O-Methylation of flavonoids using DnrK based on molecular docking

Omicron-Methylation is a common substitution reaction found in microbes as well as in mammalians. Some of the Omicron-methyltransferases (OMTs) have broad substrate specificity and could be used to methylate various compounds. DnrK from Streptomyces peucetius encodes an anthracycline 4-Omicron-methyltransferase, which uses carminomycin as a substrate, and its crystal structure has been determined. Molecular docking experiments with DnrK using various flavonoids were successfully conducted, and some of the flavonoids such as apigenin and genistein were predicted to serve as substrates. Based on these results, Omicron-methylations of various flavonoids with the DnrK were successfully carried out. The methylation position was determined to be at the hydroxyl group of C7. Important amino acid residues for the enzymatic reaction of DnrK with apigenin could be identified using site-directed mutagenesis. Molecular docking could be useful to predict the substrate specificity ranges of other OMTs.     

Molecular docking analysis of flavonoids with aldose reductase

Diabetes mellitus is a group of metabolic disorders that has risen to become the third most common cause in humans in recent years. The development of new bioactive substances from natural sources is a relatively new area. Flavonoids are believed to have a variety of beneficial properties in nature, including anti-inflammatory, antimicrobial, anticancer, antioxidant, neuroprotective, and anti-HIV properties. 15 naturally occurring flavonoids docked with the selected target aldose reductase. We report the optimal binding of Acumitin, Agathisflavone, Agehoustin B, and alpha-Toxicarol with aldose reductase for further consideration in drug discovery for T2DM.     

Metabolic pathway analysis and molecular docking analysis for identification of putative drug targets in Toxoplasma gondii: novel approach

Toxoplasma gondii is an obligate intracellular apicomplexan parasite that can infect a wide range of warm-blooded animals including humans. In humans and other intermediate hosts, toxoplasma develops into chronic infection that cannot be eliminated by host's immune response or by currently used drugs. In most cases, chronic infections are largely asymptomatic unless the host becomes immune compromised. Thus, toxoplasma is a global health problem and the situation has become more precarious due to the advent of HIV infections and poor toleration of drugs used to treat toxoplasma infection, having severe side effects and also resistance have been developed to the current generation of drugs. The emergence of these drug resistant varieties of T. gondii has led to a search for novel drug targets. We have performed a comparative analysis of metabolic pathways of the host Homo sapiens and the pathogen T. gondii. The enzymes in the unique pathways of T. gondii, which do not show similarity to any protein from the host, represent attractive potential drug targets. We have listed out 11 such potential drug targets which are playing some important work in more than one pathway. Out of these, one important target is Glutamate dehydrogenase enzyme; it plays crucial part in oxidation reduction, metabolic process and amino acid metabolic process. As this is also present in the targets of tropical diseases of TDR (Tropical disease related Drug) target database and no PDB and MODBASE 3D structural model is available, homology models for Glutamate dehydrogenase enzyme were generated using MODELLER9v6. The model was further explored for the molecular dynamics simulation study with GROMACS, virtual screening and docking studies with suitable inhibitors against the NCI diversity subset molecules from ZINC database, by using AutoDock-Vina. The best ten docking solutions were selected (ZINC01690699, ZINC17465979, ZINC17465983, ZINC18141294_03, ZINC05462670, ZINC01572309, ZINC18055497_01, ZINC18141294, ZINC05462674 and ZINC13152284_01). Further the Complexes were analyzed through LIGPLOT. On the basis of Complex scoring and binding ability it is deciphered that these NCI diversity set II compounds, specifically ZINC01690699 (as it has minimum energy score and one of the highest number of interactions with the active site residue), could be promising inhibitors for T. gondii using Glutamate dehydrogenase as Drug target.     

Chemical inhibition of fatty acid synthase: molecular docking analysis and biochemical validation in ocular cancer cells

Fatty acid biosynthesis is an attractive target for anti-cancer therapeutics. The ocular cancer, retinoblastoma cells were treated with fatty acid synthase (FASN) enzyme inhibitors: cerulenin, triclosan and orlistat. The IC₅₀ and dose-dependent sensitivity of cancer cells to FASN inhibitors decrease in biologic enzyme activity, and cell morphology alterations were analysed. Molecular interactions of enzyme-inhibitor complexes were studied by molecular modelling and docking simulations. The crystal structures of ketoacyl synthase (PDB ID:3HHD) (cerulenin) and thioesterase (PDB ID:2PX6) (orlistat) domains of human FASN were utilized for docking, while for the non-crystallised human FASN enoyl reductase domain (triclosan), homology model was built and used for docking. All three inhibitors showed significant binding energy indicating stable complex formation with their respective FASN subunits. The predicted Ki value of the FASN inhibitors corroborated well with their corresponding anti-cancer effects.     

Molecular docking analysis of lupeol with different cancer targets

Lupeol is one of the secondary metabolite (triterpenoid) present in many medicinally effective plants. It has numerous biological and pharmacological actions. Lupeol is found to have effective herbs and has immense biological activity against several diseases including its cytotoxic effect on cancer cells. In recent drug designing, molecular study of analysis is usually used for understanding the target and the ligand interaction. Therefore, it is of interest to document the molecular docking analysis data of lupeol with different cancer targets such as Caspase- 3, BCL-2, Topoisomerase, PTK, mTOR, H-Ras, PI3K, and AKT. These molecular docking studies were carried out by using AutoDock tools 4.2 version software. Molecular docking analyses of lupeol with target protein were found to have good dock score and minimum inhibition constant. BCL-2, Topoisomerase, PTK, mTOR and PI3Kdocking studies showed the best binding energy inhibition constant and ligand efficiency. The in-silico molecular docking analysis showed that the lupeol having relatively good docking energy, affinity and efficiency towards the active macromolecule, thus it may be considered as good inhibitor of proliferating cancer cells. By this knowledge of docking results, the lupeol can be used as promising drug for anticancer activity.     

Triazolopyridazine derivatives: Synthesis,cytotoxic evaluation,c-Met kinase activity and molecular docking

Novel series of some triazolo[4,3-b]pyridazine derivatives were designed and synthesized. All the newly synthesized compounds were evaluated for their cytotoxic activity at 10⁻⁵ M concentration towards 60 cancer cell lines according to USA NCI protocol. Most of the synthesized compounds showed good activity against SR (leukemia) cell panel. The most active compounds, 2f and 4a were subjected for further evaluation at a five dose level screening and their efficacy for c-Met kinase inhibition was determined in vitro. Binding mode of these derivatives was explored via molecular docking.     

Structural analysis and molecular docking of trypanocidal aryloxy-quinones in trypanothione and glutathione reductases: a comparison with biochemical data

A set of aryloxy-quinones, previously synthesized and evaluated against Trypanosoma cruzi epimastigotes cultures, were found more potent and selective than nifurtimox. One of the possible mechanisms of the trypanocidal activity of these quinones could be inhibition of trypanothione reductase (TR). Considering that glutathione reductase (GR) is the equivalent of TR in humans, biochemical, kinetic, and molecular docking studies in TR and GR were envisaged and compared with the trypanocidal and cytotoxic data of a set of aryloxy-quinones. Biochemical assays indicated that three naphthoquinones (Nq-h, Nq-g, and Nq-d) selectively inhibit TR and the TR kinetic analyses indicated that Nq-h inhibit TR in a noncompetitive mechanism. Molecular dockings were performed in TR and GR in the following three putative binding sites: the catalytic site, the dimer interface, and the nicotinamide adenine dinucleotide phosphate-binding site. In TR and GR, the aryloxy-quinones were found to exhibit high affinity for a site near it cognate-binding site in a place in which the noncompetitive kinetics could be justified. Taking as examples the three compounds with TR specificity (TRS) (Nq-h, Nq-g, and Nq-d), the presence of a network of contacts with the quinonic ring sustained by the triad of Lys62, Met400′, Ser464′ residues, seems to contribute hardly to the TRS. Compound Nq-b, a naphthoquinone with nitrophenoxy substituent, proved to be the best scaffold for the design of trypanocidal compounds with low toxicity. However, the compound displayed only a poor and non-selective effect toward TR indicating that TR inhibition is not the main reason for the antiparasitic activity of the aryloxy-quinones.     

Structure-activity relationships and molecular docking of thirteen synthesized flavonoids as horseradish peroxidase inhibitors

For the first time, the structure–activity relationships of thirteen synthesized flavonoids have been investigated by evaluating their ability to modulate horseradish peroxidase (HRP) catalytic activity. Indeed, a modified spectrophotometrically method was carried out and optimized using 4-methylcatechol (4-MC) as peroxidase co-substrate.The results show that these flavonoids exhibit a great capacity to inhibit peroxidase with Ki values ranged from 0.14 ± 0.01 to 65 ± 0.04 mM. Molecular docking has been achieved using Auto Dock Vina program to discuss the nature of interactions and the mechanism of inhibition. According to the docking results, all the flavonoids have shown great binding affinity to peroxidase. These molecular modeling studies suggested that pyran-4-one cycle acts as an inhibition key for peroxidase. Therefore, potent peroxidase inhibitors are flavonoids with these structural requirements: the presence of the hydroxyl (OH) group in 7, 5 and 4′ positions and the absence of the methoxy (O–CH₃) group. Apigenin contributed better in HRP inhibitory activity.The present study has shown that the studied flavonoids could be promising HRP inhibitors, which can help in developing new molecules to control thyroid diseases.     

A comparative modeling and molecular docking study on Mycobacterium tuberculosis targets involved in peptidoglycan biosynthesis

An alarming rise of multidrug-resistant Mycobacterium tuberculosis strains and the continuous high global morbidity of tuberculosis have reinvigorated the need to identify novel targets to combat the disease. The enzymes that catalyze the biosynthesis of peptidoglycan in M. tuberculosis are essential and noteworthy therapeutic targets. In this study, the biochemical function and homology modeling of MurI, MurG, MraY, DapE, DapA, Alr, and Ddl enzymes of the CDC1551 M. tuberculosis strain involved in the biosynthesis of peptidoglycan cell wall are reported. Generation of the 3D structures was achieved with Modeller 9.13. To assess the structural quality of the obtained homology modeled targets, the models were validated using PROCHECK, PDBsum, QMEAN, and ERRAT scores. Molecular dynamics simulations were performed to calculate root mean square deviation (RMSD) and radius of gyration (Rg) of MurI and MurG target proteins and their corresponding templates. For further model validation, RMSD and Rg for selected targets/templates were investigated to compare the close proximity of their dynamic behavior in terms of protein stability and average distances. To identify the potential binding mode required for molecular docking, binding site information of all modeled targets was obtained using two prediction algorithms. A docking study was performed for MurI to determine the potential mode of interaction between the inhibitor and the active site residues. This study presents the first accounts of the 3D structural information for the selected M. tuberculosis targets involved in peptidoglycan biosynthesis.     

Spectral and molecular docking studies on the interaction of three flavonoids with bovine serum albumin

Communicated by Ramaswamy H. Sarma     

Therapeutic properties and molecular docking study of some phenolic compounds as anti-human lung cancer potential: A biochemical approach

Chloroxine (5,7-dichloro-8-hydroxyquinoline) is a molecule utilized in some shampoos for the therapy of seborrheic dermatitis of the scalp and dandruff. In this study, we investigated the inhibition effects of 5,7-dichloro-8-hydroxyquinoline and methyl 3,4,5-trihydroxybenzoate compounds on the 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA Reductase) and urease enzymes. We have obtained results for the HMG-CoA Reductase and urease enzymes at the micromolar level. In our study, inhibition result of 5,7-dichloro-8-hydroxyquinoline and Methyl 3,4,5-trihydroxybenzoate on HMG-CoA reductase showed lower values 2.28 ± 0.78 and 33.25 ± 5.04 µg/ml, respectively. Additionally, inhibition result of 5,7-dichloro-8-hydroxyquinoline and methyl 3,4,5-trihydroxybenzoate on urease showed lower values 6.18 ± 1.38 and 8.51 ± 1.35 µg/ml, respectively. Molecular docking calculations were made for their biological activities were compared. In the present work, the structures of the related compounds ( 1 and 2 ) were drawn using Gaussian 09 software and done geometry optimization at DFT/B3LYP/6-31G* basis set with aforementioned program. Cytotoxicity potential of these compounds against human lung cancer demonstrated that these compounds had good cytotoxic effects. Both compounds significantly decreased lung cell viability from low doses. In addition, 100 µM dose of all compounds caused significant reductions in lung cell viability. In general, we can say that of the two tested compounds, 5,7-dichloro-8-hydroxyquinoline and methyl 3,4,5-trihydroxybenzoate have cytotoxic effects in all cell types, and this effect is particularly strong in lung cells. Activities were performed at concentrations of 10, 20, 50, 70, and 100 µl and we achieved good results. Lung cell viability (%) value was better at 100 µl concentration and IC₅₀ of them were 54.28 and 48.05 µM.     

Hydrophobic docking: A proposed enhancement to molecular recognition techniques

In the classical procedures for predicting the structure of protein complexes two molecules are brought in contact at multiple relative positions, the extent of complementarity (geometric and/or energy) at the surface of contact is assessed at each position, and the best fits are retrieved. In view of the higher occurrence of hydrophobic groups at contact sites, their contribution results in more intermolecular atom–atom contacts per unit area for correct matches than for false positive fits. The hydrophobic groups are also potentially less flexible at the surface. Thus, from a practical point of view, a partial representation of the molecules based on hydrophobic groups should improve the quality of the results in finding molecular recognition sites, as compared to full representation. We tested this proposal by applying the idea to an existing geometric fit procedure and compared the results obtained with full vs. hydrophobic representations of molecules in known molecular complexes. The hydrophobic docking yielded distinctly higher signal-to-noise ratio so that the correct match is discriminated better from false positive fits. It appears that nonhydrophobic groups contribute more to false matches. The results are discussed in terms of their relevance to molecular recognition techniques as compared to energy calculations. © 1994 Wiley-Liss, Inc.     

Biochemical characterization,cytotoxic, antimutagenic,anticancer and molecular docking studies on Tecomella undulata

In this study bioassay-guided screening of Tecomella undulate was performed for its cytotoxic, antimutagenic and anticancer potential. The ariel parts were extracted on a polarity basis (methanol, dichloromethane and hexane). The in vivo toxicity was assessed on Caenorhabditis elegans, and its locomotion was affected by Tecomella undulata hexane (TUAH) the most. Ames test for antimutagenicity showed Tecomella undulata methanol (TUAM) exhibited against mutagen 2AA showed inhibition of 71.03% and 26.32% 2AA in TA98 while in in vitro MTT assay on carcinoma cell lines TUAM showed 68.1% cytotoxicity. Moreover, In resazurin assay on fibroblast cells African green monkey kidney VERO and on the panel of carcinoma cell lines, the most effective extract was TUAM on liver HepG-2 with CC₅₀ value 117.37 ± 4.73 µg/ml followed by on lungs A549 with 142.01 ± 5.3. Furthermore, for the bioassay-guided screening, the selectivity index was calculated for TUAM CC₅₀ ratio on HepG-2 and VERO which showed a decent 2.77 score. After column chromatography, the fraction TU-63 should remarkable cytotoxic effect in dose–response manner assay as (Hep-G2) CC₅₀ value 11. 67 ± 1.37 µg/ml followed by (A549) CC₅₀ value 17.23 ± 0.58 µg/ml. For qualitative analysis of anticancer potential LC-ESI-MS/MS the potential phytochemicals were identified. In silico molecular modelling against selected carcinogenic proteins. The results suggest Tecomella undulate the substantial anticancer potential which supports potential natural anticancer therapeutic drug candidate development for combating cancer.     

PTools: an opensource molecular docking library

Background  

Macromolecular docking is a challenging field of bioinformatics. Developing new algorithms is a slow process generally involving routine tasks that should be found in a robust library and not programmed from scratch for every new software application.     

Congenital myasthenic syndromes: A diverse array of molecular targets

The neuromuscular junction (NMJ) has served as a prototype for understanding mechanisms underlying synaptic transmission over the past 50 years. More recently, analysis of congenital myasthenic syndromes (CMS) revealed a diverse array of molecular targets and delineated their contributions to synaptic function. Clinical, electrophysiologic and morphologic studies have paved the way for detecting CMS-related mutations in proteins such as choline acetyltransferase acetylcholinesterase, the acetylcholine receptor, rapsyn, and the voltage-gated sodium channel of the Na_v1.4 type. Further studies of the mutant proteins have allowed us to correlate the effects of the mutations with predicted alterations in protein structure. In this review, we focus on the symptomatology of the CMS, consider the factors that impair neuromuscular transmission, survey the mutations that have been uncovered in the different synaptic proteins, and consider the functional implications of the identified mutations.     

Muscarinic receptors: A comparative analysis of structural features and binding modes through homology modelling and molecular docking

Three-dimensional models of the five human muscarinic receptors were obtained from their known sequences. Homology modelling based on the crystallographic structure of bovine rhodopsin yielded models compatible with known results from site-directed mutagenesis studies. The only exceptions were the cytoplasmic loop 3 (CL3) in the five receptors, and the large C-terminal domain in M(1). Here, homology modelling with other closely related proteins allowed to solve these gaps. A detailed comparative discussion of the five models is given. The second part of the work involved docking experiments with the physiological ligand acetylcholine, again yielding results entirely compatible with results from mutagenesis experiments. The study revealed analogies and differences between the five receptors in the residues, and interactions leading to the recognition and binding of acetylcholine.     

Comparative molecular docking analysis of essential oil constituents as elastase inhibitors

Elastase is a protease or proteolytic enzyme, responsible for the breakdown of protein. There are eight human genes encoding for elastase, of which Elastase-1 (CELA-1) and Elastase-2 (ELANE) has significant implications on human diseases. Elastase-1 is primarily expressed in skin keratinocytes and is regarded as the major cause for the blistering in bullous pemphigoid, which affects the skin. On the other hand, Elastase-2 (ELANE), is expressed in the azurophil granules of neutrophils, is responsible for pulmonary emphysema and cyclic hematopoiesis a rare genetic disorder. Elastase is also produced by bacteria such as Pseudomonas aeruginosa, and forms the virulent factor in human. The ingredients from essential natural oils were found to have wound healing effects on non-healing wounds that is interfered by elastase due to microbial infection. Essential oils such as citral, citronellal, geranial, geraniol, and thymol were screened for their inhibitory activity on elastase produced by neutrophil, skin, and Pseudomonas aeruginosa by docking and were analyzed for their subcutaneous ADMET properties by ADME - TOX - Web server.     

Synthesis, characterization, molecular docking and cytotoxic activity of novel plumbagin hydrazones against breast cancer cells

Novel plumbagin hydrazonates were prepared, structurally characterized and evaluated for anti-proliferative activity against estrogen receptor-positive MCF-7 and triple negative MDA-MB-231 and MDA-MB-468 breast cancer cell lines which exhibited superior inhibitory activity than parent plumbagin compound. Molecular docking studies indicated that hydroxyl groups on plumbagin and hydrazonate side chain favor additional hydrogen bonding interactions with amino acid residues in p50-subunit of NF-κB protein and these compounds inhibited NF-κB expression which may be responsible for the enhanced anti-proliferative activity. These compounds were found to be more effective against triple negative breast cancer cells and might serve as a starting point for building future strategies against triple negative breast cancers which are known for their increased drug resistance and poor prognosis of breast cancer patients.     

Click chemistry based synthesis,cytotoxic activity and molecular docking of novel triazole-thienopyrimidine hybrid glycosides targeting EGFR

In the current study, new thienopyrimidine conjugates bearing 1,2,3-triazole core and different sugar moieties have been designed and synthesized by Cu(I)-catalysed click dipolar cycloaddition. The cytotoxic activity of the synthesised conjugates 2, 5, 7, and 13–18 was studied against HCT-116 and MCF-7 cell lines by the MTT assay. The triazole glycosides 16 and 18 provided significant cytotoxic activities against HCT-116 cell lines comparable to that of doxorubicin and other studied compounds. The cytotoxic behaviour against MCF-7 exhibited that all the investigated compounds were more potent than doxorubicin. Moreover, all screened targets were evaluated against mutant EGFR kinase type L858R and the results revealed that the acetylated 1,2,3-triazole glycosides 13–18 exhibited excellent EGFR inhibitory activity in comparison with gefitinib. Furthermore, molecular modelling studies were performed to investigate the binding affinity of the most active compounds to EGFR enzyme.