Toward Unveiling Putative Binding Sites of Interleukin-33: Insights from Mixed-Solvent Molecular Dynamics Simulations of the Interleukin-1 Family.

The interleukin (IL)-1 family is a major proinflammatory cytokine family, ranging from the well-studied IL-1s to the most recently discovered IL-33. As a new focus, IL-33 has attracted extensive research for its crucial immunoregulatory roles, leading to the development of notable monoclonal antibodies as clinical candidates. Efforts to develop small molecules disrupting IL-33/ST2 interaction remain highly desired but encounter challenges due to the shallow and featureless interfaces. The information from relative cytokines has shown that traditional binding site identification methods still struggle in mapping cryptic sites, necessitating dynamic approaches to uncover druggable pockets on IL-33. Here, we employed mixed-solvent molecular dynamics (MixMD) simulations with diverse-property probes to map the hotspots of IL-33 and identify potential binding sites. The protocol was first validated using the known binding sites of two IL-1 family members and then applied to the structure of IL-33. Our simulations revealed several binding sites and proposed side-chain rearrangements essential for the binding of a known inhibitor, aligning well with experimental NMR findings. Further microsecond-time scale simulations of this IL-33-protein complex unveiled distinct binding modes with varying occurrences. These results could facilitate future efforts in developing ligands to target challenging flexible pockets of IL-33 and IL-1 family cytokines in general.

Valorization of the treatment of antibiotic and organic contents generated from an in-situ-RAS-like shrimp farming pond by using graphene-quantum-dots deposited graphitic carbon nitride photocatalysts.

In this study, we investigated the possibility of a photocatalytic system that uses graphene-quantum-dot (GQD)-deposited graphitic carbon nitride (g-C3N4) to treat tetracycline (TC) and other organic compounds generated from an in-situ-recirculatory-aquaculture-system (RAS)-like shrimp farming pond. GQDs were successfully deposited on the exfoliated g-C3N4 base through a hydrothermal treatment. The results showed that the incorporation of GQDs into the g-C3N4 enhanced its porosity without aggregating its mesoporous structure. The GQDs-deposited g-C3N4 photocatalysts revealed sheet-like structures with nanopores on their surface that facilitate photocatalysis. More than 90% of the TC was removed by the photocatalysts under UV-LED irradiation. Low loadings of GQDs over g-C3N4 resulted in a faster and more effective photocatalysis of TC, mainly driven by.O2- radicals. The photocatalysts were also applicable in the degradation of organic compounds with 27% of the total organic compounds (TOC) being removed from the wastewater of a RAS-like shrimp farming pond.

Response surface methodology for aqueous two-phase system extraction: An unprecedented approach for the specific flavonoid-rich extraction of Houttuynia cordata Thunb. leaves towards acne treatment.

Background: Houttuynia cordata Thunb. has long been widely used as a daily vegetable and traditional medicine. The flavonoid component of H. cordata has plenty of pharmacological effects, such as antibacterial, anti-inflammatory, and antioxidant. In this study, we applied the aqueous two-phase system (ATPS) combined with ultrasonic extraction for extracting H. cordata leaves. Methods: We optimized the extraction process to improve the extraction efficiency of the two flavonoids, hyperin and quercitrin, by Surface Method Response - Central Composite Design (RSM-CCD). Next, we investigated the antibacterial ability of H. cordata ATPS extract from optimal conditions against two bacterial strains, Cutibacterium acnes and Staphylococcus epidermidis. Results: The results showed that using 10% (NH4)2SO4 and 35% ethanol for ATPS extraction resulted in the highest hyperin and quercitrin contents. From the RSM-CCD results, the optimal extraction conditions were determined to be ultrasonic extraction at 50 °C for 30 min, giving results consistent with the predicted model and obtaining hyperin and quercitrin contents at 1.5681 ± 0.0114 and 4.6225 ± 0.0327 mg/g, respectively.Furthermore, ATPS extract has excellent antibacterial activity with a minimum inhibitory concentration (MIC) value of 250 µg/mL on both C. acnes and S. epidermidis. This MIC is significantly lower than the H. cordata ultrasound-assisted (UA) extract, with MICs of 1500.00 and 156.25 µg/mL on C. acnes and S. epidermidis, respectively. In addition, the results from the disk diffusion assay also showed that ATPS extraction has superior internal antibacterial activity with a zone of inhibition diameter at 250 µg/mL of 8.67 ± 1.15 and 5.00 ± 2.00 mm. Meanwhile, those of UA extract on C. acnes is 5.67 ± 1.53 mm (at 1500 µg/mL), and on S. epidermidis is 1.34 ± 0.58 mm (at 156.25 µg/mL). Conclusion: To sum up, our research highlights the potential of H. cordata ATPS extracts as the starting material for topical preparations for effectively treating acne.

Prevalence and drug susceptibility of clinical Candida species in nasopharyngeal cancer patients in Vietnam.

In the nature, Candida species are normal inhabitants and can be observed in a wide variety of vertebrates. In humans, especially for cancer patients who fall prey to opportunistic pathogens, this group of susceptible multi-drug resistant and biofilm-forming yeasts, are among the commonest ones. In this study, Candida species in 76 oral lesion samples from Vietnamese nasopharyngeal-cancer patients were isolated, morphologically identified using CHROMagar™, germ tube formation, and chlamydospore formation tests, and molecularly confirmed by PCR-RFLP. The drug susceptibility of these isolates was then tested, and the gene ERG11 was DNA sequenced to investigate the mechanism of resistance. The results showed that Candida albicans remained the most prevalent species (63.16% of the cases), followed by Candida glabrata, Candida tropicalis, and Candida krusei. The rates of resistance of non-albicans Candida for tested drugs were 85.71%, 53.57%, and 57.14% to fluconazole, clotrimazole, and miconazole, respectively. Although the drug-resistance rate of Candida albicans was lower than that of non-albicans Candida, it was higher than expected, suggesting an emerging drug-resistance phenomenon. Furthermore, ERG11 DNA sequencing revealed different mutations (especially K128T), implying the presence of multiple resistance mechanisms. Altogether, the results indicate an alarming drug-resistance situation in Candida species in Vietnamese cancer patients and emphasize the importance of species identification and their drug susceptibility prior to treatment.

Computational assessment and in vitro test of phytochemicals of Usnea aciculifera as potential inhibitors of Escherichia coli efflux pump AcrB.

Lichens produce secondary metabolites that have many pharmaceutical activities such as antimicrobial, antioxidant, antiviral, anticancer, antigenotoxic, anti-inflammatory, analgesic and antipyretic activities. However, there is limited research on their efflux pump inhibitory activities. Twelve phytochemicals were isolated from Usnea aciculifera, and their activity of AcrAB-TolC efflux pump inhibition was evaluated. Four potential compounds, which are diffractaic acid (2), 8' -O- methylstictic acid (5), 3-hydroxy-4-(methoxycarbonyl)-2,5-dimethylphenyl 2,4-dimethoxy-3,6-dimethylbenzoate (8) and 3-hydroxy-4-(methoxycarbonyl)-2,5-dimethylphenyl 2-hydroxy-4-methoxy-3,6-dimethylbenzoate (9), were found by virtual screening using pharmacophore and 2D-QSAR model. Compound 8 exhibited AcrB inhibition activity in vitro with an accumulation H33342 percentage compared with untreated control of 202% at a concentration of 50 µM and increased the antibacterial activity of levofloxacin by four-fold at a concentration of 200 µM. By molecular docking and molecular dynamics (MD) simulation, the binding affinity of depside and depsidone derivatives to AcrB was also clarified. Despite the poor docking score to the AcrB binding site, compound 8 was the most stable among the four complexes at 20 ns of MD simulation. The analysis of long MD at 100 ns indicated that compound 8 interacts strongly with the residues in the distal pocket, creating a stable complex with ΔGbind of -31.51 kcal.mol-1. According to the ADMETlab 2.0 web server's predictions of pharmacokinetics and toxicities, compound 8 has the potential for drug development.Communicated by Ramaswamy H. Sarma.

Identification of efflux pump inhibitors for Pseudomonas aeruginosa MexAB-OprM via ligand-based pharmacophores, 2D-QSAR, molecular docking, and molecular dynamics approaches.

Efflux pumps have been reported as one of the significant mechanisms by which bacteria evade the effects of multiple antibiotics. The tripartite efflux pump MexAB-OprM in Pseudomonas aeruginosa is one of the most significant multidrug efflux systems due to its broad resistance to antibiotics such as chloramphenicol, fluoroquinolones, lipophilic ß-lactam antibiotics, nalidixic acid, novobiocin, rifampicin, and tetracycline. A promising strategy to overcome this resistance mechanism is to combine antibiotics with efflux pump inhibitors (EPIs), which can increase their intracellular concentration to enhance their biological activities. Based on 143 EPIs with chemically diverse skeletons, the 3D pharmacophore and 2D-QSAR modelings were developed and used for the virtual screening on 9.2 million compounds including ZINC15, DrugBank, and Traditional Chinese Medicine databases to identify new EPIs. The molecular docking was also performed to evaluate the binding affinity of potential EPIs to the distal-binding pocket of MexB and resulted in 611 potential EPIs. The structure-activity relationship analyses suggested that nitrogen heterocyclic compounds, piperazine and pyridine scaffolds, and amide derivatives are the most favorable chemically features for MexAB inhibitory activities. The results from molecular dynamics analysis in 100 ns indicated that ZINC009296881 and ZINC009200074 were the most potential MexB inhibitors with strong binding affinity to the distal pocket and MM/GBSA ∆Gbind values of - 38.97 and - 30.19 kcal mol-1, respectively. The predicted pharmacokinetic properties and toxicity of these compounds indicated their potential oral drugs. Multistep virtual screening of EPIs for MexAB-OprM, efflux pump multidrug resistant of P. aeruginosa.

RP-HPLC-Based Flavonoid Profiling Accompanied with Multivariate Analysis: An Efficient Approach for Quality Assessment of Houttuynia cordata Thunb Leaves and Their Commercial Products.

Chemical profiling for quality monitoring and evaluation of medicinal plants is gaining attention. This study aims to develop an HPLC method followed by multivariate analysis to obtain HPLC profiles of five specific flavonoids, including rutin (1), hyperin (2), isoquercitrin (3), quercitrin (4), and quercetin (5) from Houttuynia cordata leaves and powder products and assess the quality of H. cordata samples. Eventually, we successfully established HPLC-based flavonoid profiles and quantified the contents of 32 H. cordata fresh leave samples and four powder products. The study also quantified the contents of those five essential flavonoids using an optimized RP-HPLC method. Peak areas of samples were then investigated with principal component analysis (PCA) and hierarchical cluster analysis (HCA) to evaluate the similarity and variance. Principal components in PCA strongly influenced by hyperin and quercetin showed that the samples were clustered into subgroups, demonstrating H. cordata samples' quality. The results of HCA showed the similarity and divided the samples into seven subgroups. In conclusion, we have successfully developed a practical methodology that combined the HPLC-based flavonoid profiling and multivariate analysis for the quantification and quality control of H. cordata samples from fresh leaves and powder products. For further studies, we will consider various environmental factors, including climate and soil factors, to investigate their effects on the flavonoid contents of H. cordata.

Targeting Olokizumab-Interleukin 6 interaction interface to discover novel IL-6 inhibitors.

The IL-6/IL-6R or IL-6/GP130 protein-protein interactions play a significant role in controlling the development of chronic inflammatory diseases, such as rheumatoid arthritis, Castleman disease, psoriasis, and, most recently, COVID-19. Modulating or antagonizing protein-protein interactions of IL6 binding to its receptors by oral drugs promises similar efficacy to biological therapy in patients, namely monoclonal antibodies. In this study, we used a crystal structure of the Fab part of olokizumab in a complex with IL-6 (PDB ID: 4CNI) to uncover starting points for small molecule IL-6 antagonist discovery. Firstly, a structure­based pharmacophore model of the protein active site cavity was generated to identify possible candidates, followed by virtual screening with a significant database Drugbank. After the docking protocol validation, a virtual screening by molecular docking was carried out and a total of 11 top hits were reported. Detailed analysis of the best scoring molecules was performed with ADME/T analysis and molecular dynamics simulation. Furthermore, the Molecular Mechanics-Generalized Born Surface Area (MM/GBSA) technique has been utilized to evaluate the free binding energy. Based on the finding, one newly obtained compound in this study, namely DB15187, may serve as a lead compound for the discovery of IL-6 inhibitors.Communicated by Ramaswamy H. Sarma.

Discovery of AcrAB-TolC pump inhibitors: Virtual screening and molecular dynamics simulation approach.

AcrAB-TolC tripartite efflux pump, which belongs to the RND superfamily, is a main multi-drug efflux system of Escherichia coli (E. coli) because of the broad resistance on various antibiotics. With the discovering of efflux pump inhibitors (EPIs), a combination between these and antibiotics is one of the most promising therapies. Therefore, building a virtual screening model with prediction capacities for the efflux pump inhibitory activities of candidates from DrugBank and ZINC15 dataset, is one of the key goals of this project. Based on the database of 170 diverse chemical structures collected from 28 research journals, two 2D-QSAR models and a 3D-pharmacophore model have been performed. On the AcrB protein (PDB 4DX7), two binding sites have been discovered that match to the hydrophobic trap in the distal pocket and the switch loop in the proximal pocket. After virtual screening processes, twenty candidate AcrAB-TolC inhibitors have been subjected to molecular dynamics simulations, binding free energy calculations and ADMET predictions. The results indicate that three compounds namely DB09233, DB02581, and DB15224 are potential inhibitors with ΔGbind of -42.30 ± 4.58, -40.76 ± 7.30 and -31.06 ± 7.63 kcal.mol-1, respectively.Communicated by Ramaswamy H. Sarma.

In silico approach to identify novel allosteric intracellular antagonist for blocking the interleukin-8/CXCR2 receptor signaling pathway.

The role of interleukin-8 (IL-8) and its receptor CXCR2 in inflammatory responses and tumor development and progression has been well documented. Our study aims to discover novel compounds as CXCR2 antagonists to block the IL-8 signaling pathway using an in silico drug design. Herein, a structure-based pharmacophore model was developed based on the crystal structure of inactive CXCR2 in a complex with an allosteric inhibitor. This model was validated and refined, followed by virtual screening with the ZINC15 database. Subsequent molecular docking allows for predicting the best pose of a ligand inside a receptor binding site. We found that the 35 top-ranked hits exhibited docking scores from -30.81 to -25.28 kJ/mol and better interaction potential comparing the reference inhibitor. Analysis of ADME and toxicity properties revealed the efficacy and safety of the selected seven compounds. To validate the stability of the protein-ligand complex structure MD simulations approach has also been performed and confirmed via the critical parameters. The MD results explained that the CXCR2 receptor bound with two best-proposed molecules, including ZINC77105530 and ZINC93176465, was quite stable states as observed from low RMSD, RMSF, Rg, SASA values, and high occupancy of the interaction types. Finally, our data identified that these compounds play as potential inhibitors of IL-8 signaling pathways with the MM/GBSA binding free energies of -41.77 ± 6.45 kcal/mol and -38.84 ± 6.16 kcal/mol, respectively.Communicated by Ramaswamy H. Sarma.

Identification of small molecules as potential inhibitors of interleukin 6: a multi-computational investigation.

IL(interleukin)-6 is a multifunctional cytokine crucial for immunological, hematopoiesis, inflammation, and bone metabolism. Strikingly, IL-6 has been shown to significantly contribute to the initiation of cytokine storm-an acute systemic inflammatory syndrome in Covid-19 patients. Recent study has showed that blocking the IL-6 signaling pathway with an anti-IL-6 receptor monoclonal antibody (mAb) can reduce the severity of COVID-19 symptoms and enhance patient survival. However, the mAb has several drawbacks, such as high cost, potential immunogenicity, and invasive administration due to the large-molecule protein product. Instead, these issues could be mitigated using small molecule IL-6 inhibitors, but none are currently available. This study aimed to discover IL-6 inhibitors based on the PPI with a novel camelid Fab fragment, namely 68F2, in a crystal protein complex structure (PDB ID: 4ZS7). The pharmacophore models and molecular docking were used to screen compounds from DrugBank databases. The oral bioavailability of the top 24 ligands from the screening was predicted by the SwissAMDE tool. Subsequently, the selected molecules from docking and MD simulation illustrated a promising binding affinity in the formation of stable complexes at the active binding pocket of IL-6. Binding energies using the MM-PBSA technique were applied to the top 4 hit compounds. The result indicated that DB08402 and DB12903 could form strong interactions and build stable protein-ligand complexes with IL-6. These potential compounds may serve as a basis for further developing small molecule IL-6 inhibitors in the future.

Identification of Diosmin and Flavin Adenine Dinucleotide as Repurposing Treatments for Monkeypox Virus: A Computational Study.

The World Health Organization declared monkeypox a global public health emergency on 23 July 2022. This disease was caused by the monkeypox virus (MPXV), which was first identified in 1958 in Denmark. The MPXV is a member of the Poxviridae family, the Chordopoxvirinae subfamily, and the genus Orthopoxvirus, which share high similarities with the vaccinia virus (the virus used to produce the smallpox vaccine). For the initial stage of infection, the MPXV needs to attach to the human cell surface glycosaminoglycan (GAG) adhesion molecules using its E8 protein. However, up until now, neither a structure for the MPXV E8 protein nor a specific cure for the MPXV exists. This study aimed to search for small molecules that inhibit the MPXV E8 protein, using computational approaches. In this study, a high-quality three-dimensional structure of the MPXV E8 protein was retrieved by homology modeling using the AlphaFold deep learning server. Subsequent molecular docking and molecular dynamics simulations (MDs) for a cumulative duration of 2.1 microseconds revealed that ZINC003977803 (Diosmin) and ZINC008215434 (Flavin adenine dinucleotide-FAD) could be potential inhibitors against the E8 protein with the MM/GBSA binding free energies of -38.19 ± 9.69 and -35.59 ± 7.65 kcal·mol-1, respectively.

Exploration of chalcones as 3-chymotrypsin-like protease (3CLpro) inhibitors of SARS-CoV-2 using computational approaches.

The main protease 3CLpro is one of the potential targets against coronavirus. Inhibiting this enzyme leads to the interruption of viral replication. Chalcone and its derivatives were reported to possess the ability to bind to 3CLpro protease in the binding pocket. This study explored an in-house database of 269 chalcones as 3CLpro inhibitors using in silico screening models, including molecular docking, molecular dynamics simulation, binding free energy calculation, and ADME prediction. C264 and C235 stand out as the two most potential structures. The top hit compound C264 was with the Jamda score of -2.8329 and the MM/GBSA binding energy mean value of -28.23 ± 3.53 kcal/mol, which was lower than the reference ligand. Despite the lower mean binding energy (-22.07 ± 3.39 kcal/mol), in-depth analysis of binding interaction suggested C235 could be another potential candidate. Further, in vitro and in vivo experiments are required to confirm the inhibitory ability. Supplementary Information: The online version contains supplementary material available at 10.1007/s11224-022-02000-3.

Opposing roles of HDAC6 in liver regeneration and hepatocarcinogenesis.

Histone deacetylase 6 (HDAC6), a deacetylase of p53, has emerged as a privileged inhibitory target for cancer therapy because of its deacetylating activity for p53 at K120 and K373/382. However, intricate roles of HDAC6 in hepatocellular carcinogenesis have been suggested by recent evidence, namely that HDAC6 ablation suppresses innate immunity, which plays critical roles in tumor immunosurveillance and antitumor immune responses. Therefore, it is valuable to determine whether HDAC6 ablation inhibits hepatocellular carcinogenesis using in vivo animal models. Here, we firstly showed that HDAC6 ablation increased K320 acetylation of p53, known as pro-survival acetylation, in all tested animal models but did not always increase K120 and K373/382 acetylation of p53, known as pro-apoptotic acetylation. HDAC6 ablation induced cellular senescence in primary MEFs and inhibited cell proliferation in HepG2 cells and liver regeneration after two-thirds partial hepatectomy. However, the genetic ablation of HDAC6 did not inhibit hepatocarcinogenesis, but instead slightly enhanced it in two independent mouse models (DEN + HFD and DEN + TAA). Notably, HDAC6 ablation significantly promoted hepatocarcinogenesis in a multiple DEN treatment hepatocellular carcinoma (HCC) mouse model, mimicking chronic DNA damage in the liver, which correlated with hyperacetylation at K320 of p53 and a decrease in inflammatory cytokines and chemokines. Our data from three independent in vivo animal HCC models emphasize the importance of the complex roles of HDAC6 ablation in hepatocellular carcinogenesis, highlighting its immunosuppressive effects.

Structure-based 3D-Pharmacophore modeling to discover novel interleukin 6 inhibitors: An in silico screening, molecular dynamics simulations and binding free energy calculations.

Interleukin 6 (IL-6) is a cytokine with various biological functions in immune regulation, hematopoiesis, and inflammation. Elevated IL-6 levels have been identified in several severe disorders such as sepsis, acute respiratory distress syndrome (ARDS), and most recently, COVID-19. The biological activity of IL-6 relies on interactions with its specific receptor, IL-6Rα, including the membrane-bound IL-6 receptor (mIL-6R) and the soluble IL-6 receptor (sIL-6R). Thus, inhibition of the interaction between these two proteins would be a potential treatment for IL-6 related diseases. To date, no orally available small-molecule drug has been approved. This study focuses on finding potential small molecules that can inhibit protein-protein interactions between IL-6 and its receptor IL-6Rα using its crystal structure (PDB ID: 5FUC). First, two pharmacophore models were constructed based on the interactions between key residues of IL-6 (Phe74, Phe78, Leu178, Arg179, Arg182) and IL-6Rα (Phe229, Tyr230, Glu277, Glu278, Phe279). A database of approximately 22 million compounds was screened using 3D-pharmacophore models, molecular docking models, and ADMET properties. By analyzing the interactive capability of successfully docked compounds with important amino acids, 12 potential ligands were selected for further analysis via molecular dynamics simulations. Based on the stability of the complexes, the high interactions rate of each ligand with the key residues of IL-6/IL-6Rα, and the low binding free energy calculation, two compounds ZINC83804241 and ZINC02997430, were identified as the most potential IL-6 inhibitor candidates. These results will pave the way for the design and optimization of more specific compounds to combat cytokine storm in severe coronavirus patients.

Chalcone Derivatives as Potential Inhibitors of P-Glycoprotein and NorA: An In Silico and In Vitro Study.

The human P-glycoprotein (P-gp) and the NorA transporter are the major culprits of multidrug resistance observed in various bacterial strains and cancer cell lines, by extruding drug molecules out of the targeted cells, leading to treatment failures in clinical settings. Inhibiting the activity of these efflux pumps has been a well-known strategy of drug design studies in this regard. In this manuscript, our earlier published machine learning models and homology structures of P-gp and NorA were utilized to screen a chemolibrary of 95 in-house chalcone derivatives, identifying two hit compounds, namely, F88 and F90, as potential modulators of both transporters, whose activity on Staphylococcus aureus strains overexpressing NorA and resistant to ciprofloxacin was subsequently confirmed. The findings of this study are expected to guide future research towards developing novel potent chalconic inhibitors of P-gp and/or NorA.

Identification of potential interleukin-8 inhibitors acting on the interactive site between chemokine and CXCR2 receptor: A computational approach.

Interactions between interleukin (IL)-8 and its receptors, CXCR1, and CXCR2, serve crucial roles in inflammatory conditions and various types of cancers. Inhibition of this signaling pathway has been exploited as a promising strategy in treating these diseases. However, most studies only focused on the design of allosteric antagonists-bound receptors on the intracellular side of IL-8 receptors. Recently, the first cryo-EM structures of IL-8-CXCR2-Gi complexes have been solved, revealing the unique binding and activation modes of the endogenous chemokine IL-8. Hence, we set to identify small molecule inhibitors for IL-8 using critical protein-protein interaction between IL-8 and CXCR2 at the orthosteric binding site. The pharmacophore models and molecular docking screened compounds from DrugBank and NCI databases. The oral bioavailability of the top 23 ligands from the screening was then predicted by the SwissAMDE tool. Molecular dynamics simulation and free binding energy calculation were performed for the best compounds. The result indicated that DB14770, DB12121, and DB03916 could form strong interactions and stable protein-ligand complexes with IL-8. These three candidates are potential IL-8 inhibitors that can be further evaluated by in vitro experiments in the next stage.

Discovery of small molecular inhibitors for interleukin-33/ST2 protein-protein interaction: a virtual screening, molecular dynamics simulations and binding free energy calculations.

The interleukin-1 receptor like ST2 has emerged as a potential drug discovery target since it was identified as the receptor of the novel cytokine IL-33, which is involved in many inflammatory and autoimmune diseases. For the treatment of such IL-33-related disorders, efforts have been made to discover molecules that can inhibit the protein-protein interactions (PPIs) between IL-33 and ST2, but to date no drug has been approved. Although several anti-ST2 antibodies have entered clinical trials, the exploration of small molecular inhibitors is highly sought-after because of its advantages in terms of oral bioavailability and manufacturing cost. The aim of this study was to discover ST2 receptor inhibitors based on its PPIs with IL-33 in crystal structure (PDB ID: 4KC3) using virtual screening tools with pharmacophore modeling and molecular docking. From an enormous chemical space ZINC, a potential series of compounds has been discovered with stronger binding affinities than the control compound from a previous study. Among them, four compounds strongly interacted with the key residues of the receptor and had a binding free energy < - 20 kcal/mol. By intensive calculations using data from molecular dynamics simulations, ZINC59514725 was identified as the most potential candidate for ST2 receptor inhibitor in this study.

Structure-Based Discovery of ABCG2 Inhibitors: A Homology Protein-Based Pharmacophore Modeling and Molecular Docking Approach.

ABCG2 is an ABC membrane protein reverse transport pump, which removes toxic substances such as medicines out of cells. As a result, drug bioavailability is an unexpected change and negatively influences the ADMET (absorption, distribution, metabolism, excretion, and toxicity), leading to multi-drug resistance (MDR). Currently, in spite of promising studies, screening for ABCG2 inhibitors showed modest results. The aim of this study was to search for small molecules that could inhibit the ABCG2 pump. We first used the WISS MODEL automatic server to build up ABCG2 homology protein from 655 amino acids. Pharmacophore models, which were con-structed based on strong ABCG2 inhibitors (IC50 < 1 µM), consist of two hydrophobic (Hyd) groups, two hydrogen bonding acceptors (Acc2), and an aromatic or conjugated ring (Aro|PiR). Using molecular docking method, 714 substances from the DrugBank and 837 substances from the TCM with potential to inhibit the ABCG2 were obtained. These chemicals maybe favor synthesized or extracted and bioactivity testing.

Prediction model of human ABCC2/MRP2 efflux pump inhibitors: a QSAR study.

The overexpression of ABCC2/MRP2, an ATP-binding cassette transporter, contributes to multidrug resistance in cancer cells. In this study, a quantitative structure-activity relationship (QSAR) analysis on ABCC2 inhibitors has been carried out, aiming to establish a computational prediction model for ABCC2 modulators. Seven classification models and two regression models were built by SONNIA 4.2, and two other regression models were built by MOE 2008.10 based on a data set comprising 372 compounds collected from 16 relevant publications. The CPG-C iABCC2 model for classifying ABCC2 inhibitors has total accuracy of 0.88 and Matthews correlation coefficient MCC = 0.75. The CPG-C iEG model for classifying ABCC2 inhibitors (substrate EG: ß-estradiol 17-ß-D-glucuronide) has total accuracy of 0.91 and MCC = 0.82. The regression model PLS EG-IC50 for predicting ABCC2 inhibitors (substrate EG) gave root-mean-square error RMSE = 0.26, Q2 = 0.73 and [Formula: see text]. The regression model PLS CDCF-IC50 for predicting ABCC2 inhibitors [substrate CDCF: 5(6)-carboxy-2',7'-dichlorofluorescein] gave RMSE = 0.31, Q2 = 0.74 and [Formula: see text]. Four 2D-QSAR models were applied to 1661 compounds, with results indicating 369 compounds having the ability to reverse the efflux of both EG and CDCF by ABCC2, 152 among them having IC50 < 100 µM.