Single-coordinate-driving method for molecular docking: application to modeling of guest inclusion in cyclodextrin

Although the antiallergic properties of compounds such as CAPE, Melatonin, Curcumin, and Vitamin C have been poorly discussed by experimental studies, the antiallergic properties of these famous molecules have never been discussed with calculations. The histamine-1 receptor (H1R) belongs to the family of rhodopsin-like G-protein-coupled receptors expressed in cells that mediate allergies and other pathophysiological diseases. In this study, pharmacological activities of FDA-approved second generation H1 antihistamines (Levocetirizine, desloratadine and fexofenadine) and molecules such as CAPE, Melatonin, Curcumin, Vitamin C, ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) profiles, density functional theory (DFT), molecular docking, biological targets and activities were compared by calculating. Since drug development is an extremely risky, costly and time-consuming process, the data obtained in this study will facilitate and guide future studies. It will also enable researchers to focus on the most promising compounds, providing an effective design strategy. Their pharmacological activity was carried out using computer-based computational techniques including DFT, molecular docking, ADMET analysis, biological targeting, and activity methods. The best binding sites of Desloratadine, Levocetirizine, Fexofenadine, CAPE, Quercetin, Melatonin, curcumin, Vitamin C ligands to Desmoglein 1, Human Histamine H1 receptor, IgE and IL13 protons were determined by molecular docking method and binding energy and interaction states were analyzed. Fexofenadine and Quercetin ligand showed the most effective binding affinity. Melatonin had the best Caco-2 permeability PPB values of Quercetin, CAPE and Curcumin were at optimal levels. On the OATP1B1 and OATP1B3 of curcumin and CAPE, Quercetin was found to have strong inhibition effects on BCRP. Melatonin and CAPE were found to have the highest inhibition values on CYP1A2, while CAPE had the highest inhibition values on CYP2C19 and CYP2C9. Vitamin C and Quercetin were found to be safer in terms of cardiac toxicity and mutagenic risks, while Desloratadine and Levocetirizine carried high risks of neurotoxicity and hematotoxicity, while CAPE was noted for its high enzyme inhibitory activities and low toxicity profiles, while the hERG blockade, DILI, and cytotoxicity values of other compounds pointed to various safety concerns. This study demonstrated the potential of machine learning methods in understanding and discovering H1 receptor blockers. The results obtained provide important clues in the development of important strategies in the clinical use of H1 receptor blockers. In the light of these data, CAPE and Quercetin are remarkable molecules.

Hydrazone derivatives possess potential antitumor activities based on modulation of the iron metabolism in cancer cell. A novel hydrazone, N'-(2,4-dimethoxybenzylidene)-2-hydroxybenzohydrazide (DBH), has been synthesized and characterized, which is an analogue of 311 possessing potent anticancer activity. The interactions between DBH and bovine serum albumin (BSA) have been investigated systematically by fluorescence, molecular docking, circular dichroism (CD), UV-vis absorption, and electrochemical impedance spectroscopy (EIS) methods under physiological conditions. The fluorescence quenching observed is attributed to the formation of a complex between BSA and DBH, and the reverse temperature effect of the fluorescence quenching has been found and discussed. The primary binding pattern is determined by hydrophobic interaction occurring in Sudlow's site I of BSA. DBH could slightly change the secondary structure and induce unfolding of the polypeptides of protein. An average binding distance of ~4.0 nm has been determined on the basis of the Förster resonance energy theory (FRET). The effects of iron on the system of DBH-BSA have also been investigated. It is found that iron could compete against BSA to bind DBH. All of these results are supported by a docking study using a BSA crystal model. It is shown that DBH can efficiently bind with BSA and be transported to the focuses needed. Subsequent antitumor test and detailed anticancer mechanism are undergoing in our lab.

Molecular docking methods were applied to simulate the coupling of a set of nineteen acyl homoserine lactone analogs into the binding site of the transcriptional receptor LasR. The best pose of each ligand was explored and a qualitative analysis of the possible interactions present in the complex was performed. From the results of the protein-ligand complex analysis, it was found that residues Tyr-64 and Tyr-47 are involved in important interactions, which mainly determine the antagonistic activity of the AHL analogues considered for this study. The effect of different substituents on the aromatic ring, the common structure to all ligands, was also evaluated focusing on how the interaction with the two previously mentioned tyrosine residues was affected. Electrostatic potential map calculations based on the electron density and the van der Waals radii were performed on all ligands to graphically aid in the explanation of the variation of charge density on their structures when the substituent on the aromatic ring is changed through the elements of the halogen group series. A quantitative approach was also considered and for that purpose the ONIOM method was performed to estimate the energy change in the different ligand-receptor complex regions. Those energy values were tested for their relationship with the corresponding IC50 in order to establish if there is any correlation between energy changes in the selected regions and the biological activity. The results obtained using the two approaches may contribute to the field of quorum sensing active molecules; the docking analysis revealed the role of some binding site residues involved in the formation of a halogen bridge with ligands. These interactions have been demonstrated to be responsible for the interruption of the signal propagation needed for the quorum sensing circuit. Using the other approach, the structure-activity relationship (SAR) analysis, it was possible to establish which structural characteristics and chemical requirements are necessary to classify a compound as a possible agonist or antagonist against the LasR binding site.

The objective in molecular docking is to determine the best binding mode of two molecules in silico. A common applica- tion of molecular docking is in drug discovery where a large number of ligands are docked against a protein to identify potential drug candidates. This is a computationally in- tensive problem especially if flexibility of the molecules are taken into account. In this paper we show how MolDock, which is a high accuracy method for flexible molecular dock- ing using a variant of differential evolution, can be paral- lelised on both CPU and GPU. The methods presented for parallelising the workload result in an average speedup of 3.9x on a 4-core CPU and 27.4x on a comparable CUDA enabled GPU when docking 133 ligands of different sizes. Furthermore, the presented parallelisation schemes are gen- erally applicable and can easily be adapted to other common flexible docking methods.

Our work investigates the interaction of synthesized graphene with the SARS-CoV-2 virus using molecular docking and molecular dynamics (MD) simulation method. The layer dependent inhibitory effect of graphene nanosheets on spike receptor-binding domain of 6LZG, complexed with host receptor i.e. angiotensin-converting enzyme 2 (ACE2) of SARS-CoV-2 was investigated through computational study. Graphene sample was synthesized using mechanical exfoliation with shear stress and its mechanism of inhibition towards the SARS-CoV-2 virus was explored by molecular docking and molecular dynamics (MD) simulation method. The thermodynamics study for the free binding energy of graphene towards the SARS-CoV-2 virus was analyzed. The binding energy of graphene towards the virus increased with an increasing number of layers. It shows the highest affinity of −17.5 Kcal/mol in molecular docking while ΔGbinding is in the order of −28.01 ± 0.04 5 Kcal/mol for the seven-layers structure. The increase in carbon layers is associated with an increasing number of edge sp3 –type carbon, providing greater curvature, further increase the surface reactivity responsible for high binding efficiency. The MD simulation data reveals the high inhibition efficiency of the synthesized graphene towards SARS-CoV-2 virus which would help to design future in-vitro studies. The graphene system could find potential applications in personal protective equipment and diagnostic kits. Communicated by Ramaswamy H. Sarma

This study explores the potential mechanisms of Liujunzi Tang combined with Suanzaoren Tang in treating lung cancer with insomnia through network pharmacology and molecular docking methods. In the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database, each single herb in the formula of Liujunzi Tang combined with Suanzaoren Tang was used as a search term, with repeated traditional Chinese medicines (TCMs) searched only once. Oral bioavailability (OB) ≥ 30% and drug-likeness (DL) ≥ 0.18 were set as screening criteria to obtain active components and targets of TCM. Disease-related targets for lung cancer with insomnia were obtained from the Gene Cards database, OMIM database, and PharmGKB database. The disease targets and drug effective component targets were intersected, and a disease-component intersection Venn diagram was drawn. The common intersection targets were imported into the DAVID database for Kyoto Encyclopedia of Genes and Genomics (KEGG) pathway and gene ontology (GO) function enrichment analysis, and molecular docking was performed to verify the affinity of active components with key targets. A total of 185 effective active components and 241 targets were obtained for Liujunzi Tang combined with Suanzaoren Tang. A total of 4290 disease targets were obtained from 3 disease databases. After removing 138 duplicate targets, a total of 4152 disease targets were obtained. The intersection of component targets and disease targets yielded 120 common targets. KEGG pathway enrichment was found in lipid and atherosclerosis, AGE-RAGE signaling pathway in diabetes complications, Kaposi sarcoma-related herpes virus infection, and other signaling pathways. Molecular docking showed that the core components naringenin had good binding activity with AKT1, quercetin and ginsenoside Rh2 with IL1B, and other targets. Through network pharmacology and molecular docking methods, it was explored that Liujunzi Tang combined with Suanzaoren Tang may treat lung cancer with insomnia through multiple components, multiple targets, and multiple pathways, regulating cancer pathways, lipid and atherosclerosis, and other signaling pathways, providing new ideas for the treatment of lung cancer with insomnia.

Characterization of interaction between isoliquiritigenin and bovine serum albumin: Spectroscopic and molecular docking methods

Atherosclerosis is a chronic inflammatory disease that begins with endothelial dysfunction, it caused fat accumulation and plaque growth in the inner arteries walls. Endothelial dysfunction will activate the Mitogen Activated Protein Kinase (MAPK) pathway involving ERK1, ERK2, JNK1, JNK2, and p38MAPK proteins, as well as the Nuclear Factor Kappa B (NF-kB) pathway involving IKK proteins. Terpinen-4-ol is constituent found in the bangle rhizome. The purpose of this study were to determine the affinity and mechanisms of terpinen-4-ol against ERK1, ERK2, JNK1, JNK2, and p38MAPK proteins as anti-inflammatory in atherosclerosis performed using molecular docking method. The study was conducted exploratively with several steps such as preparation and optimization of terpinen-4-ol structure, preparation of 3D ERK1, ERK2, JNK1, JNK2, and p38MAPK proteins, validation method of molecular docking, and docking terpinen-4-ol in these proteins. The docking result are assessed from the binding energy and hydrogen bonds formed between terpinen-4-ol and proteins. The smaller value of binding energy terpinen-4-ol with target proteins showed the complex that form more stable. The result showed that terpinen-4-ol and has activity in inhibiting the inflammatory process because it is able to disturb ERK1, ERK2, JNK1, JNK2, and p38MAPK proteins with respective bond energy values -5,12; -5,24; -5,08; -5,88; and -4,99 Kcal/mol. The molecular mechanism in inhibiting the activity of ERK1, ERK2, JNK1, JNK2, and p38MAPK proteins is through the formation of hydrogen bonds in these proteins. These results show that terpinen-4-ol have the potential to inhibit inflammatory process and the formation of atherosclerotic plaque can be obstructed.
 Keywords : atherosclerosis, terpinen-4-ol, molecular docking, in silico

Background: HER2-positive breast cancer is a breast cancer that tests positive with human epidermal growth factor receptor 2 (HER2). Human Epidermal Growth Factor Receptor-2 (HER2) promotes the proliferation of breast cancers cells. This research aimed to find the bioactive compounds from Allium sativum for inhibiting HER2 enzyme by using molecular docking method. Materials and method: The protein tyrosin kinase HER2 structure was obtained from Protein Data Bank. Compounds were collected from previous publications of Allium sativum and these structures were retrieved from PubChem database. Molecular docking was done by Autodock vina software. Lipinski’s rule of 5 is used to compare compounds with drug-like and non-drug-like properties. Pharmacokinetic parameters of potential compounds were evaluated using the pkCSM tool. Results: Based on previous publication of Allium sativum, we have collected 55 compounds. The results showed that 2 compounds have HER2 inhibitory activity stronger than the reference compounds including biochanin A và cyanidin 3-malonylglucoside. The Lipinski’s rule of Five showed that these two compounds had propietary drug-likenesss. Moreover, predict ADMET of these compounds was also analyzed. Conclusion: Therefore, biochanin A and cyanidin 3-malonylglucoside may be potential natural product compounds for HER2-positive breast cancer treatment.
 Keywords:
 Allium sativum, tyrosin kinase HER2, breast cancer HER2 positive, in silico, molecular docking.
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IntroductionThe objective of this study is to investigate the shear bonding strength of a glycoalkaloid, also a novel matrix metalloproteinase enzyme known as α-tomatine, on two different surfaces of dentin (sound & caries-affected) and its efficacy against cariogenic microorganisms using in vitro and in silico methods.MethodsThe effect of a-tomatine at different concentrations (0.75 / 1 / 1.5 µM) on shear bonding strength in caries-affected and sound dentin was also investigated (n = 10; each per subgroup). The analysis of shear bonding and failure tests was conducted after a 24-hour storage period. Fracture surfaces were examined under a scanning electron microscope. A stock solution 3 mM of a-tomatine was prepared for antimicrobial evaluation. Antimicrobial activities of the agents against Streptococcus mutans ATCC 25175, Lactobacillus casei ATCC 4646, and Candida albicans ATCC 10231 standard strains were investigated by microdilution method. In addition, through the method of molecular docking and dynamic analysis, the affinity of a-tomatine for certain enzymes of these microorganisms was examined.ResultsThe pretreatment agent and dentin type significantly influenced shear bonding strength values (p < 0.05). As the molarity of a-tomatine increased, the bonding value decreased in sound dentin, while the opposite was true in caries-affected dentin. According to molecular docking and dynamic analysis, the highest affinity was observed in L. casei’s signaling protein. Microdilution assays revealed a-tomatine to exhibit fungicidal activity against C. albicans and bacteriostatic effects against S. mutans. No antimicrobial effect was observed on L. casei.Conclusiona-tomatine demonstrates a positive impact by serving as both a pretreatment agent for bonding strength and an inhibitor against certain cariogenic microorganisms.

Exploring the active compounds of traditional Mongolian medicine in intervention of novel coronavirus (COVID-19) based on molecular docking method.

Background: Chai-Ling decoction (CLD), derived from a modification of Xiao-Chai-Hu (XCH) decoction and Wu-Ling-San (WLS) decoction, has been used to treat the early-stage of coronavirus disease 2019 (COVID-19). However, the mechanisms of CLD in COVID-19 remain unknown. In this study, the potential mechanisms of CLD in COVID-19 were preliminarily investigated based on network pharmacology and molecular docking method. Methods: Initially, the active components and targets of CLD were screened based on Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform and PharmMapper database. The targets of COVID-19 were obtained from GeneCards database. The protein-protein interaction network was established using STRING database to analyze the key targets. Gene Oncology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes analysis were also conducted to evaluate the pathways related to the targets of CLD on COVID-19. Moreover, the compound-target-pathway network was established using Cytoscape 3.2.7. Subsequently, the molecular docking method was performed to select the active compounds with high binding affinity on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and angiotensin-converting enzyme 2 (ACE2), which is the key target of SARS-CoV-2 in entering target cells. The possible binding sites were also visualized by a three-dimensional graph. Results: Network pharmacology analysis showed that there were 106 active components and 160 targets of CLD. Additionally, 251 targets related to COVID-19 were identified, and 24 candidates of CLD on COVID-19 were selected. A total of 283 GO terms of CLD on COVID-19 were identified, and 181 pathways were screened based on GO and Kyoto Encyclopedia of Genes and Genomes analyses. CLD might alleviate the inflammatory response and improve lung injury to treat COVID-19 through interleukin 17 signaling, T helper cell 17 differentiation, tumor necrosis factor signaling, and hypoxia inducible factor-1 signaling. Besides, molecular docking indicated that beta-sitosterol, kaempferol, and stigmasterol were the top three candidates in CLD with the highest affinity to SARS-CoV-2 and ACE2. Conclusion: Our study identifies the potential mechanisms of CLD on COVID-19 and beta-sitosterol, kaempferol, and stigmasterol may be the key compounds that exert antiviral effects against SARS-CoV-2.

Fufang Honghua Buji (FHB) granules, have proven efficacy against vitiligo in long-term clinical practice. However, its major active chemical components and molecular mechanisms of action remain unknown. The purpose of this study was to confirm the molecular mechanism of FHB's therapeutic effect on vitiligo utilizing network pharmacology, molecular docking, and molecular dynamics simulation prediction, as well as experimental verification. Traditional Chinese Medicine Systems Pharmacology (TCMSP) and HERB databases were used to obtain the chemical composition and action targets of FHB. Online Mendelian Inheritance in Man (OMIM), DrugBank, DisGeNET, GeneCards, and Therapeutic Target Database (TTD) databases were applied to screen for vitiligo-related targets. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed through the Matascape database. Molecular docking and dynamics simulation methods were for the analysis of the binding sites and binding energies between the FHB's active components and the targets. Finally, a vitiligo mouse model was created, and the therapeutic effect and molecular mechanism of action of FHB were validated using enzyme linked immunosorbent assay (ELISA), western blot (WB), and quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Additionally, hematoxylin-eosin staining (HE) and blood biochemical assays were conducted to assess the biosafety of FHB. The screening of chemical composition and targets suggested that 94 genetic targets of FHB were associated with vitiligo. The bioinformatics analysis suggested that luteolin, quercetin, and wogonin may be major active components, and nuclear factor-kappa B p65 subunit (RELA), signal transducer, and activator of transcription (STAT) 3 and RAC-alpha serine/threonine-protein kinase (AKT) 1 may be potential targets of FHB-vitiligo therapy. Molecular docking and dynamics simulation further demonstrated that luteolin, quercetin, and wogonin all bound best to STAT3. Through experimental verification, FHB has been demonstrated to alleviate the pathogenic characteristics of vitiligo mice, suppress the JAK-STAT signaling pathway, reduce inflammation, and increase melanogenesis. The in vivo safety evaluation experiments also demonstrated the non-toxicity of FHB. FHB exerts anti-inflammatory and melanogenesis-promoting effects via the effect of multi-component on multi-target, among which the JAK-STAT pathway is a validated FHB-vitiligo target, providing new ideas and clues for the development of vitiligo therapy.

Spectroscopic and theoretical investigation of oxali–palladium interactions with β-lactoglobulin

Methyl parathion and its degradation product p-nitrophenol have become important environmental problems due to their high toxicity and persistence. In this study, the toxicological mechanism of methyl parathion and p-nitrophenol exposure increasing the risk of depression was studied through network toxicology and molecular docking methods. Based on the comprehensive analysis of PharmMapper, STITCH, SwissTargetPrediction, Similarity ensemble approach (SEA) and GeneCards databases, 35 potential targets related to methyl parathion and p-nitrophenol exposure were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed the key pathways of methyl parathion and p-nitrophenol affecting depression, included insulin-like growth factor receptor signaling pathway, serotonergic synapse. Combined with protein-protein interaction (PPI) network analysis and KEGG analysis, 14 core targets of depression related to methyl parathion and p-nitrophenol were screened out. Further, the targets MAP2K1 and APP with the highest binding scores with methyl parathion and p-nitrophenol, respectively, were screened by DeepPurpose, and the common target HRAS for molecular docking was determined. The molecular docking analysis further verified that methyl parathion and p-nitrophenol may have good binding activity with HRAS. This study provides valuable insights for understanding the molecular mechanism of environmental pollutants methyl parathion and p-nitrophenol affecting depression, and provides a theoretical basis for understanding the health risks of methyl parathion and p-nitrophenol.