Vina Scores Research Articles

In-silico molecular interactions among the secondary metabolites of Caulerpa spp. and colorectal cancer targets.

Caulerpa spp. secrete more than thirty different bioactive chemicals which have already been used in cancer treatment research since they play a pivotal role in cancer metabolism. Colorectal cancer is one of the most common cancer types, thus using novel and effective chemicals for colorectal cancer treatment is crucial. In the cheminformatics pipeline of this study, ADME-Tox and drug-likeness tests were performed for filtering the secondary metabolites of Caulerpa spp. The ligands which were selected from the ADME test were used for in silico molecular docking studies against the enzymes of the oxidative branch of the pentose phosphate pathway (glucose-6-phosphate dehydrogenase and 6-phosphoglutarate dehydrogenase), which is of great importance for colorectal cancer, by using AutoDock Vina. Pharmacophore modeling was carried out to align the molecules. Molecular dynamic simulations were performed for each target to validate the molecular docking studies and binding free energies were calculated. According to the ADME test results, 13 different secondary metabolites were selected as potential ligands. Molecular docking studies revealed that vina scores of caulerpin and monomethyl caulerpinate for G6PDH were found as -10.6 kcal mol-1, -10.5 kcal mol-1, respectively. Also, the vina score of caulersin for 6PGD was found as -10.7kcal mol-1. The highest and the lowest binding free energies were calculated for monomethyl caulerpinate and caulersin, respectively. This in silico study showed that caulerpin, monomethyl caulerpinate, and caulersin could be evaluated as promising marine phytochemicals against pentose phosphate pathway enzymes and further studies are recommended to investigate the detailed activity of these secondary metabolites on these targets.

Interaction of Epigallocatechin Gallate and Quercetin with Spike Glycoprotein (S-Glycoprotein) of SARS-CoV-2: In Silico Study.

Severe acute respiratory syndrome (SARS)-CoV-2 from the family Coronaviridae is the cause of the outbreak of severe pneumonia, known as coronavirus disease 2019 (COVID-19), which was first recognized in 2019. Various potential antiviral drugs have been presented to hinder SARS-CoV-2 or treat COVID-19 disease. Side effects of these drugs are among the main complicated issues for patients. Natural compounds, specifically primary and secondary herbal metabolites, may be considered as alternative options to provide therapeutic activity and reduce cytotoxicity. Phenolic materials such as epigallocatechin gallate (EGCG, polyphenol) and quercetin have shown antibacterial, antifungal, antiviral, anticancer, and anti-inflammatory effects in vitro and in vivo. Therefore, in this study, molecular docking was applied to measure the docking property of epigallocatechin gallate and quercetin towards the transmembrane spike (S) glycoprotein of SARS-CoV-2. Results of the present study showed Vina scores of -9.9 and -8.3 obtained for EGCG and quercetin by CB-Dock. In the case of EGCG, four hydrogen bonds of OG1, OD2, O3, and O13 atoms interacted with the Threonine (THR778) and Aspartic acid (ASP867) amino acids of the spike glycoprotein (6VSB). According to these results, epigallocatechin gallate and quercetin can be considered potent therapeutic compounds for addressing viral diseases.

Stilbene-based derivatives as potential inhibitors of trimethylamine (TMA)-lyase affect gut microbiota in coronary heart disease.

Coronary heart disease (CHD) is defined by atherosclerosis, which may result in stenosis or blockage of the arterial cavity, leading to ischemic cardiac diseases such as angina and myocardial infarction (MI). Accumulating evidence indicates that the gut microbiota play a critical role in the initiation and progression of CHD. The gut microbial metabolite trimethylamine N-oxide (TMAO) is intimately linked to the pathophysiology of CHD. The hepatic flavin-containing monooxygenases (FMOs) convert trimethylamine (TMA) to TMAO. As a result, it is critical to prevent TMA generation. Stilbenes could reduce cardiovascular disease mortality. Twelve stilbenes with inhibitory activity against TMA-lyase were compiled and evaluated in this study. Docking results showed Resveratroloside had the highest Vina score, indicating that it was the most active and might be employed as a lead molecule for further structural modification.

Virtual Screening and Molecular Docking Analysis of Degradation Products of Curcumin as Inhibitors of EGFR

Epidermal growth factor receptor (EGFR), a member of ErbB family of receptor tyrosine kinases, is reportedly overexpressed in various types of human malignancies. Curcumin, a derived phytochemical compound, has demonstrated antiproliferative effects in various cancer cell lines. Since curcumin degrades into different bioactive compounds, attention has been drawn to analyze if these degradation products are primarily responsible for the observed biological activity of curcumin. In the current work 11 degradation products of curcumin were selected and assessed for their drug likeness, ADME and toxicity properties using a diverse range of advanced computational methods. Binding characteristics of EGFR with these ligand molecules were examined using in silico single ligand molecular docking and multi-ligand simultaneous docking (MLSD) methods. Spiroepoxide, one intermediate product of spontaneous oxidation of curcumin, docked with minimum energy ([Formula: see text]9.123[Formula: see text]kcal/mol) as compared to parent curcumin and co-crystallized Erlotinib inhibitor. Vina score for simultaneously docked autooxidation compounds at the binding site of EGFR, where one ligand was curcumin, was lower than the predicted binding energies of singly docked compounds, thus indicating that curcumin-derived compounds produced by the oxidative pathway do take part along with curcumin in inhibiting EGFR. The best ‘posed’ complex, spiroepoxide bound to EGFR, was chosen for MD simulation to examine the stability of this protein–ligand complex.

Proximicin A-C as prospective HER2-positive and negative breast cancer drugs: Molecular docking and in silico ADME modeling

Breast cancer is the second leading cause of cancer-related death among women worldwide. Proximicin A-C are bioactive chemicals produced by the marine Verrucosispora strain, which have been shown to have potent cytostatic effect against human breast cancer [MCF 7]. HER2 (Human epidermal growth factor receptor 2) is a gene that has been linked to breast cancer development. The study’s goals are to (1) forecast the intensity of binding affinity and interactions between HER2 and proximicin A-C, and (2) analyze ADME characteristics of proximicin A-C (Absorption, Distribution, Metabolism, and Excretion). The CB-Dock web service was used to dock proximicin A-C and commonly used breast cancer medicines Neratinib (Nerlynx) and Talazoparib against HER2, and protein-ligand interaction findings were collected via the protein-ligand interaction profiler (PLP) web server. The SwissADME web server was used to investigate ADME properties of the substances. In terms of docking, proximicin A has a vina score of -8.6, proximicin B and C has a score of -10, Talazoparib has a vina score of -8.5, and Neratinib (Nerlynx) has a vina score of -10.2 on CB-Dock. This means that proximicin B and C bind to HER2 more strongly than proximicin A and Talazoparib. Furthermore, their high binding affinity is nearly equivalent to Neratinibs (Nerlynx). Talazoparib has a lower binding affinity for HER2 than proximicin A. With HER2, all three chemicals have a strong hydrogen bond and hydrophobic contact. SwissADME estimated that all three substances follow the Lipinski rule (RO5) and have a bioavailability score of 0.55. They don’t have any structural issue in medicinal chemistry (no alerts in PAINS and Brenk forecasts), and their synthetic accessibility scales range from 3 to 3.5. Only proximicin A, on the other hand, has the leadlikeness feature. All three drugs failed to cross the blood-brain barrier (BBB) in terms of pharmacokinetics. Proximicin A has a high absorption rate in the GI tract, whereas proximicin B-C has a low absorption rate in the GI tract (GI). Similarly, proximicin A is neither a P-gp substrate nor a CYP1A2, CYP2C19, CYP2C9, CYP2D6, or CYP3A4 inhibitor. Proximicin B-C, on the other hand, are P-gp substrates, and proximicin C is an inhibitor of all provided CYP enzymes, whilst proximicin B inhibits only three. Overall, proximicin A-C could be used as a possible breast cancer therapeutic candidate. Proximicin B-C will outperform proximicin A in terms of therapeutic efficacy. Proximicin A, on the other hand, will have better ADME qualities than Proximicin B-C. This study will provide the lead information for developing a new breast cancer medication with a good pharmacological profile.

Design, synthesis and biological evaluation of novel N-phosphorylated and O-phosphorylated tacrine derivatives as potential drugs against Alzheimer’s disease

In this work, we designed, synthesised and biologically investigated a novel series of 14 N- and O-phosphorylated tacrine derivatives as potential anti-Alzheimer’s disease agents. In the reaction of 9-chlorotacrine and corresponding diamines/aminoalkylalcohol we obtained diamino and aminoalkylhydroxy tacrine derivatives. Next, the compounds were acid to give final products 6–13 and 16–21 that were characterised by 1H, 13 C, 31 P NMR and MS. The results of the docking studies revealed that the designed phosphorus hybrids, in theory can bind to AChE and BChE. All compounds exhibited significantly lower AutoDock Vina scores compared to tacrine. The inhibitory potency evaluation was performed using the Ellman’s method. The most inhibitory activity against AChE exhibited compound 8 with an IC50 value of 6.11 nM and against BChE 13 with an IC50 value of 1.97 nM and they were 6- and 12-fold potent than tacrine. Compound 19 showed the lack of hepatocytotoxicity in MTT assay.

Improving protein-ligand docking and screening accuracies by incorporating a scoring function correction term.

Scoring functions are important components in molecular docking for structure-based drug discovery. Traditional scoring functions, generally empirical- or force field-based, are robust and have proven to be useful for identifying hits and lead optimizations. Although multiple highly accurate deep learning- or machine learning-based scoring functions have been developed, their direct applications for docking and screening are limited. We describe a novel strategy to develop a reliable protein–ligand scoring function by augmenting the traditional scoring function Vina score using a correction term (OnionNet-SFCT). The correction term is developed based on an AdaBoost random forest model, utilizing multiple layers of contacts formed between protein residues and ligand atoms. In addition to the Vina score, the model considerably enhances the AutoDock Vina prediction abilities for docking and screening tasks based on different benchmarks (such as cross-docking dataset, CASF-2016, DUD-E and DUD-AD). Furthermore, our model could be combined with multiple docking applications to increase pose selection accuracies and screening abilities, indicating its wide usage for structure-based drug discoveries. Furthermore, in a reverse practice, the combined scoring strategy successfully identified multiple known receptors of a plant hormone. To summarize, the results show that the combination of data-driven model (OnionNet-SFCT) and empirical scoring function (Vina score) is a good scoring strategy that could be useful for structure-based drug discoveries and potentially target fishing in future.

Interaction Analysis of MRP1 with Anticancer Drugs Used in Ovarian Cancer: In Silico Approach.

Multidrug resistance (MDR) is one of the major therapeutic challenges that limits the efficacy of chemotherapeutic response resulting in poor prognosis of ovarian cancer (OC). The multidrug resistance protein 1 (MRP1) is a membrane-bound ABC transporter involved in cross resistance to many structurally and functionally diverse classes of anticancer drugs including doxorubicin, taxane, and platinum. In this study, we utilize homology modelling and molecular docking analysis to determine the binding affinity and the potential interaction sites of MRP1 with Carboplatin, Gemcitabine, Doxorubicin, Paclitaxel, and Topotecan. We used AutoDock Vina scores to compare the binding affinities of the anticancer drugs against MRP1. Our results depicted Carboplatin < Gemcitabine < Topotecan < Doxorubicin < Paclitaxel as the order of binding affinities. Paclitaxel has shown the highest binding affinity whereas Carboplatin displayed the lowest affinity to MRP1. Interestingly, our data showed that Carboplatin, Paclitaxel, and Topotecan bind specifically to Asn510 residue in the transmembrane domains 1 of the MRP1. Our results suggest that Carboplatin could be an appropriate therapeutic choice against MRP1 in OC as it couples weakly with Carboplatin. Further, our findings also recommend opting Carboplatin with Gemcitabine as a combinatorial chemotherapeutic approach to overcome MDR phenotype associated with recurrent OC.

Flavonoids in Lu'an GuaPian tea as potential inhibitors of TMA-lyase in acute myocardial infarction.

Current studies have shown that plasma trimethylamine N-oxide (TMAO) level is closely related to the risk of acute myocardial infarction (AMI), that is, the possibility of AMI occurrence is positively correlated with TMAO level. The production of TMAO is mainly due to the transformation of trimethylamine (TMA) through the hepatic flavin-containing monooxygenase. Hence, inhibition of TMA production is essential. Flavonoids are considered to be mainly responsible for the health-promoting effects, and tea is rich in a variety of flavonoids. However, it is not clear that flavonoids from Lu'an GuaPian tea regulate gut microflora by inhibiting TMA-lyase activity to prevent AMI. Sixteen flavonoids from Lu'an GuaPian tea for the treatment of AMI based on the inhibition of TMA-lyase were summarized and screened. Docking results showed kaempferol 3-O-rutinoside had the highest Vina score, which means that it is the most active and can be used as lead compounds for structural modification. PRACTICAL APPLICATIONS: TMAO can be used as a marker of CHD and thus as a potential research object. Lu'an GuaPian tea is one of the top 10 famous teas in China and has the aroma of chestnuts and orchids. The flavonoids in Lu'an GuaPian tea are mainly composed of flavonoid aglycones and flavonoid glycosides. Since flavonoids have cardiovascular protection and can regulate gut microbiota, and gut microbiota is directly related to TMAO, reduction of TMAO level is to inhibit the transformation from TMA to TMAO. Kaempferol 3-O-rutinoside, quercetin 3-O-rhamnosylgalactoside, kaempferol 3-O-rhamnosylgalactoside, and myricetin 3-O-galactoside in Lu'an GuaPian tea have good binding affinities with TMA-lyase.

Utilization of Quercetin Flavonoid Compounds in Red Onion (Allium cepa L.) as Inhibitor of Spike Sars-CoV-2 Protein against ACE2 Receptors

The world is facing the challenge of the COVID-19 disease, which is now stated as a pandemic. Inside the host cell, spike envelope protein (spike) of SARS-CoV-2 interact with the Angiotensin-converting Enzyme 2 (ACE2) receptor. It can be inhibited by bioactive compounds such as flavonoids which have anti-viral and broad pharmacological effect. This study aimed to determine the spike protein inhibitory activity by quercetin against the ACE2 receptor using the molecular docking method. This study focused on the inhibitory of the penetration activity of s proteins in ACE2 by utilizing natural material compounds that have the potential to be used as anti-SARS-CoV-2 drug development agents. The flavonoid compound quercetin was extracted by the maceration method. The quantitative analysis was carried out using a UV-Vis spectrophotometer to prove the presence of quercetin content. Molecular docking simulations were carried out to look for the binding affinity between the spike protein and quercetin. Docking was carried out using the Autodock, PyRx, and visualization using Discovery Studio. Indicators that prove that quercetin forms binding affinity and protein complexes with spikes are the Vina Score and RMSD. It is also supported by ADME analysis and conformity to Lipinski's rules of five. That matter becomes a success indicator of the spike activity inhibition by quercetin, which makes it possible to be used as an anti-SARS-CoV-2 drug development agent. The novelty from this study is molecular docking method that used to show that quercetin in red onion had inhibitory activity on the penetration process of protein spike in SARS-CoV-2. Results obtained from this study can be used as a recommendation for advanced research in invitro and invivo studies as a drug which has potential to inhibit protein spike of SARS-CoV-2.

Identification of Potential Inhibitors of SARS-CoV-2 Main Protease from Allium roseum L. Molecular Docking Study

The recent outbreak of the respiratory pandemic known as novel coronavirus SARS-CoV-2 disease “COVID-19” was first identified in Wuhan, China and quickly spread to other countries. The 3CL protease (3CLpro) enzyme is the main protease of the SARS-CoV-2, which is responsible for coronavirus replication and therefore, the 3CLpro is considered a drug discovery target. The study reports that the molecular docking approach of 30 compounds had been identified from Allium roseum against two 3CL proteases (3CLpro) targets (PDB: 6LU7) (PDB: 6M2N) of SARS-CoV-2 using Autodock Vina. The docking results revealed that the top three compounds, Kaempferol-7-O-rutinoside, Kaempferol-3-O-glucuronoside and Apigenin-7-O-glucoside, displayed high affinity against the two 3CLproteas binding pockets. The free energy of binding (FEB) were − 12.10, − 11.80 and − 11.52 against 6LU7 and − 11.83, − 11.34 and − 11.01 kcal/mol against 6M2N for Autodock, while AutoDock Vina scores were − 11.6, − 11.2 and − 10.3 kcal/mol against 6LU7 and − 11.1, − 10.8 and − 10.5 kcal/mol against 6M2N. The results reveal that the three compounds fully interact with the essential amino acids in the binding pocket catalytic dyad Cys145 and His41 of the two 3CLpro. Consequently, they are expected to hinder SARS-CoV-2 3CLpro activity. In conclusion, our In-silico results suggest that the three identified compounds could serve as a potential lead that could inhibit the function of 3CLprotease (3CL pro) of Coronavirus. However, in-vitro and in-vivo experiments are necessary to certify and confirm the docking results reported here.

Artificial Intelligence-Guided De Novo Molecular Design Targeting COVID-19.

An extensive search for active therapeutic agents against the SARS-CoV-2 is being conducted across the globe. While computational docking simulations remain a popular method of choice for the in silico ligand design and high-throughput screening of therapeutic agents, it is severely limited in the discovery of new candidate ligands owing to the high computational cost and vast chemical space. Here, we present a de novo molecular design strategy that leverages artificial intelligence (AI) to discover new therapeutic agents against SARS-CoV-2. A Monte Carlo tree search algorithm combined with a multitask neural network surrogate model for expensive docking simulations, and recurrent neural networks for rollouts, is used in an iterative search and retrain strategy. Using Vina scores as the target objective to measure binding to either the isolated spike protein (S-protein) at its host receptor region or to the S-protein/angiotensin converting enzyme 2 receptor interface, we generate several (∼100’s) new therapeutic agents that outperform Food and Drug Administration (FDA) (∼1000’s) and non-FDA molecules (∼million). Our AI strategy is broadly applicable for accelerated design and discovery of chemical molecules with any user-desired functionality.

Inverse Molecular Docking Study of NS3-Helicase and NS5-RNA Polymerase of Zika Virus as Possible Therapeutic Targets of Ligands Derived from Marcetia taxifolia and Its Implications to Dengue Virus.

Dengue and Zika are two mosquito-borne diseases of great impact on public health around the world in tropical and subtropical countries. DENV and ZIKV belong to the Flaviviridae family and the Flavivirus genus. Currently, there are no effective therapeutic agents to treat or prevent these pathologies. The main objective of this work was to evaluate potential inhibitors from active compounds obtained from Marcetia taxifolia by performing inverse molecular docking on ZIKV-NS3-helicase and ZIKV-NS5-RNA polymerase as targets. This computational strategy is based on renormalizing the binding scores of the compounds to these two proteins, allowing a direct comparison of the results across the proteins. The crystallographic structures of the ZIKV-NS3-helicase and ZIKV-NS5-RNA-polymerase proteins share a great similarity with DENV homologous proteins. The P-loop active site of the crystallographic structure of ZIKV-NS3-helicase presents a high percentage of homology with the four dengue serotypes. It was found that most ligands of the active compounds (5,3’-dihydroxy-3,6,7,8,4′-pentamethoxyflavone (5DP); 5-hydroxy-3,6,7,8,3′,4′-hexamethoxyflavone (5HH); myricetin-3-O-rhamnoside (M3OR)) from Marcetia taxifolia had a better affinity for ZIKV-NS3-helicase than for ZIKV-NS5-RNA polymerase, as indicated by the negative multiple active site correction (MASC) score, except for M3RG that showed a higher affinity for ZIKV-NS5-RNA polymerase. On the other hand, the AutoDock Vina scores showed that M3OR had the highest score value (−9.60 kcal/mol) and the highest normalized score (1.13) against ZIKV-NS3-helicase. These results in silico demonstrated that the nonstructural proteins NS3-helicase and NS5-RNA polymerase, which share similar molecular structures between the selected viruses, could become therapeutic targets for some bioactive compounds derived from Marcetia taxifolia.

Identification of Potential Inhibitors of 3CL Protease of SARS-CoV-2 From ZINC Database by Molecular Docking-Based Virtual Screening.

The rapid outbreak of Coronavirus Disease 2019 (COVID-19) that was first identified in Wuhan, China is caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The 3CL protease (3CLpro) is the main protease of the SARS-CoV-2, which is responsible for the viral replication and therefore considered as an attractive drug target since to date there is no specific and effective vaccine available against this virus. In this paper, we reported molecular docking-based virtual screening (VS) of 2000 compounds obtained from the ZINC database and 10 FDA-approved (antiviral and anti-malaria) on 3CLpro using AutoDock Vina to find potential inhibitors. The screening results showed that the top four compounds, namely ZINC32960814, ZINC12006217, ZINC03231196, and ZINC33173588 exhibited high affinity at the 3CLpro binding pocket. Their free energy of binding (FEB) were −12.3, −11.9, −11.7, and −11.2 kcal/mol while AutoDock Vina scores were −12.61, −12.32, −12.01, and -11.92 kcal/mol, respectively. These results were better than the co-crystallized ligand N3, whereby its FEB was −7.5 kcal/mol and FDA-approved drugs. Different but stable interactions were obtained between the four identified compounds with the catalytic dyad residues of the 3CLpro. In conclusion, novel 3CLpro inhibitors from the ZINC database were successfully identified using VS and molecular docking approach, fulfilling the Lipinski rule of five, and having low FEB and functional molecular interactions with the target protein. The findings suggests that the identified compounds may serve as potential leads that act as COVID-19 3CLpro inhibitors, worthy for further evaluation and development.

A Computational Approach for Identifying Potential Phytochemicals Against Non-structural Protein 1 (Nsp1) of SARS-CoV-2.

A recent study has revealed that non-structural protein 1 (Nsp1) of the SARS-CoV-2 is one of the novel targets for developing new antiviral drugs. To date, there is no significant exact medication available to treat Covid-19. As a result, both the death toll and the number of people affecting by this disease are increasing with each passing day. 35 phytochemicals having antiviral properties were taken to get the best compounds against Nsp1 Materials and Methods: As no PDB structure of this protein is available, homology modeling was done to predict the probable structure. After homology modeling, the best model was taken according to C-score and TM- score and then validated using different web servers. After validation, docking of these compounds was done using AutoDock vina, vega zz, and PyRx, and consensus docking score was considered to select molecules after docking. Finally, the orbitals energy calculation of these compounds was done to check their activity and the binding interactions of these molecules also analyzed. Molecules having a consensus score of -8kcal/mol or more negative were kept for further study and it was seen that 16 molecules had the given criteria. Then, drug-likeness filtration was done according to Lipinski's rule of five and 11 molecules remained. Out of these 11 molecules, 5 molecules had satisfactory ADMET properties. Calculation of orbital energy revealed their activity. It is expected that this research might be helpful for the development of new antiviral drugs active against SARS-CoV-2 targeting Nsp1.

Molecular mechanism of Puerariae Lobatae Radix in treatment of hepatocellular carcinoma based on network pharmacology

To investigate the potential mechanism of Puerariae Lobatae Radix in the treatment of hepatocellular carcinoma by network pharmacology and in vitro cell experiment. The main active components of Puerariae Lobatae Radix and their predicted targets were obtained from TCMSP, and the disease targets were obtained from GeneCards database. The disease and drug prediction targets were intersected to select the common potential therapeutic targets. The &quot;compound-target-disease&quot; network diagram was constructed in Cytoscape 3.7.1, and the common targets were input into the STRING database to build the PPI network of proteins interaction. GO function and KEGG pathway enrichment analysis on effective targets were performed by using R software. Autodock vina 1.1.2 was used for molecular docking. Finally, the core targets and pathways were preliminarily verified by in vitro experiments. The proliferation of human hepatocellular carcinoma cells was detected by CCK-8 and EDU enzyme staining, and the expressions of PTEN, PDK1, Akt and GSK3 were detected by Western blot. In this study, 10 components of Puerariae Lobatae Radix(9 components involved in hepatocellular carcinoma-related targets and signaling pathways), and 149 hepatocellular carcinoma-related targets and 156 signaling pathways were screened out. The results of network analysis indicated that Puerariae Lobatae Radix may play an anti-hepatocellular carcinoma effect on key targets, such as Akt, IL6, MAPK3, EGFR, and key pathways, such as PI3 K-Akt. The results of molecular docking indicated that puerarin, genistein and daidzein had a good binding ability with the key targets such as AKT1, MAPK3, MAPK1 and CASP3, and puerarin had the lowest Vina score with AKT1 and MAPK3 and also similar to them. In vitro cell experiments confirmed that puerarin has a significantly inhibitory effect on the proliferation of human hepatocellular carcinoma cells. Western blot results showed that puerarin could increase the phosphorylation of PTEN in human hepatocellular carcinoma cells through the PTEN/Akt/GSK3β signaling pathway, and the phosphorylation level of its downstream Akt decreased. This series of studies confirm that puerarin can treat hepatocellular carcinoma by blocking PTEN/Akt/GSK3β cellular signaling pathway, so as to provide ideas for subsequent studies for the molecular mechanism of puerarin in the treatment of liver cancer.

Molecular interaction of 4-amino-N’-(benzoyloxy)-N-(2,4- dimethylphenyl)-1,2,5-oxadiazole-3-carboximidamide with the methotrexate binding site of human DHFR, and its implication in rheumatoid arthritis

Purpose: To identify an improved lead molecule for the human dihydrofolate reductase (DHFR) inhibition that ‘sits’ in the same binding cavity as methotrexate by high throughput computationalscreening.Methods: The 3-D structure of the DHFR binding site was examined using ‘CASTp3.0’. Structure based in silico screening of about 5 million drug candidates housed in the MCULE database was performed. The obtained molecule-hits were ranked in accordance with their VINA scores, made to pass through drug-likeness filters, ΔG cut-off criterion, toxicity-checker and finally ‘zero RO5 criterion’.Results: The ‘top molecule’, namely, 4-amino-N'-(benzoyloxy)-N-(2,4-dimethylphenyl)-1,2,5-oxadiazole- 3-carboximidamide, displayed robust binding with human DHFR through 21 amino acid residues (ΔG = - 9.6 kcal/mol) while 10 of these residues were the same as those displayed by ‘methotrexate binding interactions’. It passed through relevant drug screening filters including the ‘Toxicity Checker’.Conclusion: This research work describes the molecular interaction of human DHFR with an improved lead molecule named, 4-amino- N’-(benzoyloxy)-N-(2,4-dimethylphenyl)-1,2,5-oxadiazole-3- carboximidamide, with a ΔG of -9.6 kcal/mol, thus satisfying adequate ADME features for further in vitro and in vivo validation in the context of rheumatoid arthritis.&#x0D; Keywords: Dihydrofolate reductase, In silico screening, Methotrexate, Rheumatoid arthritis, DHFR

Novel Acetylcholinesterase Inhibitors Identified from ZINC Database Using Docking‐Based Virtual Screening for Alzheimer's Disease.

AbstractAlzheimer's disease (AD) is a neurodegenerative disease related to ageing. Cholinesterases are a family of enzymes that catalyse the hydrolysis of acetylcholine (ACh), which is an essential process in the cholinergic neurotransmission. Cholinesterases can be divided into two types, namely acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). This paper reports virtual screening and molecular docking of 200 compounds obtained from the ZINC database, using AutoDock Vina and AutoDock 4.2 to find potential AChE inhibitors. Only compounds that are compliant with Lipinski's rule of five for drug‐likeness properties were virtually screened to identify novel compounds that show similar or better interaction with the target protein compared to the coordinated ligand galantamine. The results showed that 6 compounds, namely ZINC10140364, ZINC08061148, ZINC34735322, ZINC05151975, ZINC33126088 and ZINC15805418, exhibited better free energy of binding (FEB) than galantamine, with AutoDock Vina scores of −9.88, −10.44, −10.30, −9.63, −8.35 and −9.42 kcal/mol and AutoDock scores of −12.3, −11.6, −11.0, −10.9, −10.5 and −9.3 kcal/mol, respectively. In conclusion, the results obtained suggest that the 6 compounds are potential AChE inhibitors suitable for further evaluation and development as potential agents for treatment.

Novel quinolinone-pyrazoline hybrids: synthesis and evaluation of antioxidant and lipoxygenase inhibitory activity.

The present project deals with the investigation of structure-activity relationship of several quinolinone-chalcone and quinolinone-pyrazoline hybrids, in an effort to discover promising antioxidant and anti-inflammatory agents. In order to accomplish this goal, four bioactive hybrid quinolinone-chalcone compounds (8a-8d) were synthesized via an aldol condensation reaction, which were then chemically modified, forming fifteen new pyrazoline analogues (9a-9o). All the synthesized analogues were in vitro evaluated in terms of their antioxidant and soybean lipoxygenase (LOX) inhibitory activity. Among all the pyrazoline derivatives, compounds 9b and 9m were found to possess the best combined activity, whereas 9b analogue exhibited the most potent LOX inhibitory activity, with IC50 value 10μM. The in silico docking results revealed that the synthetic pyrazoline analogue 9b showed high AutoDock Vina score (- 10.3kcal/mol), while all the tested derivatives presented allosteric interactions with the enzyme.

AlphaSpace 2.0: Representing Concave Biomolecular Surfaces Using β-Clusters.

Modern rational modulator design and structure-function characterization often concentrate on concave regions of biomolecular surfaces, ranging from well-defined small-molecule binding sites to large protein-protein interaction interfaces. Here, we introduce a β-cluster as a pseudomolecular representation of fragment-centric pockets detected by AlphaSpace [J. Chem. Inf. Model. 2015, 55, 1585], a recently developed computational analysis tool for topographical mapping of biomolecular concavities. By mimicking the shape as well as atomic details of potential molecular binders, this new β-cluster representation allows direct pocket-to-ligand shape comparison and can be used to guide ligand optimization. Furthermore, we defined the β-score, the optimal Vina score of the β-cluster, as an indicator of pocket ligandability and developed an ensemble β-cluster approach, which allows one-to-one pocket mapping and comparison among aligned protein structures. We demonstrated the utility of β-cluster representation by applying the approach to a wide variety of problems including binding site detection and comparison, characterization of protein-protein interactions, and fragment-based ligand optimization. These new β-cluster functionalities have been implemented in AlphaSpace 2.0, which is freely available on the web at http://www.nyu.edu/projects/yzhang/AlphaSpace2.