This study not only expounds the pathogenesis of ileus and, at the same time systematically illuminates the curative mechanism of HD, but also provides a novel SP method to explore the therapeutic mechanism of TCM in treating complicated GI diseases.

Increased resistance of Staphylococcus aureus (S. aureus) poses a significant threat to disease control in animal husbandry and human public health. Eukaryotic-like Ser / Thr phosphatase (Stp1) is an effective target for the regulation of bacterial virulence. In this study, potential Stp1 inhibitors were screened through virtual screening, and the inhibitory mechanism of these compounds was explored using molecular dynamics simulations.

Virtual screening studies were performed using AutoDock vina 4.0 software. The SwissADME server predicted the properties of chemical absorption, distribution, metabolism, excretion, and toxicity (ADMET). Molecular dynamics simulation was performed using the Gromacs software package, and molecular mechanics/generalized Born surface area (MM/GBSA) was calculated using the Amber 10 package. The inhibition mechanism was verified using phosphatase, mutagenesis, and fluorescence quenching assays.

The 2-methylvaleric acid from foods was found to be a competitive inhibitor of Stp1, based on the kinetics of the enzymatic reaction and virtual screening. Molecular dynamics simulations revealed that 2-methylvaleric acid binds to the active center of Stp1 and reduces enzyme activity by competing with its substrate. Interestingly, the molecular modeling and kinetics of the enzymatic reactions were consistent. Energy decomposition indicated that Met39, Thr102, Ile164, Val167, and Thr170 played important roles in complex binding. Additionally, the SwissADME server showed that 2-methylvaleric acid possesses drug-like properties.

Therefore, 2-methylvaleric acid is a promising compound for further exploration because of its potential to reduce S. aureus virulence. These findings are conducive to additional discovery and design of new inhibitors.

Intervertebral Disc Degeneration (IDD) is a major cause of lower back pain. Ginsenoside compound C (GCC) has shown potential in treating IDD, but its specific targets and mechanisms remain unclear.

This study aimed to investigate the potential molecular mechanisms of GCC in the treatment of IDD using network pharmacology and molecular docking approaches.

Public databases were utilized to identify 100 targets related to GCC and 20,757 targets associated with IDD, of which 96 common targets were determined through cross-analysis. A Protein-Protein Interaction (PPI) network was constructed using the STRING database, and key gene clusters were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to explore the biological processes and pathways involved. Molecular docking was conducted to verify the binding of GCC to key proteins.

Six key genes, including HSP90AA1, CASP3, MAPK1, EGFR, HIF1A, and PIK3CA, were identified as central to the PPI network. GO analysis suggested that GCC's targets are involved in intracellular processes, while KEGG analysis highlighted the IL-17 and TNF signaling pathways. Molecular docking confirmed stable binding between GCC and key proteins, with binding energies ranging from -3.58 to -2.01 Kcal/mol.

GCC may inhibit the IL-17 and TNF signaling pathways by interacting with key proteins, potentially contributing to the treatment of IDD.

A new set of 1,2,4-triazine combined 1, 2, 3-triazole hybrids were designed computationally for predicting anti-diabetic potential. All the derivatives taken for study exhibited excellent anti-diabetic potential with significant IC50 values.

The present research includes the development of pharmacophore models, 3D QSAR, virtual screening, molecular docking, and evaluation of models based on certain criteria. The DHRRR_1 showed the best pharmacophore model with a survival score of 5.9937. The 3D QSAR analysis developed a model with the values of R² = 0.9714 and Q² = 0.7202. The binding pose and affinity of the most potent compound, 10c, in the active site of α-glucosidase was investigated using in-silico molecular docking analysis.

It was observed that compound 10c demonstrated promising binding affinity with a score of -8.078 kcal/mol and exhibited binding interaction with the essential amino acids ASN301 and LEU227. There were five compounds (1-5) that showed significant binding affinity towards the target comprising active amino acids (ASH202, ASP333 and VAL335). The molecular dynamic study showed the stability of ligand-protein binding interactions.

The results of the present investigation can accelerate the optimization and reformation of the latest anti-diabetic agents that target the α-glucosidase.