In Silico profiling of the Angiotensin converting enzyme binding affinities, toxicity and Pharmacokinetics of compounds from the nuts of Areca Catechu, Linn. and its bioisosteres

Background@#Hypertension is a worldwide epidemic that has been recognized as the most leading global risk for mortality, with its prevalence associated with increased blood pressure, concomitant risks of cardiovascular and kidney diseases, and major commonality in individuals advanced in age. With the current treatment options for hypertension management, there is still a need to develop therapies that directly target receptors that aid in hypertension treatment.@*Methodology@#The study focused on the in-silico profiling of the reported compounds from Areca catechu L. (fam. Arecaceae) towards the n-domain and c-domain angiotensin converting enzyme (ACE) receptor models. Bioisosteric replacement was used to create bioisosteres investigated for similar binding affinity.@*Results@#Some A. catechu compounds exhibited favorable binding energies towards the n- and c-domain receptor models of ACE, binding in the same ACE ligand binding site as lisinopril, benazepril, and sampatrilat via similar interactions and amino acid residues. The majority of A. catechu compounds with favorable ACE binding energies belong to the phytochemical classes of flavonoids, polyphenols and phenolics, glycosides, and steroids. After in silico toxicity and pharmacokinetic profiling, the bioisosteres Leuco-DM02-39, Leuco-DM02-66, Leuco-DM05-60, Querc-DM09-63, and Querc-DM14-31 with binding energies higher than their parent compounds and comparable to lisinopril, benazepril, and sampatrilat were deemed the best.@*Conclusion@#A. catechu compounds have the potential to target ACE n-domain and c-domain receptor models. Three leucocyanidin and two quercetin bioisosteres exhibited favorable binding to the n-domain and c-domain ACE receptor models and could be further optimized to derive a promising antihypertensive agent through ACE inhibition.

Theoretical analysis and practical applications of the catalytic mechanism of flavonoid 6-hydroxylase / 生物工程学报

Insufficient catalytic efficiency of flavonoid 6-hydroxylases in the fermentative production of scutellarin leads to the formation of at least about 18% of by-products. Here, the catalytic mechanisms of two flavonoid 6-hydroxylases, CYP82D4 and CYP706X, were investigated by molecular dynamics simulations and quantum chemical calculations. Our results show that CYP82D4 and CYP706X have almost identical energy barriers at the rate-determining step and thus similar reaction rates, while the relatively low substrate binding energy of CYP82D4 may facilitate product release, which is directly responsible for its higher catalytic efficiency. Based on the study of substrate entry and release processes, the catalytic efficiency of the L540A mutation of CYP82D4 increased by 1.37-fold, demonstrating the feasibility of theoretical calculations-guided engineering of flavonoid 6-hydroxylase. Overall, this study reveals the catalytic mechanism of flavonoid 6-hydroxylases, which may facilitate the modification and optimization of flavonoid 6-hydroxylases for efficient fermentative production of scutellarin.

Anti-Biofilm Activity of Monolaurin on Staphylococcus aureus: An in-silico Study

Background: Background: Staphylococcus aureus is a gram-negative bacterium that can build strong biofilms on biotic and abiotic surfaces, quickly acquire drug resistance mechanisms, and cause major issues with the treatment of hospital infections. The creation of new therapeutic options has become important due to the limited supply of new antibacterial medications. One of the main sources of bioactive molecules is medicinal plants, and monolaurin is a naturally occurring substance with a variety of biological functions. In light of this, the goal of this study was to assess monolaurin's antibiofilm activity against S. aureus. Methods: Using the AutoDock programme, a docking study of monolaurin against Clf A (clumping factor A) was carried out, and Pymol software was used to evaluate the generated hydrogen bonds in the docked complex. This study demonstrates the positive potential of monolaurin as an antibacterial product and lends support to upcoming pharmacological research on this molecule with an eye toward its therapeutic use. Results: Research was done to support the theoretical absorption of monolaurin in this work and in silico. It was feasible to forecast if the monolaurin molecule may be produced as a medication based on the values of the physical-chemical parameters evaluated using the online tool Swiss ADME. Conclusion: The compound monolaurin demonstrated good receptor ClfA binding affinity with an estimated binding energy of kcal/mol. Natural anti-staphylococcal chemical monolaurin was used as a possible medicine for treating staphylococcal infections in humans by carrying out drug design studies for S. aureus.

Computational studies on the structural variations of MAO-A and MAO-B inhibitors - An in silico docking approach-Supplementary data

The neurological disorder is a concerning problem in the present social scenario. The malfunction of the monoamine oxidase (MAO) enzyme is the responsible factor behind this disorder because this enzyme regulates the metabolism of monoamine neurotransmitters. This work aimed to design and propose the best MAO inhibitors through extensive computational analysis so that the favourable drug-like molecules could be identified for future synthesis. The drugs selected in this study were three MAO-A inhibitors namely Moclobemide, Tolxatone and Brofaromine and two MAO-B inhibitors namely Selegiline and Rasagiline. By substituting hydrophilic and hydrophobic groups at the specified positions, structural variations were designed for each drug. The designed variations and their parent drugs were optimized (basis set is B3LYP/6-311G(d, p)) and the optimized structures were docked to the target using PyRx software. The binding energy of each variation was compared to that of parent drug. The drug-likeness, physicochemical properties (solubility, polarity, flexibility, gastrointestinal absorption, saturation etc.) and toxicity of the lower binding energy variations were analysed using the swissADME, Osiris property explorer and ProTox-II servers. The interacting residues of the enzymes were obtained from the LigPlot+ program. The safe and low binding energy variations with favourable drug properties are suggested for further drug research

Computational studies on the structural variations of MAO-A and MAO-B inhibitors - An in silico docking approach-Supplementary data

The neurological disorder is a concerning problem in the present social scenario. The malfunction of the monoamine oxidase (MAO) enzyme is the responsible factor behind this disorder because this enzyme regulates the metabolism of monoamine neurotransmitters. This work aimed to design and propose the best MAO inhibitors through extensive computational analysis so that the favourable drug-like molecules could be identified for future synthesis. The drugs selected in this study were three MAO-A inhibitors namely Moclobemide, Tolxatone and Brofaromine and two MAO-B inhibitors namely Selegiline and Rasagiline. By substituting hydrophilic and hydrophobic groups at the specified positions, structural variations were designed for each drug. The designed variations and their parent drugs were optimized (basis set is B3LYP/6-311G(d, p)) and the optimized structures were docked to the target using PyRx software. The binding energy of each variation was compared to that of parent drug. The drug-likeness, physicochemical properties (solubility, polarity, flexibility, gastrointestinal absorption, saturation etc.) and toxicity of the lower binding energy variations were analysed using the swissADME, Osiris property explorer and ProTox-II servers. The interacting residues of the enzymes were obtained from the LigPlot+ program. The safe and low binding energy variations with favourable drug properties are suggested for further drug research

Computational studies on the structural variations of MAO-A and MAO-B inhibitors - An in silico docking approach

The neurological disorder is a concerning problem in the present social scenario. The malfunction of the monoamine oxidase (MAO) enzyme is the responsible factor behind this disorder because this enzyme regulates the metabolism of monoamine neurotransmitters. This work aimed to design and propose the best MAO inhibitors through extensive computational analysis so that the favourable drug-like molecules could be identified for future synthesis. The drugs selected in this study were three MAO-A inhibitors namely Moclobemide, Tolxatone and Brofaromine and two MAO-B inhibitors namely Selegiline and Rasagiline. By substituting hydrophilic and hydrophobic groups at the specified positions, structural variations were designed for each drug. The designed variations and their parent drugs were optimized (basis set is B3LYP/6-311G(d, p)) and the optimized structures were docked to the target using PyRx software. The binding energy of each variation was compared to that of parent drug. The drug-likeness, physicochemical properties (solubility, polarity, flexibility, gastrointestinal absorption, saturation etc.) and toxicity of the lower binding energy variations were analysed using the swissADME, Osiris property explorer and ProTox-II servers. The interacting residues of the enzymes were obtained from the LigPlot+ program. The safe and low binding energy variations with favourable drug properties are suggested for further drug research

Simultaneous enantioseparation and simulation studies of atenolol,metoprolol and propranolol on Chiralpak(R) IG column using supercritical fluid chromatography / 药物分析学报

Enantioseparation of three β-blockers,i.e.,atenolol,metoprolol and propranolol,was studied on amylose tris(3-chloro-5-methylphenylcarbamate) immobilized chiral stationary phase using supercritical fluid chromatography (SFC).The effect of organic modifiers (methanol,isopropanol and their mixture),col-umn temperature and back pressure on chiral separation of β-blockers was evaluated.Optimum chro-matographic separation with respect to resolution,retention,and analysis time was achieved using a mixture of CO2 and 0.1％ isopropyl amine in isopropanol:methanol (50:50,V/V),in 75:25 (V/V) ratio.Under the optimized conditions,the resolution factors (Rs) and separation factors (α) were greater than 3.0 and 1.5,respectively.Further,with increase in temperature (25-45 ℃) and pressure (100-150 bars)there was corresponding decrease in retention factors (k),α and Rs.However,a reverse trend (α and Rs)was observed for atenolol with increase in temperature.The thermodynamic data from van't Hoff plots revealed that the enantioseparation was enthalpy driven for metoprolol and propranolol while entropy driven for atenolol.To understand the mechanism of chiral recognition and the elution behavior of the enantiomers,molecular docking studies were performed.The binding energies obtained from simulation studies were in good agreement with the elution order found experimentally and also with the free energy values.The method was validated in the concentration range of 0.5-10 μg/mL for all the enan-tiomers.The limit of detection and limit of quantitation ranged from 0.126 to 0.137 μg/mL and 0.376-0.414 μg/mL,respectively.The method was used successfully to analyze these drugs in pharmaceutical preparations.

Lead Molecule Identification From Vitex Trifolia Linn For Helminthiasis Using In Vitro And In Silico Methods

Objective: The study was an attempt to discover a lead molecule to treat helminthiasis using Vitex trifolia. Linn (V. folia Linn) through sterile effect, in vitro and in silico evaluation. Methods: The antibacterial activity was done by Kirby-Bauer disc diffusion method in three different concentrations of extract and in vitro anthelmintic activity was carried out by petri dish and organ bath method. Further, the in silico docking studies were carried out by 11 phytoconstituents against phosphoethanolamine methyltransferase (4FGZ) using Auto Dock 4.2, it was working based on the principle of Lamarckian genetic algorithm. In docking studies, three important parameters such as binding energy, inhibition constant and intermolecular energy are determined. Results: The extracts showed an antibacterial effect in three different concentrations. At 16 mcg/disc a significant effect was observed when compared to blank and ciprofloxacin 5 mcg/disc. The anthelmintic activity in the petri dish method, means paralyzing time of Pheretimaposthuma with the dose of 25, 50 and 100 mg/ml were 13.78, 5.79 and 4.57 min respectively and Piperazine citrate (10 mg/ml) showed paralysis in 21.58 min. In the organ bath method, the time for paralysis of the worm was recorded on a slow-moving Sherrington rotating drum and the study report showed that paralyzing time was decreased at increasing concentrations of the extract. The results of in silico studies exhibited a binding energy of-10.25kcal/mol, inhibitory constant (Ki) 30.91nM, intermolecular energy,-10.84kcal/mol for abietatriene-3-ol which is lesser than the standard ligand phosphoethanolamine (-6.03kcal/mol, 38.29µM,-7.82kcal/mol) respectively. Conclusion: The study reports conclude that the active constituents in V. folia Linn having better anthelmintic activity, thus the active constituents may be optimized and make way to a new moiety for the treatment of helminthiasis.

Thermodynamics of ABC transporters

ABC transporters form the largest of all transporter families, and their structural study has made tremendous progress over recent years. However, despite such advances, the precise mechanisms that determine the energy-coupling between ATP hydrolysis and the conformational changes following substrate binding remain to be elucidated. Here, we present our thermodynamic analysis for both ABC importers and exporters, and introduce the two new concepts of differential-binding energy and elastic conformational energy into the discussion. We hope that the structural analysis of ABC transporters will henceforth take thermodynamic aspects of transport mechanisms into account as well.

Molecular Dynamics Simulation of Β-Melanotropin Stimulating Hormone (Β-MSH) Docked Onto the Receptor MC4R.

Melanocortin system is composed of four peptide hormones known as α, β, γ and adrenocorticotropic hormone (ACTH), derived from post-translational cleavage of a polypeptide precursor ‘proopiomelanocortin (POMC)’. Among these hormones; β-melanotropin stimulating hormone (β-MSH), an 18 amino acid residue peptide fragment is an important hormone as it is involved in activation of MC4R to induce lean phenotype ‘balance between energy intake and energy expenditure’. In addition to this, MC4R is also involved in the modulation of erectile function, including the spinal cord and pelvic ganglion of rats and the penis of both rats and humans, providing an anatomical basis for melanocortin effects on sexual function. MC4R is one of the five melanocortin receptors (MC1R–MC5R) which have been characterized with tissue-specific expression patterns and different binding affinities for each of the melanocortin hormones to regulate various biological functions. In the present work, 3D models of MC4R and β-MSH have been predicted, followed by docking and molecular dynamics simulation. While the 3D model of MC4R receptor has been predicted through threading approach, structure of β- MSH was built based on ab initio technique. The β-MSH model was later successfully docked onto the MC4R protein. Molecular dynamics (MD) simulation for 15 ns was used to compute the electrostatic solvation energy as well as binding energy between MC4R with β-MSH model under implicit solvent conditions.

THEORETICAL MODEL OF CARBON NANOTUBES AS DELIVERY TO FLUOROURACIL (Anticancer) / MODELO TEÓRICO DE NANOTUBOS DE CARBONO COMO LIBERADORES DE FLUOROURACILO (Anticancerígeno) / MODELO TEÓRICO DE NANOTUBOS DE CARBONO COMO LIBERADORES DE FLUOROURACIL (Anticancerígeno)

The quantum modeling interaction properties of fluorouracil radicals on the single walled carbon nanotubes surface is researched via MNDO/d calculations. We have studied the effect of diameter, length, position and rotational characteristics of CNT on binding fluorouracil. Our results suggest that the binding energy is lower as the CNT diameter increases, while as the CNT length increases the binding energy initially increases and then slightly increases.

Las propiedades de interacción, según el modelo cuántico, de los radicales de flourouracil ubicados en la superficie de los nanotubos de carbono de pared simple se investigan a través de cálculos MNDO/d. Hemos estudiado el efecto del diámetro, la longitud, la posición y las características rotacionales de CNT en la síntesis de fruorouracil. Nuestros resultados sugieren que la energía de síntesis baja en la medida en que aumenta el diámetro, mientras que a medida que aumenta la longitud, la energía de síntesis inicialmente disminuye y luego aumenta levemente.

As propriedades da interação, segundo o modelo quântico, do radicais de flourouracil localizados na superfície de nanotubos de carbono com paredes simples são pesquiçadas a traverso de cálculos MNDO/d. Estudamos o efeito do diâmetro, comprimento, posição e características rotacionais do CNT na síntese de fruorouracil. Nossos resultados sugerem que a energia de síntese baixa à medida que aumenta o diâmetro, enquanto que à medida que o comprimento aumenta, a energia de síntese inicialmente diminui e depois aumenta um pouco.

Molecular mechanism of facilitated transport by carrier ionophores:A study of energetics.

The mechanism of ion transport by carrier ionophores is investigated. The electrostatic potential is used as index of the binding energy of a cation with valinomycin and enniatin B. The ion binding capacities of these ionophores are studied as functions of conformation and of distance of an approaching ion-complex. The energetics of dirnerisation and the binding energy profile of an ion in dimers of valinomycin and enniatin B are examined. The binding energy profiles and the electrostatic potential surfaces of valinomycin and enniatin B are compared in relation to their biological activities.