Docking Validation Research Articles

Mechanistic Study of Schisandra chinensis Fruit Mixture Based on Network Pharmacology, Molecular Docking and Experimental Validation to Improve the Inflammatory Response of DKD Through AGEs/RAGE Signaling Pathway.

Diabetic kidney disease (DKD) is a major cause of end-stage renal disease (ESRD), and inflammation is the main causative mechanism. Schisandra chinensis fruit Mixture (SM) is an herbal formulation that has been used for a long time to treat DKD. However, its pharmacological and molecular mechanisms have not been clearly elucidated. The aim of this study was to investigate the potential mechanisms of SM for the treatment of DKD through network pharmacology, molecular docking and experimental validation. The chemical components in SM were comprehensively identified and collected using liquid chromatography-tandem mass spectrometry (LC-MS) and database mining. The mechanisms were investigated using a network pharmacology, including obtaining SM-DKD intersection targets, completing protein-protein interactions (PPI) by Cytoscape to obtain key potential targets, and then revealing potential mechanisms of SM for DKD by GO and KEGG pathway enrichment analysis. The important pathways and phenotypes screened by the network analysis were validated experimentally in vivo. Finally, the core active ingredients were screened by molecular docking. A total of 53 active ingredients of SM were retrieved by database and LC-MS, and 143 common targets of DKD and SM were identified; KEGG and PPI showed that SM most likely exerted anti-DKD effects by regulating the expression of AGEs/RAGE signaling pathway-related inflammatory factors. In addition, our experimental validation results showed that SM improved renal function and pathological changes in DKD rats, down-regulated AGEs/RAGE signaling pathway, and further down-regulated the expression of TNF-α, IL-1β, IL-6, and up-regulated IL-10. Molecular docking confirmed the tight binding properties between (+)-aristolone, a core component of SM, and key targets. This study reveals that SM improves the inflammatory response of DKD through AGEs/RAGE signaling pathway, thus providing a novel idea for the clinical treatment of DKD.

Exploring the Active Compounds of Traditional Mongolian Medicine Baolier Capsule (BLEC) in Patients with Coronary Artery Disease (CAD) Based on Network Pharmacology Analysis, Molecular Docking and Experimental Validation.

Baolier Capsule (BLEC) is a Traditional Mongolian Medicine comprising fifteen herbs. This study aims to illustrate the synergistic mechanism of BLEC in the treatment of Coronary Artery Disease (CAD) by using network pharmacology method, molecular docking and experimental validation. Searching and screening the active ingredients of different herbs in BLEC and target genes related to CAD in multiple databases. Subsequently, Protein-Protein Interactions Network (PPI-Net), gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment were used to identify the key targets. AutoDock was used to verify the binding ability between the active ingredient and key target through molecular docking. Reverse Transcription-QuantitativeReal-TimePolymeraseChainReaction (RT-qPCR) was used to verify the effect of active ingredient of BLEC on the key target gene. Finally, effect of BLEC on the degree of blood lipids and atherosclerosis was validated by animalexperiment. There are 144 active components and 80 CAD-related targets that are identified in BLEC in the treatment of CAD. What is more, 8 core genes were obtained by clustering and topological analysis of PPI-Net. Further, GO and KEGG analysis showed that fluid shear stress and atherosclerosis are the key pathways for BLEC to treat CAD. These results were validated by molecular docking method. In vitro, active compounds of BLEC (Quercetin, luteolin, kaempferol, naringenin, tanshinone IIA, β-carotene, 7-O-methylisomucronulatol, piperine, isorhamnetin and Xyloidone) can inhibit 8 core gene (AKT1, EGFR, FOS, MAPK1, MAPK14, STAT3, TP53 and VEGFA) expression. Moreover, BLEC not only improve blood lipid levels but also inhibit the development of atherosclerosis in ApoE-knockout mice. Our research first revealed the basic pharmacological effects and related mechanisms of in the treatment of CAD. The predicted results provide some theoretical support for BLEC or its important active ingredients to treat CAD.

Structure-based virtual screening of novel natural products as chalcone derivatives against SARS-CoV-2 Mpro

Coronavirus disease 2019 (COVID-19), which is caused by SARS-CoV-2, has spread quickly around the world, causing a global pandemic. It has infected more than 500 million people as of April 28, 2022. Much research has been reported to stop the virus from spreading, but there are currently no approved medicines to treat COVID-19. In this work, a dataset of 142 natural products collected from various medicinal plants was used to perform structure-based virtual screening (SBVS) through the combined application of molecular docking and molecular dynamics (MD) simulation methods. First, the dataset of compounds was optimized using the density functional theory (DFT) approach. The optimized compounds were then submitted to the first screening, which was done by the pKCM web server to look for drug-likeness and the PyRx to look for binding affinity. Among the 142 natural substances, 10 compounds were selected for docking validation. Compounds that interact with CYS145 and LEU141, the essential catalytic residues, as well as compounds with binding affinities less than −8.0 kcal/mol, are considered promising anti-SARS-CoV-2 drug candidates. The top-ranked compounds were then evaluated by MD simulations and MM-GBSA method. These results could help researchers come up with new natural compounds that could be used to treat SARS-CoV-2. Communicated by Ramaswamy H. Sarma

Molecular docking and experimental validation of the effect of ergothioneine on heat shock protein-70 following endurance exercise by Arabian stallions

BackgroundExercise-induced oxidative stress is a challenge in equine sports. This study aims at determining the effects of ergothioneine on heat shock protein-70 (HSP-70) following the stress of an endurance exercise of 30 km by Arabian stallions. Molecular docking was also done to investigate the interaction between the ligand ergothioneine and heat shock protein-70 using sulfogalactosylceramide and sulfogalactoglycerolipid as standards.The study involved a total of 18 clinically healthy stallions, with an average age of 6.7 ± 2.4 years and an average weight of 411.54 ± 12.46 kg. Only clinically healthy stallions were selected as subjects. The stallions were divided into two groups of nine stallions each. Group I (ERGX) was administered ergothioneine at a dose of 0.02 mg/kg once daily orally for four weeks while group II (ERGN) was not administered ergothioneine. The activities of the antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase were determined in the two groups before and post-exercise. The concentrations of malondialdehyde and HSP-70 were also determined.ResultsThe results obtained showed that the activities of the antioxidant enzymes and concentration of HSP-70 were higher (P < 0.05) in the ERGX group compared to the ERGN group. The concentration of malondialdehyde was however lower in the ERGX group. Following molecular docking, ergothioneine and the selected standards have common amino acids at the site of interaction with the target protein (HSP-70) suggesting that ergothioneine may have a modulatory effect on the synthesis of HSP-70.ConclusionThe results obtained indicated that ergothioneine modulated the synthesis of HSP-70 and the biomarkers of oxidative stress. It was therefore concluded that ergothioneine may be beneficial to horses subjected to endurance exercise.

Exploring the pharmacological mechanisms of Shuanghuanglian against T-cell acute lymphoblastic leukaemia through network pharmacology combined with molecular docking and experimental validation

Context Due to the poor prognosis of T-cell acute lymphoblastic leukaemia (T-ALL), there is an urgent need to identify safer and more cost-effective drugs. Objective This study evaluated the antitumour activity of Shuanghuanglian (SHL) on T-ALL cells and elucidated the mechanism. Materials and methods Jurkat and Molt4 cells were treated with SHL (0.1, 0.2 and 0.4 mg/mL) for 24 and 48 h. The controls were treated with RPMI 1640 containing 10% foetal bovine serum. Cell viability was evaluated through Cell Counting Kit-8 assay. Patterns of death and signalling pathway alterations caused by SHL were identified by network pharmacology combined with GO enrichment analysis and then were verified by Hoechst 33342 staining, Annexin V-FITC/PI staining and Western blotting. Interactions of the active ingredients with targets were analysed by molecular docking. Results The IC50 values of SHL in Jurkat and Molt4 cells were 0.30 ± 0.10 and 0.48 ± 0.07 mg/mL, respectively, at 24 h and 0.27 ± 0.05 and 0.30 ± 0.03 mg/mL at 48 h. In T-ALL, 117 target genes of SHL were mainly enriched in the apoptosis and NOTCH signalling pathways. SHL induced apoptosis was confirmed by Hoechst 33342 staining and flow cytometry. The protein levels of cleaved caspase-7 and cleaved PARP were significantly increased but those of cleaved NOTCH1 and MYC were reduced. The active ingredients of SHL can interact with γ-secretase. Discussion and conclusions: SHL induces apoptosis in T-ALL cells via the NOTCH1-MYC pathway and may be a potential drug for the treatment of T-ALL.

Multi-dimensional deep learning drives efficient discovery of novel neuroprotective peptides from walnut protein isolates.

Neurodegenerative diseases, such as Alzheimer's and Parkinson's, are multi-factor induced neurological disorders that require management from multiple pathologies. The peptides from natural proteins with diverse physiological activity can be candidates as multifunctional neuroprotective agents. However, traditional methods for screening neuroprotective peptides are not only time-consuming and laborious but also poorly accurate, which makes it difficult to effectively obtain the needed peptides. In this case, a multi-dimensional deep learning model called MiCNN-LSTM was proposed to screen for multifunctional neuroprotective peptides. Compared to other multi-dimensional algorithms, MiCNN-LSTM reached a higher accuracy value of 0.850. The MiCNN-LSTM was used to acquire candidate peptides from walnut protein hydrolysis. Following molecular docking, behavioral and biochemical index experimental validation eventually found 4 hexapeptides (EYVTLK, VFPTER, EPEVLR and ELEWER) demonstrating excellent multifunctional neuroprotective properties. Therein, EPEVLR performed the best and can be investigated in depth as a multifunctional neuroprotective agent. This strategy will greatly improve the efficiency of screening multifunctional bioactive peptides, and it will be beneficial for the development of food functional peptides.

Exploring Myocardial Ischemia-Reperfusion Injury Mechanism of Cinnamon by Network Pharmacology, Molecular Docking, and Experiment Validation.

Myocardial ischemia-reperfusion injury (MIRI) is a common complication of acute myocardial infarction that seriously endangers human health. Cinnamon, a traditional Chinese medicine, has been used to counteract MIRI as it has been shown to possess anti-inflammatory and antioxidant properties. To investigate the mechanisms of action of cinnamon in the treatment of MIRI, a deep learning-based network pharmacology method was established to predict potential active compounds and targets. The results of the network pharmacology showed that oleic acid, palmitic acid, beta-sitosterol, eugenol, taxifolin, and cinnamaldehyde were the main active compounds, and phosphatidylinositol-3 kinase (PI3K)/protein kinase B (Akt), mitogen-activated protein kinase (MAPK), interleukin (IL)-7, and hypoxia-inducible factor 1 (HIF-1) are promising signaling pathways. Further molecular docking tests revealed that these active compounds and targets exhibited good binding abilities. Finally, experimental validation using a zebrafish model demonstrated that taxifolin, the active compound of cinnamon, has a potential protective effect against MIRI.

Potential Mechanisms of Yiqi Jiedu Huayu Decoction in the Treatment of Diabetic Microvascular Complications Based on Network Analysis, Molecular Docking, and Experimental Validation.

Diabetic microvascular complications are the main causes of organ dysfunction and even death in diabetic patients. Our previous studies confirmed the beneficial effects of Yiqi Jiedu Huayu Decoction (YJHD) on diabetic cardiomyopathy and diabetic nephropathy. It is not clear whether YJHD can treat multiple diabetic microvascular complications including diabetic retinopathy, diabetic cardiomyopathy, and diabetic nephropathy through some common mechanisms. TCMSP, SymMap, STITCH, Swiss Target Prediction, and SEA databases were used to collect and analyze the components and targets of YJHD. GeneCards, DrugBank, DisGeNET, OMIM, and GEO databases were used to obtain target genes for diabetic retinopathy, diabetic cardiomyopathy, and diabetic nephropathy. The GO and KEGG enrichment analyses were performed on the DAVID and STRING platforms. Molecular docking was used to evaluate the binding sites and affinities of compounds and target proteins. Animal experiments were designed to validate the network pharmacology results. Through network pharmacological analysis, oxidative stress, inflammatory response, and apoptosis were identified as key pathological phenotypes for the treatment of diabetic microvascular complications with YJHD. In addition, JNK, p38, and ERK1/2 were predicted as key targets of YJHD in regulating the abovementioned pathological phenotypes. The results of animal experiments showed that YJHD could ameliorate retinal pathological changes of diabetes rats. YJHD can inhibit oxidative stress and inflammation in heart and kidney of diabetic rats. Molecular docking showed strong binding between compounds and JNK, p38, and ERK1/2. Berlambine may play a key role in the treatment process and is considered as a promising regulator of MAPK protein family. The regulatory effects of YJHD on JNK, p38, and ERK1/2 were demonstrated in animal experiments. YJHD may play a therapeutic role in diabetic microvascular complications by regulating oxidative stress, inflammatory response, and apoptosis. The regulation of JNK, p38, and ERK1/2 phosphorylation may be the key to its therapeutic effect.

Identification of NQO1 as a target of herbal drug agrimol B in hepatocellular carcinoma

Agrimol B is a small molecule isolated from traditional Chinese herbal medicine with a potential anti-cancer effect. However, the molecular target of agrimol B remains unclear. In this report, we found that agrimol B inhibits the growth of hepatocellular carcinoma (HCC) cells. A combination of network pharmacology strategy, bioinformatics analysis, molecular docking and target validation experiments was performed to identify and verify the protein targets of agrimol B in HCC. Bioinformatics analysis suggests that the activity of agrimol B against HCC was related to a cellular response to chemical stress and oxidative stress, folate biosynthesis, the complement and coagulation cascade and FoxO signaling pathway. We further identified 10 core targets through network pharmacology analysis. Among them, NAD(P)H: quinone dehydrogenase 1 (NQO1) was screened as the most promising target based on a molecular docking analysis. The interaction between agrimol B and NQO1 was corroborated by a cellular thermal shift assay. In addition, agrimol B inhibited the growth of HCC cells by decreasing NQO1 activity. Taken together, we identified NQO1 as a molecular target of agrimol B, which provides a new insight into the anti-cancer mechanism of agrimol B in HCC.

Green tea EGCG inhibits naïve CD4+ T cell division and progression in mice: An integration of network pharmacology, molecular docking and experimental validation

Dietary green tea epigallocatechin-3-gallate (EGCG) could attenuate experimental autoimmune encephalomyelitis via the modification of the balance of CD4+ T helper (Th) cells. Moreover, EGCG administration in vitro has a direct impact on the regulatory cytokines and differentiation of CD4+ T cells. Here, we aim to determine whether EGCG directly affects the cell division and progression in naive CD4+ T cells. We first investigate the effect of EGCG on naïve CD4+ T cell division and progression in vitro. An integrated analysis of network pharmacology and molecular docking was utilized to further identify the targets of EGCG for T cell-mediated autoimmune diseases and multiple sclerosis (MS). EGCG treatment prevented naïve CD4+ T cells from progressing through the cell cycle when stimulated with anti-CD3/CD28 antibodies. This was achieved by increasing the proportion of cells arrested in the G0/G1 phase by 8.6% and reducing DNA synthesis activity by 51% in the S phase. Furthermore, EGCG treatment inhibited the expression of cyclins (cyclin D1, cyclin D3, cyclin A, and cyclin B1) and CDKs (CDK2 and CDK6) during naïve CD4+ T cell activation in response to anti-CD3/CD28 stimulation. However, EGCG inhibited the decrease of P27Kip1 (CDKN1B) during naïve CD4+ T cell activation, whereas it inhibited the increase of P21Cip1 (CDKN1A) expression 48 h after mitogenic stimulation. The molecular docking analysis confirmed that these proteins (CD4, CCND1, and CDKN1A) are the primary targets for EGCG, T cell-mediated autoimmune diseases, and MS. Finally, target enrichment analysis indicated that EGCG may affect the cell cycle, T cell receptor signaling pathway, Th cell differentiation, and NF-κB signaling pathway. These findings reveal a crucial role of EGCG in the division and progression of CD4+ T cells, and underscore other potential targets of EGCG in T cell-mediated autoimmune diseases such as MS.

Analysis of Potential Mechanism of Herbal Formula Taohong Siwu Decoction against Vascular Dementia Based on Network Pharmacology and Molecular Docking.

Vascular dementia (VaD) is the second most prevalent dementia, which is attributable to neurovascular dysfunction. Currently, no approved pharmaceuticals are available. Taohong Siwu decoction (TSD) is a traditional Chinese medicine prescription with powerful antiapoptosis and anti-inflammatory properties. In this study, a network pharmacology approach together with molecular docking validation was used to explore the probable mechanism of action of TSD against VaD. A total of 44 active components, 202 potential targets of components, and 3,613 VaD-related targets including 161 intersecting were obtained. The potential chemical components including kaempferol, baicalein, beta-carotene, luteolin, quercetin, and beta-sitosterol involved in the inflammatory response, oxidative stress, and apoptosis might have potential therapeutic effects on the treatment of VaD. The potential core targets including AKT1, CASP3, IL1β, JUN, and TP53 associated with cell apoptosis and inflammatory might account for the essential therapeutic effects of TSD in VaD. The results indicated that TSD protected against VaD through multicomponent and multitarget modes. Though the detailed mechanism of action of various active ingredients needs to be further illustrated, TSD still showed a promising therapeutic agent for VaD due to its biological activity.

Uncovering ferroptosis in Parkinson's disease via bioinformatics and machine learning, and reversed deducing potential therapeutic natural products.

Objective: Ferroptosis, a novel form of cell death, is closely associated with excessive iron accumulated within the substantia nigra in Parkinson's disease (PD). Despite extensive research, the underlying molecular mechanisms driving ferroptosis in PD remain elusive. Here, we employed a bioinformatics and machine learning approach to predict the genes associated with ferroptosis in PD and investigate the interactions between natural products and their active ingredients with these genes. Methods: We comprehensively analyzed differentially expressed genes (DEGs) for ferroptosis associated with PD (PDFerDEGs) by pairing 3 datasets (GSE7621, GSE20146, and GSE202665) from the NCBI GEO database and the FerrDb V2 database. A machine learning approach was then used to screen PDFerDEGs for signature genes. We mined the interacted natural product components based on screened signature genes. Finally, we mapped a network combined with ingredients and signature genes, then carried out molecular docking validation of core ingredients and targets to uncover potential therapeutic targets and ingredients for PD. Results: We identified 109 PDFerDEGs that were significantly enriched in biological processes and KEGG pathways associated with ferroptosis (including iron ion homeostasis, iron ion transport and ferroptosis, etc.). We obtained 29 overlapping genes and identified 6 hub genes (TLR4, IL6, ADIPOQ, PTGS2, ATG7, and FADS2) by screening with two machine learning algorithms. Based on this, we screened 263 natural product components and subsequently mapped the "Overlapping Genes-Ingredients" network. According to the network, top 5 core active ingredients (quercetin, 17-beta-estradiol, glycerin, trans-resveratrol, and tocopherol) were molecularly docked to hub genes to reveal their potential role in the treatment of ferroptosis in PD. Conclusion: Our findings suggested that PDFerDEGs are associated with ferroptosis and play a role in the progression of PD. Taken together, core ingredients (quercetin, 17-beta-estradiol, glycerin, trans-resveratrol, and tocopherol) bind well to hub genes (TLR4, IL6, ADIPOQ, PTGS2, ATG7, and FADS2), highlighting novel biomarkers for PD.

Mechanism of Zuojin Pill in the treatment of anxiety disorder and Major depressive disorder based on network pharmacology and molecular docking validation

Mechanism of Zuojin Pill in the treatment of anxiety disorder and Major depressive disorder based on network pharmacology and molecular docking validation

Exploring the mechanism of MP gel against skin photoaging based on network pharmacology, molecular docking, and experimental validation.

Long-term and high exposure to UV radiation can lead to the development of skin photoaging diseases. Therefore, there is an ongoing need for more natural and safe drugs to prevent or treat skin photoaging diseases. The Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform database were used to collect the active compounds and corresponding targets of Cnidii Fructus, Arnebiae Radix, Angelicae Sinensis Radix, Poria, and Borneolum. The GeneCards database and the NCBI Gene database were used to collect the targets of skin photoaging diseases. The STRING database was used to construct a protein-protein interaction network formed by the intersecting targets of drugs and diseases. The Metascape database was applied for Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis of the targets. Molecular docking between active compounds and targets was verified by Autodock. After that, the skin photoaging model of mice was established and treated with MP gel. The skin characterization on the back of mice was observed, and the ameliorative effect of MP gel on skin photoaging was evaluated by histological and epidermal thickness assays. The MDA content and SOD activity were measured. Caspase-3 expression in mouse skin tissues was detected by immunohistochemistry, quantitative real-time polymerase chain reaction assay, and Western blot. The results of network pharmacology experiments showed that the natural drugs have multi-component, multi-target therapeutic disease characteristics. The results of animal studies showed that MP gel improved the health of photoaged skin, promoted skin structural integrity, had antioxidant properties and significantly inhibited caspase-3 expression. The experimental validation of the results of the preliminary network pharmacology analysis was carried out in animal experiments, which confirmed part of the mechanism of action of MP gel in the prevention and treatment of skin photoaging.

Effects and mechanisms of Xiaochaihu Tang against liver fibrosis: An integration of network pharmacology, molecular docking and experimental validation

Ethnopharmacological relevanceLiver fibrosis is a potentially harmful chronic liver disease caused by various etiologies. There is currently no specific drug for liver fibrosis. Xiaochaihu Tang (XCHT) is a traditional formula combined of seven herbs, which was first recorded in the Treatise on Febrile Diseases in Han Dynasty of ancient China. It is widely used in clinic to hepatic protection, analgesic, antipyretic and anti-inflammatory treatment. And it has been recommended for treating chronic hepatitis and chronic cholecystitis in the latest guidelines for the diagnosis and treatment of liver fibrosis with integrated traditional and western medicine. However, the underlying regulatory mechanisms remain elusive. Aim of the studyThis study aims to explore the therapeutic effects of XCHT on liver fibrosis and its underlying molecular mechanisms from the perspective of network pharmacology and experimental research. Materials and methodsCarbon tetrachloride (CCl4) induced and bile duct ligation (BDL) induced liver fibrosis models in mice were established to evaluate the anti-fibrosis effects of XCHT in vivo. Potential anti-fibrosis targets of XCHT were screened via network establishment. The underlying mechanisms were uncovered through GO and pathway enrichment analysis. Then, the core targets were identified from protein-protein interaction network by means of the Cytohubba plug-in of Cytoscape. Furthermore, two effective monomer components of XCHT were recognized by molecular docking. Moreover, the predicted components and pathways were verified by in vitro experiments. ResultsWhen treated with XCHT, liver fibrosis was alleviated in both mice models, showing as the improvement of liver function, the protection of hepatocytes, the inhibition of HSC activation and the reduction of hepatic collagen accumulation. 540 monomer components, 300 therapeutic targets, 109 signaling pathways, 246 GO biological processes, 77 GO cellular components, 107 GO molecular functions items and core targets were identified by network analysis. Then, 6-gingerol and baicalein were identified as the core components of anti-fibrosis effects of XCHT via leptin or Nrf2 signaling pathway. Furthermore, the experiment in vitro also validated the results. ConclusionsOur study suggests XCHT could alleviate liver fibrosis through multi-targets and multi-pathways; 6-gingerol and baicalein are its core components which may play an important role via leptin or Nrf2 signaling pathway.

Zeolite A/ZnCl2 nanoparticles as a catalyst for eco-friendly synthesis of pyrazole-1- carbothioamides with docking validation as Covid-19 main protease (MPRO) inhibitor

ABSTRACT. The synthesized Zeolite A/ZnCl2 nanoparticles via the hydrothermal route were characterized using FTIR, XRD, and SEM/EDAX techniques. The characterized catalyst was used for the eco-friendly synthesis of 4,5-dihydro-pyrazole-1-carbothioamide derivatives. Under solvent-free conditions, a multi-component reaction between hydrazine, isothiocyanate, and chalcone was done with a prepared nano-catalyst as an inexpensive, recyclable, easy-to-get, and nontoxic catalyst. The molecular docking study explained that dihydro-1-carbothioamide pyrazoles can be considered COVID-19 main protease (Mpro) inhibitors. In order to investigate the 3D conformation of the compounds that were synthesized, the density functional theory (DFT) was applied with a B3LYP hybrid functional and a 6-311++ G(d,p) basis set. This allowed us to investigate the compounds' electronic and charge transfer properties. In this series of compounds, the derivative 30d showed the lowest HOMO–LUMO energy gap.&#x0D; &#x0D; KEY WORDS: Zeolite A/ZnCl2 nanoparticles, Pyrazole-1-carbothioamides, Docking, XRD, SEM/EDX, HRTEM&#x0D; &#x0D; Bull. Chem. Soc. Ethiop. 2023, 37(2), 391-404. &#x0D; DOI: https://dx.doi.org/10.4314/bcse.v37i2.11

Molecular docking-based virtual screening: Challenges in hits identification for Anti-SARS-Cov-2 activity

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) requires finding new drugs or repurposing drugs for clinical use. Molecular docking belongs to structure-based drug design providing a fast method for identifying the hit compounds with antiviral activity against SARS-Cov-2. However, the weakness of the docking method is compounded by the limited crystallographic information and comparison drugs due to the novelty of this virus can present challenges in identifying hits of anti-SARS-Cov-2. In the current review, we highlighted several aspects, especially those related to the target structure, docking validation, and virtual hit selection, that need to be considered to obtain reliable docking results. Here, we discussed several cases pertaining to the issue highlighted and approaches that could be used to solve them.

Computational medicinal chemistry role in clinical pharmacy education: Ingavirin for coronavirus disease 2019 (COVID-19) discovery model.

Given the major shift to patient-directed education, novel coronavirus (nCoV) provides a live example on how medicinal chemistry could be a key science to teach pharmacy students. In this paper, students and clinical pharmacy practitioners will find a stepwise primer on identifying new potential nCoV treatments mechanistically modulated through angiotensin-converting enzyme 2 (ACE2). First, we identified the maximum common pharmacophore between carnosine and melatonin as background ACE2 inhibitors. Second, we performed a similarity search to spot out structures containing the pharmacophore. Third, molinspiration bioactivity scoring enabled us to promote one of the newly identified molecules as the best next candidate for nCoV. Preliminary docking in SwissDock and visualization through University of California San Francisco (UCSF) chimera made it possible to qualify one of them for further detailed docking and experimental validation. Ingavirin had the best docking results with full fitness of -3347.15 kcal/mol and estimated ΔG of -8.53 kcal/mol compared with melatonin (-6.57 kcal/mol) and carnosine (-6.29 kcal/mol). UCSF chimera showed viral spike protein elements binding to ACE2 retained in the best ingavirin pose in SwissDock at 1.75 Angstroms. Ingavirin has a promising inhibitory potential to host (ACE2 and nCoV spike protein) recognition, and hence could offer the next best mitigating effect against the current coronavirus disease (COVID-19) pandemic.

Mechanism of Epimedium intervention in heart failure based on network pharmacology and molecular docking technology.

To analyze the pharmacological mechanism of Epimedium in regulating heart failure (HF) based on the network pharmacology method, and to provide a reference for the clinical application of Epimedium in treating HF. Obtaining the main active ingredients and their targets of Epimedium through TCMSP (Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform) database. Access to major HF targets through Genecards, OMIM, PharmGKB, Therapeutic Target Database, Drug Bank database. Protein interaction analysis using String platform and construction of PPI network. Subsequently, Cytoscape software was used to construct the "Epimedium active ingredient-heart failure target" network. Finally, the molecular docking is verified through the Systems Dock Web Site. The core active ingredients of Epimedium to regulate HF are quercetin, luteolin, kaempferol, etc. The core targets are JUN, MYC, TP53, HIF1A, ESR1, RELA, MAPK1, etc. Molecular docking validation showed better binding activity of the major targets of HF to the core components of Epimedium. The biological pathways that Epimedium regulates HF mainly act on lipid and atherosclerotic pathways, PI3K-Akt signaling pathway, and chemoattractant-receptor activation. And its molecular functions are mainly DNA-binding transcription factor binding, RNA polymerase II-specific DNA-binding transcription factor binding, and neurotransmitter receptor activity. This study reveals the multi-component, multi-target and multi-pathway mechanism of action of Epimedium in regulating mental failure, and provides a basis for the clinical development and utilization of Epimedium to intervene in HF.

Network pharmacology and molecular docking-based analysis of protective mechanism of MLIF in ischemic stroke.

This study aimed to evaluate the potential mechanism by which Monocyte locomotion inhibitory factor (MLIF) improves the outcome of ischemic stroke (IS) inflammatory injury. Potential MLIF-related targets were predicted using Swiss TargetPrediction and PharmMapper, while IS-related targets were found from GeneCards, PharmGKB, and Therapeutic Target Database (TTD). After obtaining the intersection from these two datasets, the Search Tool for Retrieval of Interacting Genes/Protein (STRING11.0) database was used to analyze the protein-protein interaction (PPI) network of the intersection and candidate genes for MLIF treatment of IS. The candidate genes were imported into the Metascape database for Gene Ontology (GO) functional analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. The top 20 core genes and the "MLIF-target-pathway" network were mapped using the Cytoscape3.9.1. Using AutoDock Vina1.1.2, the molecular docking validation of the hub targets and MLIF was carried out. In the experimental part, transient middle cerebral artery occlusion (tMCAO) and oxygen and glucose deprivation (OGD) models were used to evaluate the protective efficacy of MLIF and the expression of inflammatory cytokines and the putative targets. MLIF was expected to have an effect on 370 targets. When these targets were intersected with 1,289 targets for ischemic stroke, 119 candidate therapeutic targets were found. The key enriched pathways were PI3K-Akt signaling pathway and MAPK signaling pathway, etc. The GO analysis yielded 1,677 GO entries (P < 0.01), such as hormone stimulation, inflammatory response, etc. The top 20 core genes included AKT1, EGFR, IGF1, MAPK1, MAPK10, MAPK14, etc. The result of molecular docking demonstrated that MLIF had the strong binding capability to JNK (MAPK10). The in vitro and in vivo studies also confirmed that MLIF protected against IS by lowering JNK (MAPK10) and AP-1 levels and decreasing pro-inflammatory cytokines (IL-1, IL-6). MLIF may exert a cerebral protective effect by inhibiting the inflammatory response through suppressing the JNK/AP-1 signaling pathway.