Energy supply in early development of living cell

It is proposed that before light and oxidation of organic compounds became the predominant energy suppliers of the living cell, electron charge energy derived from heat energy by mineral particles, was the first energy source. The basis of this hypothesis is the finding that Al2O3 in electrolytic condensors can produce an electron driving force with a potential high enough for electrolysis of water and subsequent reduction of CO2 into organic molecules. This electron driving force is likely to originate from one-way movement of electrons in tunnel structures of the Al2O3 layer, driven by temperature kinetic energy.     

Computational finding of potential inhibitor for Cytochrome P450 Mono-oxygenases Enzyme of Mycobacterium tuberculosis

Cytochrome P450 mono-oxygenases (2UUQ) enzyme from Mycobacterium tuberculosis catalyzes oxidation of organic compounds such as lipids and steroidal hormones therefore remain as potential drug target. Currently available first line anti-tuberculosis drugs have been caused several side effects in the body as well as resistance development by mycobacterium against these drugs, necessitates the considerable need for finding new drugs. Therefore, we propose a structure based computational method to find a new potential inhibitor for cytochrome P450 mono-oxygenases enzyme. Compounds from several ligand databases were docked against the functional sites of 2UUQ (A) through the standard GEMDOCK v2.0 and AUTODOCK4.0 molecular docking tools. Commercially available chemical compound ZINC00004165 (5-[3-(2-nitroimidazol-1-yl) propyl] phenanthridine) has produced top rank with lowest interaction energy of -113.2 (via GEMDOCK) and lowest docking energy of -9.80 kcal/mol (via AUTODOCK) as compared to first line anti TB compounds. Z score and normal distribution analysis verified that the ZINC00004165 compound has more affinity towards 2UUQ in comparison to large number of random population of compounds. ZINC00004165 is also in agreement with the drug likeness properties of Lipinski rule of five without any violation. Therefore, our finding concludes that the commercial compound ZINC00004165 can act as a potential inhibitor against cytochrome P450 mono-oxygenases enzyme of Mycobacterium tuberculosis.     

Thermodynamic electron equivalents model for bacterial yield prediction: modifications and comparative evaluations

Modifications are made to an earlier thermodynamic model (TEEM1) for prediction of maximum microbial yields from aerobic and anaerobic as well as heterotrophic and autotrophic growth. The revised model (TEEM2) corrects for lower yields found with aerobic oxidations of organic compounds where an oxygenase is involved and with growth on single-carbon (C1) compounds. TEEM1 and TEEM2 are based on energy release and consumption as determined from the reduction potential or Gibbs free energy of (1/2)-reaction reduction equations together with losses of energy during energy transfer. Energy transfer efficiency is a key parameter needed to make predictions with TEEM2, and was determined through evaluations with extensive data sets on aerobic heterotrophic yield available in the literature. For compounds following normal catabolic pathways, the best-fit value for energy transfer efficiency was 0.37, which permitted accurate predictions of growth with a precision of 15%-20% as determined by standard deviation. Using the same energy transfer efficiency, a similar precision, but somewhat less accuracy was found for organic compounds where oxidation involves an oxygenase (estimates 8% too high) and for C1 compounds (estimates 17% too high). In spite of the somewhat lower accuracy, the TEEM2 modifications resulted in improved predictions over TEEM1 and the comparison models.     

Novel GSK-3beta inhibitors from sequential virtual screening

Glycogen synthase kinase-3 (GSK-3beta) has been emerging as a key therapeutic target for type-2 diabetics, Alzheimer's disease, cancer, and chronic inflammation. For the purpose of finding biologically active and novel compounds and providing new idea for drug-design, we performed virtual screening using commercially available database. Three-dimensional common feature pharmacophore model was developed by using HipHop program provided in Catalyst software and it was used as a query for screening database. Recursive partitioning (RP) model was developed as a filtering system, which was able to classify active and inactive compounds. Eventually, a sequential virtual screening procedure (SQSP) was conducted by applying the common feature pharmacophore and RP model in succession to discover novel potent GSK-3beta inhibitors. The final 56 hit compounds were carefully selected considering predicted docking mode in crystal structures. Subsequent enzyme assay for human GSK-3beta protein confirmed that three compounds of these hit compounds exhibit micromolar inhibitory activity. Here, we report novel hit compounds and their binding mode in the active site of GSK-3beta crystal structure.     

Chemolithoorganotrophic growth of Nitrosomonas europaea on fructose

The nitrifying bacterium Nitrosomonas europaea can obtain all its carbon for growth from CO(2) and all its energy and reductant for growth from the oxidation of NH(3) and is considered an obligate chemolithoautotroph. Previous studies have shown that N. europaea can utilize limited amounts of certain organic compounds, including amino acids, pyruvate, and acetate, although no organic compound has been reported to support the growth of N. europaea. The recently completed genomic sequence of N. europaea revealed a potential permease for fructose. With this in mind, we tested if N. europaea could utilize fructose and other compounds as carbon sources to support growth. Cultures were incubated in the presence of fructose or other organic compounds in sealed bottles purged of CO(2). In these cultures, addition of either fructose or pyruvate as the sole carbon source resulted in a two- to threefold increase in optical density and protein content in 3 to 4 days. Studies with [(14)C]fructose showed that >90% of the carbon incorporated by the cells during growth was derived from fructose. Cultures containing mannose, glucose, glycerol, mannitol, citrate, or acetate showed little or no growth. N. europaea was not able to grow with fructose as an energy source, although the presence of fructose did provide an energy benefit to the cells. These results show that N. europaea can be grown in CO(2)-free medium by using fructose and pyruvate as carbon sources and may now be considered a facultative chemolithoorganotroph.     

Solid-state fluorescence of the trihydrate phases of ampicillin and amoxicillin

The purpose of this work was to study the effects of crystal structure on the solid-state photoluminescence of the trihydrate phases of ampicillin and amoxicillin, and to contrast these spectra with analogous spectra obtained on the molecules dissolved in a solution phase. The polymorphic identity of the analytes was established using x-ray powder diffraction and Fourier transform infrared absorption spectroscopy, and the solid-state luminescence spectra obtained under ambient conditions. It was found that the solid-state excitation and emission spectra of ampicillin trihydrate and amoxicillin trihydrate were dominated by energy transfer and exciton effects, which were manifested as decreases in the energy of the excitation and emission bands of the solid-state systems relative to those of the free molecule in solution. The photoluminescence data revealed that in spite of the known structural similarity of ampicillin trihydrate and amoxicillin trihydrate, the magnitude of the Davydov splitting, and the degree of band energy shifting differed between the 2 systems. This finding indicates that the small differences in crystal structure existing between the 2 compounds leads to measurable differences in the patterns of energy transfer. Published: October 22, 2005     

Theoretical studies on pyrimidine substituent derivatives as dual inhibitors of AP-1 and NF-κB

Theoretical studies on the three-dimensional (3D) quantitative structure-activity relationship (QSAR) and mechanisms of action of a series of pyrimidine substituent derivatives as dual inhibitors of AP-1 and NF-κB were carried out using comparative molecular field analysis (CoMFA) and docking methods. The established 3D-QSAR model exhibits a satisfying statistical quality and prediction ability. Docking results show somewhat lower average values of the flexible and rigid energy scores in the chosen binding sites. The docking analysis offers appropriate orientations and conformations of these compounds at the binding sites to both AP-1 and NF-κB in good agreement with the 3D-QSAR model from CoMFA. The combined CoMFA and docking study suggests the following substituent selections: substituent R₂ should be a kind of H–N–thienyl or CH₃–N–thienyl group; substituent R₅ should be a kind of COO–tBu or COOEt group; and substituent R₄ should be a CH₂CH₃ or 2-thienyl group. The docking analysis also shows that the binding sites fall just at the joint regions between AP-1 (or NF-κB) and DNA, where these compounds can effectively prevent free AP-1 and NF-κB from binding to DNA, and this may be the reason that derivatives with pyrimidine substituents have an inhibition function. In addition, a very interesting finding was that the binding sites of both AP-1 and NF-κB have a common structural characteristic, thereby providing a reasonable explanation for the dual inhibition functions of these compounds towards both AP-1 and NF-κB. These theoretical results help to deepen our understanding of the inhibition mechanism of these pyrimidine substituent derivatives, and will aid in directing further drug-molecular design.     

Synthesis and biological evaluation of α-ketoamides as inhibitors of the Dengue virus protease with antiviral activity in cell-culture

The development of small molecule inhibitors of the viral protease is of considerable interest for the treatment of emergent flaviviral diseases such as Dengue or West Nile fever. Until today little progress has been made in finding drug-like compounds that inhibit the protease and provide a starting point for lead optimization. We describe here the initial steps of a drug discovery effort that focused on the styryl pharmacophore, combined with a ketoamide function to serve as electrophilic trap for the catalytic serine. This resulted in a fragment-like lead compound with reasonable target affinity and good ligand efficiency, which was extensively modified to explore structure-activity relationships. Selected compounds were cross-tested against the West Nile virus protease and thrombin, indicating that selectivity for one or more flaviviral proteases can be achieved. Finally, the antiviral activity of several protease inhibitors was confirmed in a cell-culture model of Dengue virus replication. The SAR presented here may serve as starting point for further drug discovery efforts with the aim of targeting flaviviral proteases.     

棉花秸秆催化热解特性及动力学的研究

通过热重分析实验观察K2CO3、KOH、KCl、NaCl、MgCl2和ZnCl26种无机催化剂对棉花秸秆热解催化效果的影响。K2CO,、KOH处理过的棉花秆与纯棉花秆相比热解发生在较低的温度范围,而KCl、NaCl、MgCl,和ZnCl2处理过的棉花秆热解发生在较高的温度范围。碱性催化剂K2C03、KOH降低了棉花秸秆的最大质量损失率,而KCl、NaCl、MgCl2和ZnCl2却增大了棉花秸秆的最大质量损失率。应用Ozawa动力学模型得到动力学参数,棉花秸秆在热解主要阶段可由一段一级反应过程描述,升温速率10K／min时活化能值EA的范围是35～66kJ／mol,频率因子自然对数的范围是4～12。     

Prediction of caspase-3 inhibitory activity of 1,3-dioxo-4-methyl-2,3-dihydro-1h-pyrrolo[3,4-c] quinolines: QSAR study

Neurodegenerative disorders are consequences of progressive and irreversible loss of neurons due to unwanted apoptosis which involves caspases, a group of cysteine proteases that cleave other proteins and inactivate them. Among several different groups of caspase enzymes, caspases-3 plays a key role in apoptosis and are a therapeutic target for their inhibition. In pursuit of better caspase-3 inhibitors, a quantitative structure-activity relationship (QSAR) analysis was performed on a series of 1,3-dioxo-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-c] quinolines as caspase-3 inhibitors using WIN CAChe 6.1 and Medicinal Chemistry Regression Machine. The best QSAR model was selected and validated by internal and external validation method. The values of statistical data are r = 0.955, F = 72.95, SEE = 0.397, q(2) = 0.885, S(PRESS) = 0.44. The present study reveals that when the conformational minimum energy is increased, and lowest unoccupied molecular orbital energy and highest occupied molecular orbital energy are decreased the biological activity can be increased. On the basis of a selected QSAR model, we designed a new series of 1,3-dioxo-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]quinolines compounds, calculated their caspases inhibitory activity and found that the designed compounds were more potent than the existing compounds.     

Prediction of caspase-3 inhibitory activity of 1,3-dioxo-4-methyl-2,3-dihydro-1h-pyrrolo[3,4-c] quinolines: QSAR study

Neurodegenerative disorders are consequences of progressive and irreversible loss of neurons due to unwanted apoptosis which involves caspases, a group of cysteine proteases that cleave other proteins and inactivate them. Among several different groups of caspase enzymes, caspases-3 plays a key role in apoptosis and are a therapeutic target for their inhibition. In pursuit of better caspase-3 inhibitors, a quantitative structure-activity relationship (QSAR) analysis was performed on a series of 1,3-dioxo-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-c] quinolines as caspase-3 inhibitors using WIN CAChe 6.1 and Medicinal Chemistry Regression Machine. The best QSAR model was selected and validated by internal and external validation method. The values of statistical data are r = 0.955, F = 72.95, SEE = 0.397, q² = 0.885, S_PRESS = 0.44. The present study reveals that when the conformational minimum energy is increased, and lowest unoccupied molecular orbital energy and highest occupied molecular orbital energy are decreased the biological activity can be increased. On the basis of a selected QSAR model, we designed a new series of 1,3-dioxo-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]quinolines compounds, calculated their caspases inhibitory activity and found that the designed compounds were more potent than the existing compounds.     

Computational selection of flavonoid compounds as inhibitors against SARS-CoV-2 main protease,RNA-dependent RNA polymerase and spike proteins: A molecular docking study

An outbreak of Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has been recognized as a global health concern. Since, no specific antiviral drug is proven effective for treatment against COVID-19, identification of new therapeutics is an urgent need. In this study, flavonoid compounds were analyzed for its inhibitory potential against important protein targets of SARS-CoV-2 using computational approaches. Virtual docking was performed for screening of flavonoid compounds retrieved from PubChem against the main protease of SARS-CoV-2 using COVID-19 docking server. The cut off of dock score was set to >?9 kcal/mol and screened compounds were individually docked against main protease, RNA-dependent RNA polymerase, and spike proteins using AutoDock 4.1 software. Finally, lead flavonoid compounds were subjected to ADMET analysis. A total of 458 flavonoid compounds were virtually screened against main protease target and 36 compounds were selected based on the interaction energy value >?9 kcal/mol. Furthermore, these compounds were individually docked against protein targets and top 10 lead compounds were identified. Among the lead compounds, agathisflavone showed highest binding energy value of ?8.4 kcal/mol against main protease, Albireodelphin showed highest dock score of ?9.8 kcal/mol and ?11.2 kcal/mol against RdRp, and spike proteins, respectively. Based on the high dock score and ADMET properties, top 5 lead molecules such as Albireodelphin, Apigenin 7-(6″-malonylglucoside), Cyanidin-3-(p-coumaroyl)-rutinoside-5-glucoside, Delphinidin 3-O-beta-D-glucoside 5-O-(6-coumaroyl-beta-D-glucoside) and (-)-Maackiain-3-O-glucosyl-6″-O-malonate were identified as potent inhibitors against main protease, RdRp, and spike protein targets of SARS-CoV-2. These all compounds are having non-carcinogenic and non-mutagenic properties. This study finding suggests that the screened compounds include Albireodelphin, Apigenin 7-(6″-malonylglucoside), Cyanidin-3-(p-coumaroyl)-rutinoside-5-glucoside, Delphinidin 3-O-beta-D-glucoside 5-O-(6-coumaroyl-beta-D-glucoside) and (-)-Maackiain-3-O-glucosyl-6″-O-malonate could be the potent inhibitors of SARS-CoV-2 targets.     

Evidence for a two-step process in prostaglandin secretion. Intracellular accumulation of prostacyclin precedes its release from human endothelial cells in culture

Cultured endothelial cells (EC) from human umbilical vein were incubated with [U-14C]arachidonic acid (AA) followed by a challenge with thrombin (2 units/ml) or calcium ionophore A23187 (5 microM) for 0.5-10 min at 37 degrees C. In both cases, AA was rapidly liberated from phospholipids and converted into prostaglandin I2 (PGI2), as determined by the radioactivity of the stable derivative 6-keto-PGF1 alpha. Maximal liberation of AA and synthesis of PGI2 were achieved within 2 min, but the two compounds first accumulated in EC prior to their release into supernatants. This finding, which was never reported before, raises the question of the mechanism of AA and PG release through the cell membranes and offers a convenient model to investigate this still obscure process.     

Alteration of hexose transport in avian erythrocytes by vinblastine and colchicine

Vinblastine and colchicine, compounds which effect the state of aggregation of microtubules, were investigated to determine if changes in the rate of sugar transport were produced by these compounds. Vinblastine accelerated 3-O-methylglucose entry into avian erythrocytes. At a concentration of 1.5 mm, transport was accelerated two-fold. The effect of vinblastine was not attributed to cell energy depletion or to increased entry by simple diffusion. Stimulation of transport did not require preincubation of the cells with vinblastine, and the effect was reversible. Colchicine (2 mm) inhibited 3-O-methylglucose entry in aerobic or anoxic intact red cells and in red cell ghosts. A change in the state of aggregation or activity of the microtubular system could represent a model for regulation of a membrane carrier. The present results would lend support to this model.     

CoMFA and CoMSIA 3D QSAR analysis on N1-arylsulfonylindole compounds as 5-HT6 antagonists

Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were conducted on a series of N(1)-arylsulfonylindole compounds as 5-HT(6) antagonists. Evaluation of 20 compounds served to establish the models. The lowest energy conformer of compound 1 obtained from random search was used as template for alignment. The best predictions were obtained with CoMFA standard model (q2 = 0.643, r2 = 0.939 ) and with CoMSIA combined steric, electrostatic, hydrophobic, and hydrogen bond acceptor fields (q2 = 0.584, r2 = 0.902 ). Both the models were validated by an external test set of eight compounds giving satisfactory predictive r2 values of 0.604 and 0.654, respectively. The information obtained from CoMFA and CoMSIA 3D contour maps can be used for further design of specific 5-HT(6) antagonists.     

The systematic modeling studies and free energy calculations of the phenazine compounds as anti-tuberculosis agents

Abstract

Phenazine compounds have good activity against Mycobacterium tuberculosis (MTB). Based on the reported activities that were obtained in MTB H37Rv, a three-dimensional quantitative structure–activity relationship (3D-QSAR) model was built to design novel compounds against MTB. A fivefold cross-validation method and external validation were used to analyze the accuracy of forecasting. The model has a cross-validation coefficient q²=0.7 and a non-cross-validation coefficient r² = 0.903, indicating that the model has good predictive possibility. The design of anti-pneumococcus MTB compounds was guided by the obtained 3D-QSAR model, and several compounds with better activity were obtained. To test the activity of these compounds, molecular docking, molecular dynamics simulation, and post-simulation analysis of the already reported drug targets in MTB were carried out. Among the total 15 drug targets, only three targets (Rv2361c, Rv2965c, and Rv3048c) were selected based on the docking results. Initial results reported that these compounds possessed good inhibition activity for Rv2361c. The top nine complexes of Rv2361 ligands were only subjected to MD simulation which resulted in a stable dynamics of the structures and showed a residual fluctuation in inhibitors binding pocket. Free energy reported that overall, the derivatives hold strong energy against the protein target. Energetic contribution results showed that residues, Asp76, Arg80, Asn124, Arg127, Arg244, and Arg250, play a major role in total energy. Systems biology approach validates shortlisted drug effect on the entire system which might be useful to predict potential drug in wet lab as well.

Communicated by Ramaswamy H. Sarma     

CNDO/2 calculations of the relative stability of poly (l-proline I) and poly (l-proline II)

The CNDO/2 method using the tight binding approximation for polymers was applied to poly(l-proline I) and poly(l-proline II). The calculations were also carried out for poly(l-alanines) and model molecules which have the same backbone geometrics as those of poly(l-prolines). The results obtained show that both forms of poly(l-proline I) and poly(l-proline II) have nearly the same energy in agreement with experimental results. From the analysis of the total energy, it was found that the intrasegment energy of poly(l-proline II) was lower than that of poly(l-proline I) while the intersegment energy of poly(l-proline I) was lower than that of poly(l-proline II). This result can be considered to correspond well with the experimental fact that poly(l-proline II) is more stable in good or polar solvents and poly(l-proline I) in poor or non-polar solvents. The analysis of the total energy of poly(l-proline) leads us to the conclusion that the α and β carbons play an important role in determining the relative stability between poly(l-proline I) and poly(l-proline II) and the γ carbon does hvae a marked effect on the electronic structures of the polymers in question. This conclusion was also confirmed by comparison of the electronic structures of poly(l-prolines) with those of poly(l-alanines) and model compounds concerned.     

Exploration of new drug-like inhibitors for serine/threonine protein phosphatase 5 of Plasmodium falciparum: a docking and simulation study

Protein phosphorylation is an important mechanism that implicates in physiology of any organism including parasitic protozoa. Metallic protein Ser/Thr protein phosphatase 5 (PP5) controls various cellular signaling pathways of Plasmodium falciparum. The structure and inhibitory mechanism of PP5 in P. falciparum is not known. In fact, no experimental structural data are available for P. falciparum Ser/Thr protein phosphatase 5 (PfPP5) till date. Hence, we have proposed computer-generated model of catalytic subunit of PfPP5 and its inhibitory mechanism was analyzed. A set of 42 known natural inhibitors of protein phosphate family were docked against metal-binding catalytic site of PfPP5 and we found that cantharidin and its derivatives shows better binding energy among them. Similarity search was performed by taking these compounds as lead compounds against PubChem and ChemBank. The search result provides 3703 similar compounds; out of which 2245 qualified the Lipinski rule of five. Further, virtual screening of these compounds was performed and selected top 25 were selected on the basis of binding energy. In continuation, rigid and flexible docking of these screened compounds was performed to get the insight of interactions. Finally, top 5 compounds were verified for ADMET properties, and then, all are subjected to MD simulations for 25 ns in order to validate their stability. Compounds CBI: 3554182, CID: 23561913, and CID: 21168680 showed most stable binding, although some of hydrogen bonds pairing varied throughout simulation. These finding would be helpful to the medicinal chemists for the development of antimalarial drugs to combat this deadly disease.