In silico study of binding affinity of nitrogenous bicyclic heterocycles: fragment-to-fragment approach

2020 ◽  
Vol 15 (2) ◽  
pp. 49-59
Author(s):  
Yevheniia Velihina ◽  
Nataliya Obernikhina ◽  
Stepan Pilyo ◽  
Maryna Kachaeva ◽  
Oleksiy Kachkovsky ◽  
...  
Keyword(s):  
Amino Acids ◽  
Binding Affinity ◽  
In Silico ◽  
Density Functional ◽  
Energy Levels ◽  
Aromatic Amino Acids ◽  
Electron System ◽  
High Energy ◽  
Proton Donor ◽  
Stabilization Energy

The binding affinity of model aromatic amino acids and heterocycles and their derivatives condensed with pyridine were investigated in silico and are presented in the framework of fragment-to-fragment approach. The presented model describes interaction between pharmacophores and biomolecules. Scrupulous data analysis shows that expansion of the π-electron system by heterocycles annelation causes the shifting up of high energy levels, while the appearance of new the dicoordinated nitrogen atom is accompanied by decreasing of the donor-acceptor properties. Density Functional Theory (DFT) wB97XD/6-31(d,p)/calculations of π-complexes of the heterocycles 1-3 with model fragments of aromatic amino acids, which were formed by π-stack interaction, show an increase in the stabilization energy of π-complexes during the moving from phenylalanine to tryptophan. DFT calculation of pharmacophore complexes with model proton-donor amino acid by the hydrogen bonding mechanism (H-B complex) shows that stabilization energy (DE) increases from monoheterocycles to their condensed derivatives. The expansion of the π-electron system by introducing phenyl radicals to the oxazole cycle as reported earlier [18] leads to a decrease in the stabilization energy of the [Pharm-BioM] complexes in comparison with the annelated oxazole by the pyridine cycle.

scholarly journals Association between alterations in plasma metabolome profiles and laminitis in intensively finished Holstein bulls in a randomized controlled study

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sonja Christiane Bäßler ◽  
Ákos Kenéz ◽  
Theresa Scheu ◽  
Christian Koch ◽  
Ulrich Meyer ◽  
...  
Keyword(s):  
Amino Acids ◽  
Aromatic Amino Acids ◽  
High Energy ◽  
Metabolizable Energy ◽  
Protein Diet ◽  
Controlled Study ◽  
Randomized Controlled ◽  
Inflammatory Phenotype ◽  
Dietary Nutrient ◽  
Holstein Bulls

AbstractMetabolic consequences of an energy and protein rich diet can compromise metabolic health of cattle by promoting a pro-inflammatory phenotype. Laminitis is a common clinical sign, but affected metabolic pathways, underlying pathophysiology and causative relationships of a systemic pro-inflammatory phenotype are unclear. Therefore, the aim of this study was to elucidate changes in metabolome profiles of 20 months old Holstein bulls fed a high energy and protein diet and to identify novel metabolites and affected pathways, associated with diet-related laminitis. In a randomized controlled feeding trial using bulls fed a high energy and protein diet (HEP; metabolizable energy [ME] intake 169.0 ± 1.4 MJ/day; crude protein [CP] intake 2.3 ± 0.02 kg/day; calculated means ± SEM; n = 15) versus a low energy and protein diet (LEP; ME intake 92.9 ± 1.3 MJ/day; CP intake 1.0 ± 0.01 kg/day; n = 15), wide ranging effects of HEP diet on metabolism were demonstrated with a targeted metabolomics approach using the AbsoluteIDQ p180 kit (Biocrates Life Sciences). Multivariate statistics revealed that lower concentrations of phosphatidylcholines and sphingomyelins and higher concentrations of lyso-phosphatidylcholines, branched chain amino acids and aromatic amino acids were associated with an inflammatory state of diet-related laminitis in Holstein bulls fed a HEP diet. The latter two metabolites share similarities with changes in metabolism of obese humans, indicating a conserved pathophysiological role. The observed alterations in the metabolome provide further explanation on the underlying metabolic consequences of excessive dietary nutrient intake.

scholarly journals In-silico Molecular Docking and ADME/Pharmacokinetic Prediction Studies of Some Novel Carboxamide Derivatives as Anti-tubercular Agents

2020 ◽  
Vol 3 (4) ◽  
pp. 989-1000
Author(s):  
Mustapha Abdullahi ◽  
Shola Elijah Adeniji
Keyword(s):  
Molecular Docking ◽  
Binding Affinity ◽  
In Silico ◽  
Density Functional ◽  
Docking Simulation ◽  
Basis Set ◽  
Hybrid Functional ◽  
Standard Drug

AbstractMolecular docking simulation of thirty-five (35) molecules of N-(2-phenoxy)ethyl imidazo[1,2-a]pyridine-3-carboxamide (IPA) with Mycobacterium tuberculosis target (DNA gyrase) was carried out so as to evaluate their theoretical binding affinities. The chemical structure of the molecules was accurately drawn using ChemDraw Ultra software, then optimized at density functional theory (DFT) using Becke’s three-parameter Lee–Yang–Parr hybrid functional (B3LYP/6-311**) basis set in a vacuum of Spartan 14 software. Subsequently, the docking operation was carried out using PyRx virtual screening software. Molecule 35 (M35) with the highest binding affinity of − 7.2 kcal/mol was selected as the lead molecule for structural modification which led to the development of four (4) newly hypothetical molecules D1, D2, D3 and D4. In addition, the D4 molecule with the highest binding affinity value of − 9.4 kcal/mol formed more H-bond interactions signifying better orientation of the ligand in the binding site compared to M35 and isoniazid standard drug. In-silico ADME and drug-likeness prediction of the molecules showed good pharmacokinetic properties having high gastrointestinal absorption, orally bioavailable, and less toxic. The outcome of the present research strengthens the relevance of these compounds as promising lead candidates for the treatment of multidrug-resistant tuberculosis which could help the medicinal chemists and pharmaceutical professionals in further designing and synthesis of more potent drug candidates. Moreover, the research also encouraged the in vivo and in vitro evaluation study for the proposed designed compounds to validate the computational findings.

scholarly journals Hyperammonaemia does not impair brain function in the absence of net glutamine synthesis

1991 ◽  
Vol 277 (3) ◽  
pp. 697-703 ◽  
Author(s):  
R A Hawkins ◽  
J Jessy
Keyword(s):  
Amino Acids ◽  
Brain Function ◽  
Aromatic Amino Acids ◽  
Preceding Paper ◽  
Glucose Consumption ◽  
High Energy ◽  
High Energy Phosphates ◽  
Intermediary Metabolites ◽  
Glutamine Synthesis ◽  
The Brain

1. It has been established that chronic hyperammonaemia, whether caused by portacaval shunting or other means, leads to a variety of metabolic changes, including a depression in the cerebral metabolic rate of glucose (CMRGlc) increased permeability of the blood-brain barrier to neutral amino acids, and an increase in the brain content of aromatic amino acids. The preceding paper [Jessy, DeJoseph & Hawkins (1991) Biochem. J. 277, 693-696] showed that the depression in CMRGlc caused by hyperammonaemia correlated more closely with glutamine, a metabolite of ammonia, than with ammonia itself. This suggested that ammonia (NH3 and NH4+) was without effect. The present experiments address the question whether ammonia, in the absence of net glutamine synthesis, induces any of the metabolic symptoms of cerebral dysfunction associated with hyperammonaemia. 2. Small doses of methionine sulphoximine, an inhibitor of glutamine synthetase, were used to raise the plasma ammonia levels of normal rats without increasing the brain glutamine content. These hyperammonaemic rats, with plasma and brain ammonia levels equivalent to those known to depress brain function, behaved normally over 48 h. There was no depression of cerebral energy metabolism (i.e. the rate of glucose consumption). Contents of key intermediary metabolites and high-energy phosphates were normal. Neutral amino acid transport (tryptophan and leucine) and the brain contents of aromatic amino acids were unchanged. 3. The data suggest that ammonia is without effect at concentrations less than 1 mumol/ml if it is not converted into glutamine. The deleterious effect of chronic hyperammonaemia seems to begin with the synthesis of glutamine.

scholarly journals In-Silico Prediction of Annihilators for Triplet Fusion Upconversion via Auxiliary-Field Quantum Monte Carlo

2020 ◽  
Author(s):  
John Weber ◽  
Emily Churchill ◽  
Evan J. Arthur ◽  
Andrew Pun ◽  
Shiwei Zhang ◽  
...  
Keyword(s):  
Monte Carlo ◽  
Electronic Structure ◽  
Quantum Monte Carlo ◽  
In Silico ◽  
Density Functional ◽  
Energy Gap ◽  
Critical Role ◽  
High Energy ◽  
Auxiliary Field ◽  
Hybrid Functional

<div>The energy of the lowest-lying triplet state (T1) relative to the ground and first-excited singlet states (S0, S1) plays a critical role in optical multiexcitonic processes of organic chromophores. Focusing on triplet fusion upconversion, the S0 to T1 energy gap, known as the triplet energy, is difficult to measure experimentally for most molecules of interest. Ab initio predictions can provide a useful alternative, however</div><div>low-scaling electronic structure methods such as the Kohn-Sham and time-dependent variants of Density Functional Theory (DFT) rely heavily on the fraction of exact exchange chosen for a given functional, and tend to be unreliable when strong electronic correlation is present. Here, we apply auxiliary-field quantum Monte Carlo (AFQMC), a scalable electronic structure method capable of accurately describing even strongly correlated molecules, to predict the triplet energies for a series of candidate annihilators for triplet fusion (TF) upconversion, including 9,10 substituted anthracenes and substituted benzothiadiazole (BTD) and benzoselenodiazole (BSeD) compounds. We compare our results to predictions from a number of commonly used DFT functionals, as well as DLPNO-CCSD(T0), a localized approximation to coupled cluster with singles, doubles, and perturbative triples. Together with S1 estimates from absorption/emission spectra, which are well-reproduced by TD-DFT calculations employing the range-corrected hybrid functional CAM-B3LYP, we provide predictions regarding</div><div>the thermodynamic feasibility of upconversion by requiring a) the measured T1 of the sensitizer exceeds that of the calculated T1 of the candidate annihilator, and b) twice</div><div>the T1 of the annihilator exceeds its S1 energetic value. We demonstrate a successful example of in silico discovery of a novel annihilator, phenyl-substituted BTD, and present experimental validation of upconverted blue light emission when coupled to a platinum octaethylporphyrin (PtOEP) sensitizer. The BTD framework thus represents a new class of annihilators for TF upconversion. Its chemical functionalization, guided by the computational tools utilized herein, provides a promising route towards high energy (violet to near-UV) emission.</div>

Site specific interaction of aromatic amino acids with ZnO nanotubes: A density functional approach

2016 ◽  
Vol 1086 ◽  
pp. 36-44 ◽  
Author(s):  
Pari Sadat Maddahi ◽  
Nasser Shahtahmassebi ◽  
Mahmood Rezaee Roknabadi ◽  
Fatemeh Moosavi
Keyword(s):  
Amino Acids ◽  
Density Functional ◽  
Specific Interaction ◽  
Aromatic Amino Acids ◽  
Functional Approach ◽  
Site Specific ◽  
Zno Nanotubes

Theoretical study of the adsorption of aromatic amino acids on a single-wall boron nitride nanotube with empirical dispersion correction

2017 ◽  
Vol 95 (6) ◽  
pp. 710-716 ◽  
Author(s):  
Guohong Fan ◽  
Sheng Zhu ◽  
Ke Ni ◽  
Hong Xu
Keyword(s):  
Amino Acids ◽  
Boron Nitride ◽  
Density Functional ◽  
Energy Charge ◽  
Tight Binding ◽  
Excited State Absorption ◽  
Aromatic Amino Acids ◽  
Boron Nitride Nanotubes ◽  
Dispersion Correction ◽  
Tight Binding Method

In the present study, the adsorption and properties of three popularly studied aromatic amino acids, namely phenylalanine, tyrosine, and tryptophan, on the surface of the single-wall boron nitride nanotubes (BNNTs) have been explored with an empirical dispersion corrected density functional tight-binding method. A serials of armchair BNNTs (n = 4–12) and zigzag BNNTs (n = 8–18) with the aromatic amino acid adsorbed on the surface are investigated. With the dispersion correction explicitly considered in the density functional tight-binding method, the adsorption properties between amino acids and BNNTs are described by including long-range van der Waals interactions. It is found that the π–π and H–π stacking interactions are the main forces stabilizing the system. Based on the evidence of adsorption energy, charge density plots, and density of states analysis, the study concludes that the BNNT adsorbs the amino acids with no bonded interactions between the two parts. The interactions of amino with the BNNT were further studied by analyzing molecular orbitals and excited state absorption spectrum of the stable complexes.

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