High-throughput Molecular Docking Research Articles

A New Optimized Hybridization Approach for in silico High Throughput Molecular Docking on FPGA Platform.

The development process of a new drug should be a subject of continuous evolution and rapid improvement as drugs are essential to treat a wide range of diseases of which many are life-threatening. The advances in technology resulted in a novel track in drug discovery and development known as in silico drug design. The molecular docking phase plays a vital role in in silico drug development process. In this phase, thousands of 3D conformations of both the ligand and receptor are generated and the best conformations that create the most stable drug-receptor complex are determined. The speed in finding accurate and high-quality complexes depends on the efficiency of the search function in the molecular docking procedure. The objective of this research is to propose and implement a novel hybrid approach called hABCDE to replace the EMC searching part inside the BUDE docking algorithm. This helps in reaching the best solution in a much accelerated time and higher solution quality compared to using the ABC and DE algorithms separately. In this work, we have employed a new approach of hybridization between the Artificial Bee Colony (ABC) algorithm and the Differential Evolution (DE) algorithm as an alternative searching part of the Bristol University Docking Engine (BUDE) in order to accelerate the search for higher quality solutions. Moreover, the proposed docking approach was implemented on Field Programmable Gate Array (FPGA) parallel platform using Vivado High-Level Synthesis Tool (HLST) in order to optimize and enhance the execution time and overall efficiency. The NDM-1 protein was used as a model receptor in our experiments to demonstrate the efficiency of our approach. The NDM-1 protein was used as a model receptor in our experiments to demonstrate the efficiency of our approach. The results showed that the execution time for the BUDE with the new proposed hybridization approach was improved by 9,236 times. Our novel approach was significantly effective to improve the functionality of docking algorithms (Bristol University Docking Engine (BUDE)).

Analysis of the anti-PCV2 mechanism of Lactobacillus acidophilus based on non-target metabolomics and high-throughput molecular docking

Analysis of the anti-PCV2 mechanism of Lactobacillus acidophilus based on non-target metabolomics and high-throughput molecular docking

Repurposing diacerein to suppress colorectal cancer growth by inhibiting the DCLK1/STAT3 signaling pathway

Double cortin-like kinase 1 (DCLK1) exhibits high expression levels across various cancers, notably in human colorectal cancer (CRC). Diacerein, a clinically approved interleukin (IL)-1β inhibitor for osteoarthritis treatment, was evaluated for its impact on CRC proliferation and migration, alongside its underlying mechanisms, through both in vitro and in vivo analyses. The study employed MTT assay, colony formation, wound healing, transwell assays, flow cytometry, and Hoechst 33342 staining to assess cell proliferation, migration, and apoptosis. Additionally, proteome microarray assay and western blotting analyses were conducted to elucidate diacerein's specific mechanism of action. Our findings indicate that diacerein significantly inhibits DCLK1-dependent CRC growth in vitro and in vivo. Through high-throughput proteomics microarray and molecular docking studies, we identified that diacerein directly interacts with DCLK1. Mechanistically, the suppression of p-STAT3 expression following DCLK1 inhibition by diacerein or specific DCLK1 siRNA was observed. Furthermore, diacerein effectively disrupted the DCLK1/STAT3 signaling pathway and its downstream targets, including MCL-1, VEGF, and survivin, thereby inhibiting CRC progression in a mouse model, thereby inhibiting CRC progression in a mouse model.

High-throughput virtual search of small molecules for controlling the mechanical stability of human CD4

Protein mechanical stability determines the function of a myriad of proteins, especially proteins from the extracellular matrix. Failure to maintain protein mechanical stability may result in diseases and disorders such as cancer, cardiomyopathies, or muscular dystrophy. Thus, developing mutation-free approaches to enhance and control the mechanical stability of proteins using pharmacology-based methods, may have important implications in drug development and discovery. Here, we present the first approach that employs computational High-Throughput Virtual Screening (HTVS) and Molecular Docking to search for small-molecules in chemical libraries that function as mechano-regulators of the stability of human CD4, receptor of HIV-1. Using single-molecule force spectroscopy we prove that these small-molecules can increase the mechanical stability of CD4D1D2 domains over 4-fold in addition to modifying the mechanical unfolding pathways. Our experiments demonstrate that chemical libraries are a source of mechanoactive molecules and that drug discovery approaches provide the foundation of a new type of molecular function, i.e., mechano-regulation, paving the way towards mechanopharmacology.

Computational exploration of novel ROCK2 inhibitors for cardiovascular disease management; insights from high-throughput virtual screening, molecular docking, DFT and MD simulation.

Cardiovascular disorders are the world's major cause of death nowadays. To treat cardiovascular diseases especially coronary artery diseases and hypertension, researchers found potential ROCK2 (Rho-associated coiled-coil-containing protein kinase 2) target due to its substantial role in NO-cGMP and RhoA/ROCK pathway. Available drugs for ROCK2 are less effective and some of them depict side effects. Therefore, a set of novel compounds were screened that can potentially inhibit the activity of ROCK2 and help to treat cardiovascular diseases by employing In-silico techniques. In this study, we undertook ligand based virtual screening of 50 million compound's library, to that purpose shape and features (contain functional groups) based pharmacophore query was modelled and validated by Area Under Curve graph (AUC). 2000 best hits were screened for Lipinski's rule of 5 compliance. Subsequently, these selected compounds were docked into the binding site of ROCK2 to gain insights into the interactions between hit compounds and the target protein. Based on binding affinity and RMSD scores, a final cohort of 15 compounds were chosen which were further refined by pharmacokinetics, ADMET and bioactivity scores. 2 potential hits were screened using density functional theory, revealing remarkable biological and chemical activity. Potential inhibitors (F847-0007 and 9543495) underwent rigorous examination through MD Simulations and MMGBSA analysis, elucidating their stability and strong binding affinities. Results of current study unveil the potential of identified novel hits as promising lead compounds for ROCK2 associated with cardiovascular diseases. These findings will further investigate via In-vitro and In-vivo studies to develop novel druglike molecules against ROCK2.

Evaluation of the FDA-approved kinase inhibitors to uncover the potential repurposing candidates targeting ABC transporters in multidrug-resistant cancer cells: an in silico approach

Multiple drug resistance (MDR) is characterized by the resistance of cancer cells to a broad spectrum of anticancer drugs. The main mechanism underlying the MDR phenotype is the overexpression of ATP-binding cassette (ABC) transporters by promoting active drug efflux from cancer cells. Some small-molecule protein kinase inhibitors have been found to overcome MDR by inhibiting ABC transporters as substrates or modulators. This study investigated the chemical activity of 58 FDA-approved anticancer kinase inhibitors against three multidrug resistance-related proteins. The studied proteins are ATP-Binding Cassette Sub-Family B Member 1 (ABCB1), ATP-Binding Cassette Subfamily C Member 1 (ABCC1), and ATP-binding cassette superfamily G member 2 (ABCG2). The drug-binding domain and ATP binding sites of the proteins were considered the kinase inhibitors’ probable target. High-throughput virtual screening and molecular docking were employed to find the hit drugs, and the drugs with the highest binding affinity were further evaluated using the molecular dynamics (MD) simulation. The virtual screening revealed that several kinase inhibitors could be considered potential inhibitors of ABCB1, ABCC1, and ABCG2, among which larotrectinib, entrectinib, and infigratinib showed the highest binding affinity, respectively. Based on the obtained results from MD simulation, these drugs can form strong interactions with the essential residues of the target proteins. In silico investigation revealed that larotrectinib, entrectinib, and infigratinib can target the key residues of the studied proteins. Therefore, these approved kinase inhibitors could be considered potential therapies for MDR cancers by targeting these transporters. Communicated by Ramaswamy H. Sarma

In Silico Study of Potential Small Molecule TIPE2 Inhibitors for the Treatment of Cancer

Context: Chronic inflammation has been linked to cancer since the 19th century. Tumor growth is supported by the proangiogenic factors that chronic inflammation requires. Polarized leukocytes initiate these angiogenic and tumorigenic factors. TIPE2, a transport protein, manages the cytoskeletal rearrangement that gives a polarized leukocyte its motility. Inhibition of this protein could lead to a therapeutic option for solid tumor cancers; however, no such inhibitors have been developed so far due to the large cavity size of the TIPE2 protein. Here we have examined possible small molecule inhibitors by combining structure-based and fragment-based drug design approaches. The highest binding ligands were complexed with the protein, and fragment libraries were docked with the complex with the intention of linking the hit compounds and fragments to design a more potent ligand. Three hit compounds were identified by in silico structure-based screening and a linked compound, C2–F14, of excellent binding affinity, was identified by linking fragments to the hit compounds. C2–F14 demonstrates good binding stability in molecular dynamic simulations and great predicted ADME properties. Methods: High throughput molecular docking calculations of mass libraries were performed using AutoDock Vina 1.1.2. Molecular docking of individual ligands was performed using AutoDock Vina with PyRx. Ligand libraries were prepared using OpenBabel, linked ligands were prepared using Avogadro. The protein was prepared using AutoDockTools-1.5.6. Protein-ligand complexes were visualized with PyMOL. Two- and three-dimensional representations of protein–ligand interactions were plotted with BIOVIA Discovery Studio Visualizer. In silico absorption, distribution, metabolism, and excretion (ADME) properties were calculated using SwissADME. Molecular dynamics simulations were conducted with GROMACS.

Integrated multi-omics analyses reveal Jorunnamycin A as a novel suppressor for muscle-invasive bladder cancer by targeting FASN and TOP1

BackgroundBladder cancer is a urological carcinoma with high incidence, among which muscle invasive bladder cancer (MIBC) is a malignant carcinoma with high mortality. There is an urgent need to develop new drugs with low toxicity and high efficiency for MIBC because existing medication has defects, such as high toxicity, poor efficacy, and side effects. Jorunnamycin A (JorA), a natural marine compound, has been found to have a high efficiency anticancer effect, but its anticancer function and mechanism on bladder cancer have not been studied.MethodsTo examine the anticancer effect of JorA on MIBC, Cell Counting Kit 8, EdU staining, and colony formation analyses were performed. Moreover, a xenograft mouse model was used to verify the anticancer effect in vivo. To investigate the pharmacological mechanism of JorA, high-throughput quantitative proteomics, transcriptomics, RT-qPCR, western blotting, immunofluorescence staining, flow cytometry, pulldown assays, and molecular docking were performed.ResultsJorA inhibited the proliferation of MIBC cells, and the IC50 of T24 and UM-UC-3 was 0.054 and 0.084 μM, respectively. JorA-induced significantly changed proteins were enriched in “cancer-related pathways” and “EGFR-related signaling pathways”, which mainly manifested by inhibiting cell proliferation and promoting cell apoptosis. Specifically, JorA dampened the DNA synthesis rate, induced phosphatidylserine eversion, and inhibited cell migration. Furthermore, it was discovered that fatty acid synthase (FASN) and topoisomerase 1 (TOP1) are the JorA interaction proteins. Using DockThor software, the 3D docking structures of JorA binding to FASN and TOP1 were obtained (the binding affinities were − 8.153 and − 7.264 kcal/mol, respectively).ConclusionsThe marine compound JorA was discovered to have a specific inhibitory effect on MIBC, and its potential pharmacological mechanism was revealed for the first time. This discovery makes an important contribution to the development of new high efficiency and low toxicity drugs for bladder cancer therapy.Graphical

In-vitro high-throughput library screening-Kinetics and molecular docking studies of potent inhibitors of α-glucosidase.

High throughput screening of synthetic compounds against vital enzymes is the way forward for the determination of potent enzyme inhibitors. In-vitro high throughput library screening of 258 synthetic compounds (comp. 1-258), was performed against α-glucosidase. The active compounds out of this library were investigated for their mode of inhibition and binding affinities towards α-glucosidase through kinetics as well as molecular docking studies. Out of all the compounds selected for this study, 63 compounds were found active within the IC50 range of 3.2 μM to 50.0 μM. The most potent inhibitor of α-glucosidase out of this library was the derivative of an oxadiazole (comp. 25). It showed the IC50 value of 3.23 ± 0.8 μM. Other highly active compounds were the derivatives of ethyl-thio benzimidazolyl acetohydrazide with IC50 values of 6.1 ± 0.5 μM (comp. 228), 6.84 ± 1.3 μM (comp. 212), 7.34 ± 0.3 μM (comp. 230) and 8.93 ± 1.0 μM (comp. 210). For comparison, the standard (acarbose) showed IC50 = 378.2 ± 0.12 μM. Kinetic studies of oxadiazole (comp. 25) and ethylthio benzimidazolyl acetohydrazide (comp. 228) derivatives indicated that Vmax and Km, both change with changing concentrations of inhibitors which suggests an un-competitive mode of inhibition. Molecular docking studies of these derivatives with the active site of α-glucosidase (PDB ID:1XSK), revealed that these compounds mostly interact with acidic or basic amino acid residues through conventional hydrogen bonds along with other hydrophobic interactions. The binding energy values of compounds 25, 228, and 212 were -5.6, -8.7 and -5.4 kcal.mol-1 whereas RMSD values were 0.6, 2.0, and 1.7 Å, respectively. For comparison, the co-crystallized ligand showed a binding energy value of -6.6 kcal.mol-1 along with an RMSD value of 1.1 Å. Our study predicted several series of compounds as active inhibitors of α-glucosidase including some highly potent inhibitors.

Structure based High-Throughput Virtual Screening, Molecular Docking and Molecular Dynamics Study of anticancer natural compounds against fimbriae (FimA) protein of Porphyromonas gingivalis in oral squamous cell carcinoma.

Oral cancer is among the most common cancer in the world. Tobacco, alcohol, and viruses have been regarded as a well- known risk factors of OCC however, 15% of OSCC cases occurred each year without these known risk factors. Recently a myriad of studies has shown that bacterial infections lead to cancer. Accumulated shreds of evidence have demonstrated the role of Porphyromonas gingivalis (P. gingivalis) in OSCC. The virulence factor FimA ofP. gingivalisactivates the oncogenic pathways in OSCC by upregulating various cytokines. It also led to the inactivation of a tumor suppressor protein p53. The present Insilico study uses High-Throughput Virtual Screening, molecular docking, and molecular dynamics techniques to find the potential compounds against the target protein FimA. The goal of this study is to identify the anti-cancer lead compounds retrieved from natural sources that can be used to develop potent drug molecules to treat P.gingivalis-related OSCC. The anticancer natural compounds library was screened to identify the potential lead compounds. Furthermore, these lead compounds were subjected to precise docking, and based on the docking score potential lead compounds were identified. The top docked receptor-ligand complex was subjected to molecular dynamics simulation. A study of this insilico finding provides potent lead molecules which help in the development of therapeutic drugs against the target protein FimA in OSCC. Workflow of Structure based High-Throughput Virtual Screening, Molecular Docking and Molecular Dynamics Study of anticancer natural compounds against Fimbriae (FimA) protein of P. gingivalis in oral squamous cell carcinoma.

Systematic exploration of the efficacy marker compounds of Danshen (Salvia miltiorrhiza Bge.) driven by the efficacy network target

IntroductionChinese Materia Medica (CMM) provides medical treatment and healthcare worldwide. However, precision quality control of CMM is considered a bottleneck in Chinese herbal modernization. Considering the multi-efficacy of the clinical applications of CMM, we adopted a novel strategy based on the efficacy network target to screen for efficacy-related constituents and efficacy markers. MethodsNetwork pharmacology and high-throughput molecular docking were integrated to construct efficacy network targets for activating blood (AB), cooling blood (CB), and easing mind (EM) in Danshen (Salvia miltiorrhiza Bge.). Cytoscape with plugins was used to analyze the structure and function of the networks. The efficacy scores of the components were calculated and ranked to identify efficacy markers, which were further verified using the PubChem database. ResultsFollowing 9164 ligand-receptor molecular docking, 328 AB efficacy targets, 88 CB efficacy targets, and 52 EM efficacy targets were validated in silico. Three efficacy network targets were then constructed, and topological and functional analyses showed that the networks were consistent with the corresponding efficacy. Six AB, three CB, and five EM efficacy markers were screened using comprehensive analysis. Most of the indices (13/14) were confirmed to be associated with matching efficacy. ConclusionThe indices selected based on efficacy level could satisfy the clinical requirements of traditional Chinese medicine (TCM). Therefore, the strategy would be conducive to providing a new approach for natural product-based drug discovery and achieving accurate quality control for Danshen following multi-efficacy application.

Efficacy Screening of Prospective Anti-allergic Drug Candidates: An In silico Study

Background: Due to the rapid rise of allergies, anti-allergy medications are commonly being utilised to reduce inflammation; however, allergen-specific inhibitors may also be utilised. Objective: Our in silico study is aimed at finding out a promising anti-allergic compound that can act against a wide range of allergens. Methods: The inhibitory efficacies of potential anti-allergic compounds were investigated by ADMET studies and were followed by high throughput molecular docking. Binding energy was calculated by AUTODOCK, which led to the identification of binding sites between the allergens and antiallergic compounds. Each of the five anti-allergic compounds interacted with allergens at various levels. The docked poses showing significant binding energy were subjected to molecular docking simulation. Results: Marrubiin exhibits higher binding affinities to the catalytic pocket against allergens from chicken, European white birch plant, bacteria, fungus, and numerous food allergens. Conclusions: We propose Marrubiin, which appears to be a promising anti-allergic candidate and antiinflammatory agent against a wide spectrum of allergens. The future directions of this research are to analyze the effects of anti-allergic mechanisms in vivo.

Rapid detection of traditional Chinese medicine with neuraminidase inhibitory activities based on high-throughput and virtual screening strategy

BackgroundOseltamivir, a neuraminidase inhibitor (NAI), is the primary and first-line anti-influenza drug. In recent years, more and more oseltamivir resistant strains appeared frequently. PurposeTo identify anti-influenza candidates to overcome oseltamivir resistance from traditional Chinese medicine. MethodsHigh-throughput screening platform was used to screen candidates with oseltamivir sensitive and resistant neuraminidase (NA) inhibitory activities from traditional Chinese medicine (TCM) and in validation of potential active components in vitro. Molecular docking is used for virtual screening of TCM compound libraries and analysis of the molecular mechanism of active compounds. ResultsSix out of 188 TCM formula granules were screened out with good inhibitory activities in oseltamivir sensitive (H5N1) and resistant NA (H274Y mutant). A compound library containing 679 candidates in the above six plants were docked into binding pockets of H5N1 NA and its H274Y mutant. The results indicated that diverse structural types, including flavonoids glycosides, alkaloids, caffeoylquinic acid derivatives, etc. showed good docking scores on the two NAs. Furthermore, 10 representative compounds tested in vitro showed inhibitory activities in both oseltamivir sensitive and resistant NA. The docking simulations revealed that natural TCM molecules bind with NA in an absolute different mode compared with oseltamivir, which occupy the extra cavities adjacent to the active site of NA, thus might make them non-susceptible to be influenced by mutation around the active sites. ConclusionsThe combination of high-throughput screening and molecular docking can efficiently screen out candidates that have the potential to overcome oseltamivir resistance from TCM.

Identification of novel natural product inhibitors of BRD4 using high throughput virtual screening and MD simulation

Bromodomains are evolutionarily conserved structural motifs that recognize acetylated lysine residues on histone tails. They play a crucial role in shaping chromatin architecture and regulating gene expression in various biological processes. Mutations in bromodomains containing proteins lead to multiple human diseases, which makes them attractive target for therapeutic intervention. Extensive studies have been done on BRD4 as a target for several cancers, such as Acute Myeloid Leukemia (AML) and Burkitt Lymphoma. Several potential inhibitors have been identified against the BRD4 bromodomain. However, most of these inhibitors have drawbacks such as non-specificity and toxicity, decreasing their appeal and necessitating the search for novel non-toxic inhibitors. This study aims to address this need by virtually screening natural compounds from the NPASS database against the Kac binding site of BRD4-BD1 using high throughput molecular docking followed by similarity clustering, pharmacokinetic screening, MD simulation and MM-PBSA binding free energy calculations. Using this approach, we identified five natural product inhibitors having a similar or better binding affinity to the BRD4 bromodomain compared to JQ1 (previously reported inhibitor of BRD4). Further systematic analysis of these inhibitors resulted in the top three hits: NPC268484 (Palodesangren-B), NPC295021 (Candidine) and NPC313112 (Buxifoliadine-D). Collectively, our in silico results identified some promising natural products that have the potential to act as potent BRD4-BD1 inhibitors and can be considered for further validation through future in vitro and in vivo studies. Communicated by Ramaswamy H. Sarma

Micropeptide MIAC inhibits the tumor progression by interacting with AQP2 and inhibiting EREG/EGFR signaling in renal cell carcinoma

BackgroundAlthough, micropeptides encoded by non-coding RNA have been shown to have an important role in a variety of tumors processes, there have been no reports on micropeptide in renal cell carcinoma (RCC). Based on the micropeptide MIAC (micropeptide inhibiting actin cytoskeleton) discovered and named in the previous work, this study screened its tumor spectrum, and explored its mechanism of action and potential diagnosis and treatment value in the occurrence and development of renal carcinoma.MethodsThe clinical significance of MIAC in RCC was explored by bioinformatics analysis through high-throughput RNA-seq data from 530 patients with kidney renal clear cell carcinoma (KIRC) in the TCGA database, and the detection of clinical samples of 70 cases of kidney cancer. In vitro and in vivo experiments to determine the role of MIAC in renal carcinoma cell growth and metastasis; High-throughput transcriptomics, western blotting, immunoprecipitation, molecular docking, affinity experiments, and Streptavidin pulldown experiments identify MIAC direct binding protein and key regulatory pathways.ResultsThe analysis of 600 renal carcinoma samples from different sources revealed that the expression level of MIAC is significantly decreased, and corelated with the prognosis and clinical stage of tumors in patients with renal carcinoma. Overexpression of MIAC in renal carcinoma cells can significantly inhibit the proliferation and migration ability, promote apoptosis of renal carcinoma cells, and affect the distribution of cells at various stages. After knocking down MIAC, the trend is reversed. In vivo experiments have found that MIAC overexpression inhibit the growth and metastasis of RCC, while the synthetized MIAC peptides can significantly inhibit the occurrence and development of RCC in vitro and in vivo. Further mechanistic studies have demonstrated that MIAC directly bind to AQP2 protein, inhibit EREG/EGFR expression and activate downstream pathways PI3K/AKT and MAPK to achieve anti-tumor effects.ConclusionsThis study revealed for the first time the tumor suppressor potential of the lncRNA-encoded micropeptide MIAC in RCC, which inhibits the activation of the EREG/EGFR signaling pathway by direct binding to AQP2 protein, thereby inhibiting renal carcinoma progression and metastasis. This result emphasizes that the micropeptide MIAC can provide a new strategy for the diagnosis and treatment of RCC.

Identification of novel inhibitors of Neisseria gonorrhoeae MurI using homology modeling, structure-based pharmacophore, molecular docking, and molecular dynamics simulation-based approach

MurI is one of the most significant role players in the biosynthesis of the peptidoglycan layer in Neisseria gonorrhoeae (Ng). We attempted to highlight the structural and functional relationship between Ng-MurI and D-glutamate to design novel molecules targeting this interaction. The three-dimensional (3D) model of the protein was constructed by homology modeling and the quality and consistency of generated model were assessed. The binding site of the protein was identified by molecular docking studies and a pharmacophore was identified using the interactions of the control ligand. The structure-based pharmacophore model was validated and employed for high-throughput virtual screening and molecular docking to identify novel Ng-MurI inhibitors. Finally, the model was optimized by molecular dynamics (MD) simulations and the optimized model complex with the substrate glutamate and novel molecules facilitated us to confirm the stability of the protein-ligand docked complexes. The 100 ns MD simulations of the potential lead compounds with protein confirmed that the modeled complexes were stable. This study identifies novel potential compounds with good fitness and docking scores, which made the interactions of biological significance within the protein active site. Hence, the identified compounds may act as new leads to design and develop Ng-MurI inhibitors. Communicated by Ramaswamy H. Sarma

Polyphenols from Prunus armeniaca.L as Promising Anticancer (Cervical Cancer): In silico studies and in vivo safety assessment

Some anogenital tract malignancies have high-risk human papillomavirus (HPV) infections as their etiological cause. Although many HPV preventative vaccines have been licensed, there is still a need for medication that targets the infection and its carcinogenic effects. One of the important elements in cell immortalization and tumor development in HPV-positive cells has been identified as the viral oncoprotein E6. The cellular ubiquitin ligase E6AP interacts with E6, which can facilitate the degradation of the tumor suppressor protein p53. One of the best ways to prevent the maintenance and growth of infected cells is to block the creation of the E6-E6AP complex. The present study aims to determine the ability of polyphenols identified in Prunus armeniaca.L, to target the HPV16 virus by virtual high-throughput screening and molecular docking, and to evaluate the safety of this plant in vivo. In silico, the PDB: 4GIZ structure of E6HPV16 was prepared as a target by Discovery Studio 2021. Virtual screening of 47 polyphenols was performed by the iGEMDOCK program, followed by an evaluation of potential inhibitors based on docking affinities obtained from the The SYBYL-X Surflex-Dock module v2.0, 21. In vivo toxicity studies of Prunus armeniaca. L aqueous extract was also conducted in Wistar rats. Of all the polyphenols investigated in this study, the compounds 3-pCoumaroylquinic, 5-pCoumaroyloquinic, Epicatechin, and Dimethoxyflavone were predicted to have the highest binding affinity for E6HPV16, also revealed several interactions with the E6 binding site area. A study on acute in vivo toxicity of Prunus armeniaca .L aqueous extract was conducted and didn't produce any harmful effects. Moreover, Epicatechin, a dimethoxyflavone from Prunus armeniaca.L, 3-pCoumaroylquinic, 5-pCoumaroylquinic, and 5-pCoumaroyloquinic were chosen as possible E6HPV16 inhibitors for novel medication development.

Discovery of TCMs and derivatives against the main protease of SARS-CoV-2 via high throughput screening, ADMET analysis, and inhibition assay in vitro

The rapidly evolving Coronavirus Disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide with thousands of deaths and infected cases. For the identification of effective treatments against this disease, the main protease (Mpro) of SARS‑CoV‑2 was found to be an attractive drug target, as it played a central role in viral replication and transcription. Here, we report the results of high-throughput molecular docking with 1,045,468 ligands’ structures from 116 kinds of traditional Chinese medicine (TCM). Subsequently, 465 promising candidates were obtained, showing high binding affinities. The dynamic simulation, ADMET (absorption, distribution, metabolism, excretion and toxicity) and drug-likeness properties were further analyzed the screened docking results. Basing on these simulation results, 23 kinds of Chinese herbal extracts were employed to study their inhibitory activity for Mpro of SARS‑CoV‑2. Plants extracts from Forsythiae Fructus, Radix Puerariae, Radix astragali, Anemarrhenae Rhizoma showed acceptable inhibitory efficiencies, which were over 70%. The best candidate was Anemarrhenae Rhizoma, reaching 78.9%.

Abstract 6254: Identification of nicotinic acid phosphoribosyltransferase inhibitors with anticancer properties by in silico drug design

Abstract Cancer cells rely heavily on sustained NAD levels to support their survival and proliferation. Thus, depleting NAD levels in tumor cells through interference with their NAD-biosynthetic machinery has been proposed as a promising anticancer strategy. Several pathways contribute to NAD production in mammals, such as the de novo and the Preiss-Handler (PH) pathways, which generate NAD from tryptophan and from nicotinic acid, respectively. In addition, the NAD salvage pathway, which utilizes nicotinamide as a substrate, is also a major NAD-producing route and its rate-limiting enzyme, nicotinamide phosphoribosyltransferase (NAMPT), is commonly overexpressed in a multitude of human cancers. Over the past two decades, several potent NAMPT inhibitors have been developed, such as FK866. However, their clinical efficacy has proven limited, suggesting that the other NAD-producing routes are frequently also active in cancer cells and are responsible for causing resistance to NAMPT inhibitors. Recently, we have shown nicotinic acid phosphoribosyl transferase (NAPRT), the key enzyme in the PH pathway, to play an important role in NAD metabolism in cancer cells. We demonstrated that NAPRT is amplified and overexpressed in several types of solid tumors and that its expression is a critical determinant of cancer cell susceptibility to NAMPT inhibitors. Although several NAPRT inhibitors have been reported, including 2-hydroxy nicotinic acid (2-HNA), their low potency and/or poor solubility limit their clinical applicability. To identify new NAPRT inhibitors with enhanced pharmacological profiles, we performed a high-throughput molecular docking screen, taking advantage of the availability of NAPRT crystal structure. The first 500 hits were visually inspected to prioritize compounds that reproduced, at least in part, the putative binding mode of known substrates and inhibitors and complied with simple physicochemical rules such as Lipinski’s rule of five. In addition, several 2-HNA analogs were selected. Altogether, this led to a final list of 50 compounds that were tested in vitro. We show that four compounds from this list were able to sensitize NAPRT-overexpressing ovarian cancer cells to FK866, resulting in a more significant reduction in intracellular NAD levels, as well as in a much more pronounced cytotoxicity as compared to FK866 alone. The inhibitory constant (Ki) of the new NAPRT inhibitors was found to be in the micromolar range. In conclusion, in silico molecular docking screens are a promising approach to identify new NAPRT inhibitors with anticancer effects. Citation Format: Moustafa Ghanem, Amr Khalifa, Irene Caffa, Aimable Nahimana, Michel Duchosal, Alberto Del Rio, Santina Bruzzone, Francesco Piancente, Alessio Nencioni. Identification of nicotinic acid phosphoribosyltransferase inhibitors with anticancer properties by in silico drug design [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6254.

Feasibility analysis and mechanism exploration of Rhei Radix et Rhizome−Schisandrae Sphenantherae Fructus (RS) against COVID-19

Introduction. As a novel global epidemic, corona virus disease 2019 (COVID-19) caused by SARS-CoV-2 brought great suffering and disaster to mankind. Recently, although significant progress has been made in vaccines against SARS-CoV-2, there are still no drugs for treating COVID-19. It is well known that traditional Chinese medicine (TCM) has achieved excellent efficacy in the treatment of COVID-19 in China. As a treasure-house of natural drugs, Chinese herbs offer a promising prospect for discovering anti-COVID-19 drugs.Hypothesis/Gap Statement. We proposed that Rhei Radix et Rhizome-Schisandrae Sphenantherae Fructus (RS) may have potential value in the treatment of COVID-19 patients by regulating immune response, protecting the cardiovascular system, inhibiting the production of inflammatory factors, and blocking virus invasion and replication processes.Aim. We aimed to explore the feasibility and molecular mechanisms of RS against COVID-19, to provide a reference for basic research and clinical applications.Methodology. Through literature mining, it is found that a Chinese herbal pair, RS, has potential anti-COVID-19 activity. In this study, we analysed the feasibility of RS against COVID-19 by high-throughput molecular docking and molecular dynamics simulations. Furthermore, we predicted the molecular mechanisms of RS against COVID-19 based on network pharmacology.Results. We proved the feasibility of RS anti-COVID-19 by literature mining, virtual docking and molecular dynamics simulations, and found that angiotensin converting enzyme 2 (ACE2) and 3C-like protease (3 CL pro) were also two critical targets for RS against COVID-19. In addition, we predicted the molecular mechanisms of RS in the treatment of COVID-19, and identified 29 main ingredients, 21 potential targets and 16 signalling pathways. Rhein, eupatin, (-)-catechin, aloe-emodin may be important active ingredients in RS. ALB, ESR1, EGFR, HMOX1, CTSL, and RHOA may be important targets against COVID-19. Platelet activation, renin secretion, ras signalling pathway, chemokine signalling pathway, and human cytomegalovirus infection may be important signalling pathways against COVID-19.Conclusion. RS plays a key role in the treatment of COVID-19, which may be closely related to immune regulation, cardiovascular protection, anti-inflammation, virus invasion and replication processes.