CDOCKER Energy Research Articles

In silico Analysis of Phytochemicals from Clove against Bronchitis

Bronchitis is an airborne disease, mostly caused by bacteria like Mycoplasma pneumonia and also by influenza virus. Due to hyper secretion and over production of mucus by goblet cells which leads to obstractle in airflow. This disease can be cured using (Syzygium aromaticum) clove extracts. Phytochemicals are secondary metabolites which are basically non-nutritive compounds but can protect from various diseases caused by microorganism. Bioactive compounds like Acetyl eugenol, Beta-caryophyllene and vanillin, crategolic acid, eugenin tannins, gallotannic acid, mrthyl salicylate (painkiller), flavonoids, kaempferol, rhamnetin, eugenitin, triterpenoid like oleanolic acid are found in clove extract. The enzyme and the phytochemicals were run using Biovia Discovery Studio and molecular docking was performed. By the help of -CDocker energy and -CDocker interaction energy the strength of the interaction was evaluated. The key enzyme involved in the biochemical pathway of mycoplasma pneumonia is Thymidine phosphorylase. High positive values for both the parameters indicated that out of different phytochemicals, Myricetin can interrupt the life cycle of Mycoplasma pneumonia spp. Effectively by deactivating the enzyme Thymidine phosphorylase (Pdb no 4LHM). The present study is to evaluate the action of phytochemicals present in clove (against brochitis diseases).

In silico Analysis of Phytochemicals from Glycyrrhiza glabra against Conjunctivitis

Phytochemicals are naturally occurring biologically active compounds found in plant parts such as roots, barks, leaves, seeds, and even pulps. It has been reported that Glycyrrhiza glabra plant extract is used for treatment of the disease conjunctivitis. The plant extract contains different phytochemicals. The agent that causes conjunctivitis is a gram positive bacterium which belongs to species Staphylococcus. One of the key enzymes involved in its biochemical pathway is Isocitrate dehydrogenase. The molecular docking of the phytochemicals with the enzyme was studied using Biovia Discovery Studio. The strength of the interaction was evaluated based on -CDocker energy and -CDocker interaction energy. High positive values for both the parameters indicated that out of different phytochemicals rosmarinic acid can effectively deactivate the is ocitrate dehydrogenase enzyme thereby inhibiting the life cycle of Staphylococcus.

In silico Analysis of Phytochemicals from Mucuna pruriens (L.) DC against Mycobacterium tuberculosis Causing Tuberculosis

Tuberculosis is somewhat a disease of poverty that mainly targets the low-income populations of developing countries. At the same time, the disease act as a barrier for economic growth to affected people and families caring for them which in turn results into increased poverty in the community. Thesepopulation below the poverty line lacks access due to higher retail price and unavailability of the medicines. To overcome these obstacles researchers are nowadays opting to derive medicines from plant extract containing phytochemicals rather than synthesizing new chemicals which proved to be more expensive and unsafe compared to their organic counterpart. Phytochemicals are non-nutritive compounds obtained from plants. It has been reported that Mucuna pruriens plant extract is expected to cure Tuberculosis, which is caused by Mycobacterium tuberculosis. The said microbe contains 3-hydroxyacyl-CoA dehydrogenase enzyme which is reported to be very crucial for the survival of the organism. The molecular docking of the phytochemicals with the microbial enzyme was studied using Biovia Discovery Studio. The machine learning protocols analyze and predict the volume of the molecular interactions occurring between the plant phytochemical and the bacterial enzyme occurring at the active site of the enzyme. The strength of the interaction was evaluated based on -CDocker energy and -CDocker interaction energy. Subsequently the study displays high positive values for both the parameters indicating that out of different phytochemicals present in Mucuna pruriens, L-Dopa can effectively deactivate the enzymatic metabolic activity by interrupting β-oxidation of fatty acid in the microbial cell which causes termination of the life cycle of Mycobacterium tuberculosis.

Design, Synthesis, Molecular Docking and Antimicrobial Evaluation of Some Tosyl Carbamate Derivatives

A series of tosyl carbamates have been synthesized and screened for their antibacterial and antifungal activities. All the synthesized compounds were characterized by spectral techniques (IR, 1H, 13C NMR and mass) and elemental analysis. in silico Molecular docking method was performed to study their antimicrobial activity against the target protein 1T9U. Compound 27 showed good antibacterial activity against Gram-positive and Gram-negative bacterial strains and compound 19 showed good antifungal activity. Molecular docking results revealed that the compound 19 exhibits minimum CDOCKER energy. Tosyl carbamate derivatives having good antimicrobial activities compared to that standard and all the synthesized compounds exhibits moderate CDOCKER scores.

Multiple-targets Directed Screening of Flavonoid Compounds from Citrus Species to find out Antimalarial Lead with Predicted Mode of Action: An In Silico and Whole Cell-based In vitro Approach.

Development of resistance by the malaria parasite Plasmodium falciparum has created challenges in the eradication of this deadly infectious disease. Hence newer strategies are adopted to combat this disease and simultaneously, new lead/hit identification is going on worldwide to develop new chemotherapeutic agents against malaria. In this study, 44 flavonoids found mainly in the fruit juice of Citrus species having traditional use in malaria-associated fever were selected for in silico multiple-target directed screening against three vital targets of the parasite namely dihydroorotate dehydrogenase (PfDHODH), dihydrofolate reductase thymidine synthase (PfDHFR-TS) and plasma membrane P-type cation translocating ATPase (PfATP4) to find out new lead molecule(s). The in silico screening was carried out using different protocols of the Biovia Discovery Studio 2018 software and Network analyzer plugin of Cytoscape 3.6.0 followed by in vitro screening of the best lead. After screening, CF8 or luteolin was found to have good binding affinity against PfDHODH and PfATP4 with -CDocker energy 42.2719 and 33.1447 with respect to their cocrystal ligands. These findings were also supported by structure-based pharmacophore, DFT (Density Functional Theory) study and finally by in vitro screening of the lead with IC50 values of 8.23 μm and 12.41 μm against 3D7 (chloroquine-sensitive) and RKL-9 (chloroquine-resistant) strain of P. falciparum, respectively. Our study found a moderately active lead molecule with the predicted mode of action which can be utilized to design some new derivatives with more safety and efficacy by targeting the two enzymes.

Docking-based inverse virtual screening strategy for identification of novel protein targets for triclosan

Triclosan (TCS) is chemically designated as 5-chloro-2-(2,4-dichlorophenoxy) phenol and is considered as endocrine-disrupting chemical (EDC). The various diseases found due to exposure of TCS, have been linked with modulation of the human enoyl-acyl carrier protein-reductase (hER). However, the new protein targets for TCS other than hER, which are responsible for various diseases, are still unknown. In the present study, a bioinformatics approach was used to identify new possible targets for TCS. A text mining study was initially performed to understand the association of TCS in various biochemical processes. Discovery studio software 4.1 was used to carry out inverse virtual screening for 226 numbers of pathway proteins by docking study using CHARMm based docking tool, and twenty proteins were screened. CDOCKER energy values lower than −12.65 kcal/mol was considered for the screening of selected proteins. Three new proteins; Receptor-interacting protein 1 (RIP1), Apoptosis signal-regulating kinase 1 (ASK1) and B-cell lymphoma 2 (Bcl-2) from Apoptosis Signaling Pathway revealed best CDOCKER energy with triclosan which was −26.88, −23.34 and −22.96 kcal/mol respectively. The interaction of TCS with RIP1 and ASK1 were mostly hydrophobic; however, hydrogen bond type interaction was found in TCS/Bcl2 complex. Therefore, docking-based inverse virtual screening study suggests that TCS has other targets rather than hER, which can modulate various biochemical processes. The docking protocol was validated through evaluation of root-mean-square deviation (RMSD), key interaction score system (KISS) and the relationship between the docking energy and toxicity data available in ToxCast database. Low RMSD value (0.55 ˚A) and high KISS score (0.66) along with higher correlation (R2 = 0.9798) between docking affinity and toxicity indicated that docking protocol can be used to optimize the binding energetics.

BCESA: a nano-scaled intercalator capable of targeting tumor tissue and releasing anti-tumoral β-carboline-3-carboxylic acid.

Background: In the discovery of DNA intercalators, β-carbolines compose one member of the most interesting alkaloid family and are of clinical importance. In the efforts, N-(3-benzyloxycarbonyl-β-carboline-1-yl)ethyl-Ser-Ala-OBzl (BCESA) was designed as a nano-scaled DNA intercalator without Dox-like toxicity.Methods: Based on the structural analysis and CDOCKER energy comparison, BCESA was rationally designed as such a nano-scaled intercalator. The anti-tumor activity, the toxicity and the tumor targeting action of BCESA were evaluated on mouse models.Results: The in vitro proliferation of cancer cells, but not non-cancer cells, was effectively inhibited by BCESA. On S180 mouse model BCESA dose-dependently slowed the tumor growth, and 0.01 μmol/kg/day was found as a minimal effective dose. Both BCESA and its moiety were found in the tumor tissue, but not in the organs and the blood, of S180 mice.Conclusion: BCESA should be a nano-scaled intercalator capable of targeting tumor tissue to release anti-tumoral β-carboline-3-carboxylic acid and its 1-methyl derivative, while Ser-Ala-OBzl is a simple and desirable carrier.

Isolation and Characterization of Peptides from Mytilus edulis with Osteogenic Activity in Mouse MC3T3-E1 Preosteoblast Cells.

Seafood provides a range of health benefits because of its high protein levels. In this study, a novel peptide, YPRKDETGAERT, was identified from NHA-2 of Mytilus edulis by capillary-electrophoresis electrospray ionization-quadrupole-time of flight (CESI-Q-TOF). Peptide YPRKDETGAERT showed the highest affinity among all the peptides, with -CDOCKER energy values of 204.482 kcal/mol on one integrin (PDB: 3VI4 ) and 210.16 kcal/mol on another integrin (PDB: 1L5G ). The secondary mass spectrogram at the m/ z of peptide YPRKDETGAERT was 1422.53 Da, which was determined by CESI-Q-TOF. Peptide YPRKDETGAERT induced an increase of 28.27 ± 3.66% in mouse-MC3T3-E1-preosteoblast-cell growth. The alkaline-phosphatase activity of peptide YPRKDETGAERT was 2.79 ± 0.07 mU, which was an increase of 21.25% compared with that of the control. These results provide theoretical and practical insights for the preparation and application of osteogenic peptides in the functional-foods industry.

In Silico Discovery of Novel Ligands for Anti-Tubercular Targets using Computer Aided Drug Design

Tuberculosis still remain one of the most burdened infectious disease in the world especially with the emergence of drug resistance to the current drug regimen. It is the second most leading reason for infectious disease related death and with the emergence of MDR and XDR TB there is a consistent need to develop novel drugs with disparate modes of actions. Our objective is to design novel benzimidazole derivatives with anti-tubercular activity. A series 4-(1H-benzimidazole-2-ylmethyl) aniline derivatives were designed using ACD/Chem Sketch and their molecular properties and ADMET properties were designed using BIOVIA Discovery Studio. Target proteins were chosen in comparison to the standard drug isoniazid which are (Enoyl-(acyl-carrier-protein) reductase, Catalase-peroxidase, Dihydrofolate reductase) and a newly developed target protein MmpL3 were taken. CDOCKER energy and CDOCKER INTERACTION energy of both ligand and standard drug on all the target candidates were determined using BIOVIA Discovery Studio. The CDOCKER energy and CDOCKER INTERACTION energy of the newly developed ligand on the above mentioned targets were found to be higher in compared to standard drug, which signifies that the ligand molecules have higher specificity towards the target than the standard drug. Newly designed derivatives were found to have a better docking score towards the target protein enoyl-acyl carrier protein reductase and MmpL3 both of which aids to the development of mycobacterial cell wall synthesis therefore blocking both or either one of the protein will result in the depletion of mycolic acid concentration in mycobacterial cell wall resulting in loss of structural integrity of bacterial cell wall resulting in mycobacterial death.

Conceptual design of hybrid PCSK9 lead inhibitors against coronary artery disease

Abstract The enzyme, Proprotein Convertase Subtilisin Kexin type-9 (PCSK 9) inhibition serves as a significant target to prevent the risk of Coronary Artery Disease. Hence, this work is focused on the exploration of novel PCSK 9 lead inhibitors through In silico approach. In abidance to the study, BREED algorithm has been taken to design novel hybridised ligands. Subsequently, various in silico screening studies were performed in Biovia Discovery Studio 2017. Novel ligand generation protocol generated 595 hybridised ligands from the 51 parent scaffolds. These ligands were mapped and screened by ludi interactions of the active site PCSK 9 and were reduced to 245 hit compounds. The docking studies showed that the berberine skeleton contained molecule possessed CDOCKER energy (−13.5582 Kcal/mol) and formed strong interactions with Arg93, Arg97 and His137 residues. The developed pharmacophore model revealed that hydrogen bond acceptor and negative ionizable charges are necessary for the inhibition of PCSK 9. The mapping of pharmacophore model confirmed that 96 molecules were as best fit. Finally, toxicity and dynamic simulation studies confirmed that safe and stable complex formation between lead molecules and PCSK 9 receptor. The results concluded that the 15 lead molecules are proved as potent and safe PCSK9 inhibitors.

Virtual identification of novel PPARα/γ dual agonists by scaffold hopping of saroglitazar

The thiazolidinedione class PPARγ agonists as antidiabetic agents are restricted in clinical use because of the side effects such as edema, weight gain, and heart failure. The single and selective agonism of PPARγ is the main cause of side effects. The multi-target cooperative PPARα/γ dual agonist development is a hot topic in the antidiabetic medicinal chemistry field. Saroglitazar is the first approved PPARα/γ dual agonist, available in India for the treatment of diabetic dyslipidemia. It got rid of these side effects. With the aim of finding more protent PPARα/γ dual agonists, the scaffold hopping was used to replace α-o phenylpropionic acid skeleton of saroglitazar with L-tyrosine skeleton. Then, the structural modification was carried out designing 72 compounds. Considering the importance of chirality, opposite configuration of 72 compounds was also studied. 12 compounds with better -cdocker energy were screened by molecular docking. Subsequently, the pharmacokinetic properties and toxicity evaluated by ADMET prediction, 11 of them showed better properties. Comp#L-17-1 and comp#L-3-1 were regarded as representatives to study the binding stability by molecular dynamics (MD) simulations. The MD simulation results of comp#L-17-1-PPARs (α, γ) and comp#L-3-1-PPARs (α, γ) provided structure reference for the research and development of novel PPARα/γ dual agonists.

Flowers of Clerodendrum volubile exacerbate immunomodulation by suppressing phagocytic oxidative burst and modulation of COX-2 activity.

The immunomodulatory potentials of the crude methanolic extract and fractions [n-hexane (Hex), n-dichloromethane (DCM), ethyl acetate (EtOAc) and n-butanol (BuOH)] of Clerodendrum volubile flowers were investigated on whole blood phagocytic oxidative burst using luminol-amplified chemiluminescence technique. They were also investigated for their free radicals scavenging activities. The DCM fraction showed significant (p<0.05) anti-oxidative burst and free radical scavenging activities indicating high immunomodulatory and antioxidant potencies respectively. Cytotoxicity assay of the DCM fraction revealed a cytotoxic effect on CC-1 normal cell line. GCMS analysis revealed the presence of triacetin; 3,6-dimethyl-3-octanol; 2R - Acetoxymethyl-1,3,3-trimethtyl - 4t - (3-methyl-2-buten-1-yl) - 1c - cyclohexanol and Stigmastan - 3,5-diene in DCM fraction. These compounds were docked with the active sites of cyclooxygenase-2 (COX-2). Triacetin, 3,6-dimethyl-3-Octanol, and 2R-Acetoxymethyl-1,3,3-trimethtyl-4t-(3-methyl-2-buten-1-yl)-1c-cyclohexanol docked comfortably with COX-2 with good scoring function (-CDocker energy) indicating their inhibitory potency against COX-2. 3,6-dimethyl-3-Octanol, displayed the lowest predicted free energy of binding (-21.4kcalmol-1) suggesting its stronger interaction with COX-2, this was followed by 2R - Acetoxymethyl-1, 3, 3-trimethtyl-4t-(3-methyl-2-buten-1-yl)-1c-cyclhexanol (BE=-20.5kcalmol-1), and triacetin (BE=-10.9kcalmol-1). Stigmastan - 3,5-diene failed to dock with COX-2. The observed suppressive effect of the DCM fraction of C. volubile flower methanolic extract on phagocytic oxidative burst indicates an immunomodulatory potential. This is further reflected in its free scavenging activities and synergetic modulation of COX-2 activities by its identified compounds in silico.

Identification and evaluation of magnolol and chrysophanol as the principle protein tyrosine phosphatase-1B inhibitory compounds in a Kampo medicine, Masiningan

Ethnopharmacological relevanceMasiningan is a traditional medicine consisting of six crude drugs that have been used for treating constipation and diabetes mellitus in both Japan and China. Masiningan has been reported to have significant PTP1B inhibitory activity and to affect cells in the insulin-signaling pathway. The aim of the present study is to identify the PTP1B inhibitory compounds in Masiningan. Materials and methodsBioactivity peaks were identified by analytical HPLC profiling and PTP1B inhibitory activity profiling of sub-fractions from Masiningan extract. The bioactive compounds were isolated by tracking two identified bioactive peaks, and the chemical structures were determined by spectroscopic analyses. The bioactive compounds were further investigated for their inhibitory effect against PTP1B by enzymatic kinetic analysis, molecular docking simulation, inhibitory selectivity against other PTPs, and cellular activity in the insulin signal transduction pathway. ResultsFrom Masiningan, magnolol (1) and chrysophanol (2) were isolated as compounds that exhibited significant dose-dependent inhibitory activities against PTP1B, with IC50 values of 24.6 and 12.3μM, respectively. Kinetic analysis revealed that 1 is a non-competitive and that 2 is a competitive PTP1B inhibitor. In the molecular docking simulation, compound 2 was stably positioned in the active pocket of PTP1B, and the CDOCKER energy was calculated to be 24.3411kcal/mol. Both compounds demonstrated remarkably high selectivity against four PTPs and revealed cellular activity against the insulin signal transduction pathway. ConclusionsMagnolol (1) and chrysophanol (2) were identified as the principle PTP1B inhibitory active compounds in Masiningan, and their actions were investigated in detail. These findings demonstrated the effectiveness of Masiningan on diabetes mellitus through the inhibition of PTP1B at a molecular level as well as the potential of magnolol (1) and chrysophanol (2) as lead compounds in future anti-diabetes drug development.

Network Based Approach in the Establishment of the Relationship between Type 2 Diabetes Mellitus and Its Complications at the Molecular Level Coupled with Molecular Docking Mechanism

Diabetes mellitus (DM) is one of the major metabolic disorders that is currently threatening the world. DM is seen associated with obesity and diabetic retinopathy (DR). In the present paper we tried to evaluate the relationship between the three aliments at the gene level and further performed the molecular docking to identify the common drug for all the three diseases. We have adopted several software programs such as Phenopedia, VennViewer, and CDOCKER to accomplish the objective. Our results revealed six genes that commonly associated and are involved in the signalling pathway. Furthermore, evaluation of common gene association from the selected set of genes projected the presence of SIRT1 in all the three aliments. Therefore, we targeted protein 4KXQ which was produced from the gene SIRT1 and challenged it with eight phytochemicals, adopting the CDOCKER. C1 compound has displayed highest -CDOCKER energy and -CDOCKER interaction energy of 43.6905 and 43.3953, respectively. Therefore, this compound is regarded as the most potential lead molecule.

Radioiodination and biological evaluation of Cladribine as potential agent for tumor imaging and therapy

Abstract Cladribine, a purine analogue antimetabolite, was radioiodinated with 125I via direct electrophilic substitution reaction. The maximum radiochemical yield (92.5 ± 0.8%) was obtained when the reaction was done at ambient temperature for 30 min using 100 μg of Cladribine and 10 μg N-chlorosuccinamide (NCS) in 150 μL of 0.2 M phosphate buffer, pH 7. In vitro stability studies of HPLC purified 125I-Cladribine sample dissolved in 0.5 ml of 0.2 M phosphate buffer pH 7 at ambient temperature showed that 125I-Cladribine is stable up to 12 h post labeling. Biodistribution results revealed excretion of 125I-Cladribine mainly by kidneys. The uptake of 125I-Cladribine in the induced Ehrlich Ascites Carcinoma was 2.8 ± 0.4 %ID/g at 1 h post injection with maximum tumor/muscle ratio of 5.5. The good uptake of 125I-Cladribine confirms the molecular docking studies results which indicate that iodinated Cladribine binds with polymerase enzyme with a good –CDOCKER energy. As a result, radioiodinated Cladribine may be used as a valuable agent for tumor diagnosis and therapy.

Molecular modeling studies and synthesis of novel quinoxaline derivatives with potential anticancer activity as inhibitors of c-Met kinase

In an effort to develop potent anti-cancer agents, we have synthesized some substituted quinoxaline derivatives. Reaction of 6-bromo-3-methylquinoxalin-2(1H)-one 1 with aromatic aldehydes furnished the styryl derivatives 2a–e. Alkylation of 1 with ethyl chloroacetate produced the N-alkyl derivatives 3. Hydrazinolysis of the ester derivative 3 with hydrazine hydrate afforded the hydrazide derivative 4. In addition, chlorination of 1 with phosphorus oxychloride afforded the 2-chloro derivative 5 which was used as a key intermediate for the synthesis of substituted quinoxaline derivatives 6–8, N-pyrazole derivative 9, tetrazolo[1,5-a]quinoxaline derivative 10 and Schiff base derivatives 13, 15 via reaction with several nucleophiles reagents. Docking methodologies were used to predict their binding conformation to explain the differences of their tested biological activities. All the tested compounds were screened in vitro for their cytotoxic effect on three tumor cell lines. Some new quinoxaline derivatives were studied as inhibitors of c-Met kinase, a receptor associated with high tumor grade and poor prognosis in a number of human cancers. Compounds 2e, 4, 7a, 12a, 12b and 13 showed the highest binding affinity with CDOCKER energy score, while showed the lowest IC50 values against three types of cancer cell lines. It is worth to mention that, compounds 2e, 7a, 12b and 13 showed comparable inhibition activity to the reference drug, while compounds 4 and 12a showed a more potent inhibition activity than Doxorubicin.