Computational screening for active compounds targeting protein sequences: methodology and experimental validation

The three-dimensional (3D) structures of most protein targets have not been determined so far, with many of them not even having a known ligand, a truly general method to predict ligand-protein interactions in the absence of three-dimensional information would be of great potential value in drug discovery. Using the support vector machine (SVM) approach, we constructed a model for predicting ligand-protein interaction based only on the primary sequence of proteins and the structural features of small molecules. The model, trained by using 15,000 ligand-protein interactions between 626 proteins and over 10,000 active compounds, was successfully used in discovering nine novel active compounds for four pharmacologically important targets (i.e., GPR40, SIRT1, p38, and GSK-3β). To our knowledge, this is the first example of a successful sequence-based virtual screening campaign, demonstrating that our approach has the potential to discover, with a single model, active ligands for any protein.     

Isomerspecific determination of sorption/desorption,transformation and bioaccumulation of hexachlorocyclohexanes at the case site Bitterfeld with special regard to ageing effects

ABSTRACT

The production of hexachlorocyclohexanes (HCHs) at Bitterfeld, Germany, caused heavy contamination of sediments in the receiving waters and soils of riverbanks and floodplains of the Spittelwasser creek with adverse effects on the rivers Mulde and Elbe. This study was launched to investigate the isomer specific behaviour of aged and non-aged hexachlorocyclohexanes focusing on their transformation, sorption and bioaccumulation. Spiked residues of α- and γ-HCH were transformed in aerobic water/sediment systems, while no elimination was observed for β-, δ- and ε-HCH. In contrast, aged residues of all HCH isomers were entirely stable under these aerobic conditions, while under anaerobic conditions a significant transformation was found for all spiked HCH isomers. Desorption hysteresis was identified for all isomers. Ageing led to an increase in the binding strength of HCH isomers to sediment, indicated by elevated logK_OC-values and increased the persistence of HCH isomers in aerobic water/sediment systems. HCH bioaccumulated in benthic organisms of Spittelwasser creek and Schachtgraben canal. After their confluence the lipid normalised HCH concentrations in benthic organisms of Spittelwasser creek increased by a factor of 10, indicating the central role of HCH residues from the Schachtgraben canal for the HCH exposure of benthic biota in the aquatic system of the Spittelwasser creek.     

Stereoselective Synthesis of Fluorinated Galactopyranosides as Potential Molecular Probes for Galactophilic Proteins: Assessment of Monofluorogalactoside–LecA Interactions

The replacement of hydroxyl groups by fluorine atoms on hexopyranoside scaffolds may allow access to invaluable tools for studying various biochemical processes. As part of ongoing activities toward the preparation of fluorinated carbohydrates, a systematic investigation involving the synthesis and biological evaluation of a series of mono- and polyfluorinated galactopyranosides is described. Various monofluorogalactopyranosides, a trifluorinated, and a tetrafluorinated galactopyranoside have been prepared using a Chiron approach. Given the scarcity of these compounds in the literature, in addition to their synthesis, their biological profiles were evaluated. Firstly, the fluorinated compounds were investigated as antiproliferative agents using normal human and mouse cells in comparison with cancerous cells. Most of the fluorinated compounds showed no antiproliferative activity. Secondly, these carbohydrate probes were used as potential inhibitors of galactophilic lectins. The first transverse relaxation-optimized spectroscopy (TROSY) NMR experiments were performed on these interactions, examining chemical shift perturbations of the backbone resonances of LecA, a virulence factor from Pseudomonas aeruginosa. Moreover, taking advantage of the fluorine atom, the ¹⁹F NMR resonances of the monofluorogalactopyranosides were directly monitored in the presence and absence of LecA to assess ligand binding. Lastly, these results were corroborated with the binding potencies of the monofluorinated galactopyranoside derivatives by isothermal titration calorimetry experiments. Analogues with fluorine atoms at C-3 and C-4 showed weaker affinities with LecA as compared to those with the fluorine atom at C-2 or C-6. This research has focused on the chemical synthesis of “drug-like” low-molecular-weight inhibitors that circumvent drawbacks typically associated with natural oligosaccharides.     

Fluorine in a C−F Bond as the Key to Cage Formation

Cage molecules have long been employed to trap reactive or transient species, as their rigid nature allows them to enforce situations that otherwise would not persist. In this Minireview, we discuss our use of rigid cage structures to investigate the close noncovalent interactions of fluorine with other functional groups and determine how mutual proximity affects both physical properties and reactivity. Unusual covalent interactions of fluorine are also explored: the cage can close to form the first solution‐phase C‐F‐C fluoronium ion.     

Synthetic approaches for BF2-containing adducts of outstanding biological potential. A review

Organic compounds containing the F or B elements in their structures have recently attracted the interest of the chemists and medicinal chemists because their improved biological properties displayed in comparison to their non-fluorinated or non-borinated parent structures. It is widely been documented that curcumine (CUR) have a high biological potential as antioxidant, anti-inflammatory and anticancer agent, among others, but some drawbacks related to its unfavorable bio-physicochemical properties have prevented its applicability as chemotherapeutic drug. Nevertheless, recent studies have shown that the introduction of the BF₂ functionality in its structure (i.e. CUR-BF₂ adducts) and analogues have significantly improved their biological properties, mainly, their anticancer and antibiotic activities.On the other hand, the BF₂-adduct BODIPY (i.e. 4,4-difluoro-4-bora-3a-azonia-4a-aza-s-indacene) and derivatives are widely known by their outstanding photophysical properties displayed. However, recently it have increased the interest in such structures, but this time, for the biological properties that these fluorescent compounds are also shown, as convenient probes for diverse biological targets.Focusing on the above findings, we were interested into compile, in this review article, the literature documented since 2000–2020 exclusively engaged with the synthetic strategies established for the synthesis of curcumine-BF₂ adducts, BODIPY and their related derivatives, in which the biological properties displayed by such structures have been highlighted. Remarkably, the biological activities displayed by the aforementioned BF₂-based compounds are mainly related with cell imaging studies, biomolecules recognition and labels, antibiotic properties and antiproliferative agents, which were conveniently used to organize them in concise Tables and Schemes to facilitate their comparisons, and to underscore the key points of the present review.     

Fluorine in crystal engineering--"the little atom that could"

In the last decade interactions of fluorine substituents in a variety of organic compounds have gained interest in life science and solid state materials. This review provides knowledge on fluorine interactions classified into phenyl-perfluorophenyl-, C-FH, FF and C-FpiF interactions. Except for phenyl-perfluorophenyl stacking featuring a stabilising energy of about 30 kJ.mol(-1), interactions involving fluorine are generally weak. Although, there is still no concise understanding of fluorine interactions, there are numerous examples showing the influence of weak synthons on chemical, physical and biological properties.     

Determination of HCHs in sediments of the River Gallego

Summary The capacity of adsortion of the River Gallego's sediments in relation to HCHs versus time was studied as well as the recoverys of extraction of sediments. Two series of dried and homogeneous sediments from the river were prepared as follows. A well-known amount of HCHs was added to two series of river's sediments containing 25% and 60% (w/w) of water each. After some controlled period of time the samples were centrifugated and the content of HCH was analyzed after the extraction and using gas chromatography and an electron capture detector for the final determination. The liquid phase was extracted with a mixture of hexane-diethylether (85:15) and the solid phase using acetone and a mixture of hexane-acetone (1:1). It has been found that between 18% and 36.9% of HCHs added were irreversibly adsorbed. Also, the elimination of sulfur compounds which act as interferences and led to incorrect quantification in the chromatogram was studied. It has been found that the main compounds present in these sediments are very soluble in water and they remain in the water after the extraction with hexane. This fact permits to avoid these interferences from the sediments only by rinsing them with distilled water.Projekt P IT 8/88 (Diputación General de Aragón)     

The role of polycyclic frameworks in modulating P2X7 receptor function

Herein we describe our recent attempts to target the P2X₇ receptor for potential treatment of neurological disorders. This work focusses on different polycycles including carborane, adamantane or cubane, joined by either a cyanoguanidine or an amide linker to phenyl or isoquinoline moieties. We have demonstrated the superiority of the adamantyl moiety over other polycycles in terms of synthetic accessibility and biological (cellular) activity. We have also shown that an amide or cyanoguanidine linker can greatly alter the biological activity of compounds. This SAR study provides important insights into the types of functionality required to target the P2X₇ receptor.     

Concentration and distribution of 17 organochlorine pesticides (OCPs) in seawater from the Japan Sea northward to the Arctic Ocean

Seventeen classic organochlorine pesticides in surface seawater were studied in terms of their composition pattern as well as their distribution pattern in the areas covering the Japan Sea,Okhotsk Sea,Bering Sea,Chukchi Sea and Arctic Ocean.Their concentrations varied,but roughly two levels were seen with one ranging between 0.1 and 1 ng L-1 for most HCH isomers and the other lower than 0.1 ng L-1 for other chemicals.Of the 17 target compounds,HCHs were dominant with a total concentration percentage general...     

Persistent Organochlorine Insecticide Residues in Some Paddy,Upland and Urban Soils of India

Abstract

A wide variety of agricultural soils from different regions of India such as paddy, wheat, mustard, potato, cotton, tea, tomato, sugarcane, grape and urban soils were surveyed for the residual levels of persistent organochlorine insecticide residues in 1988 and 1989. DDT and HCH concentrations were found to be higher in upland soils and lower in paddy field soils. These results indicate the large application of HCH and DDT compounds for agricultural purposes in India. In urban soil DDT levels were higher than HCHs reflecting the use of the former insecticide in relatively large amounts for vector control. Among DDT compounds, p,p′-DDE showed higher percentage in paddy and upland soils. On the other hand, p,p′-DDT contributed to higher levels in urban soils. The β-HCH was detected as the dominant isomer in both agricultural and non agricultural soils. The levels and percentage compositions of DDTs and HCHs revealed the extent of environmental contamination caused by the continuous usage of persistent organochlorine insecticides in large quantities in tropical areas like India.     

Synthesis of mesoporous hollow carbon hemispheres as highly efficient Pd electrocatalyst support for ethanol oxidation

The synthesis procedure of the highly mesoporous hollow carbon hemispheres (HCHs) using glucose as carbon source and solid core mesoporous shell silica (SCMSS) as template and the formation mechanism of the HCHs have been presented. The HCHs show an ultrahigh surface area of 1095.59 m² g^?1 and an average mesopore size of 9.38 nm. The hemispherical structure with large mesopores also results in the improvement in the mass transfer and therefore more concentrated ethanol solution can be used to increase the energy density. The additional advantage of the HCHs compared to the hollow carbon spheres is that they can provide the similar surface area at reduced volume. The current densities of ethanol oxidation on Pd nanoparticles supported on HCH (Pd/HCH) electrocatalyst are three times as many as on Pd/C at the same Pd loadings.     

In silico carborane docking to proteins and potential drug targets

The presence of boron atoms has made carboranes, C(2)B(10)H(12), attractive candidates for boron neutron capture therapy. Because of their chemistry and possible conjugation with proteins, they can also be used to enhance interactions between pharmaceuticals and their targets and to increase the in vivo stability and bioavailability of compounds that are normally metabolized rapidly. Carboranes are isosteric to a rotating phenyl group, which they can substitute successfully in biologically active systems. A reverse ligand-protein docking approach was used in this work to identify binding proteins for carboranes. The screening was carried out on the drug target database PDTD that contains 1207 entries covering 841 known potential drug targets with structures taken from the Protein Data Bank. First, for validation, the protocol was applied to three crystal structures of proteins in which carborane derivatives are present. Then, the model was applied to systems for which the protein structure is available, but the binding site of carborane has not been reported. These systems were used for further validation of the protocol, while simultaneously providing new insight into the interactions between cage and protein. Finally, the screening was carried out on the database to reveal potential carborane binding targets of interest for biological and pharmacological activity. Carboranes are predicted to bind well to protease and metalloprotease enzymes. Other carborane pharmaceutical targets are also discussed, together with possible protein carriers.     

Recent Progress Toward Trifluoromethylselenolation Reactions

Recently, a great deal of work has been done in the construction of C–CF₃ or C–SCF₃ bonds, because these fluorine groups display remarkable biological properties. Despite a trifluoromethylseleno group like CF₃ or SCF₃ may also have potential biological activity, the work on the construction of the C–SeCF₃ bond is rarely reported. This mini‐review highlights recent developments in trifluoromethylselenolation reactions using fluorine reagents, such as (Me₄N )SeCF₃ , ClSeCF₃ , [(bpy)Cu(SeCF₃ )]₂, Me₃SiCF₃ , and HCF₃ . Five approaches to the trifluoromethylselenolation of organic compounds are summarized: (1) trifluoromethylselenolation of aryl, alkyl, and heteroaryl halides, aromatic compounds, and boronic acids; (2) trifluoromethylselenolation of terminal alkynes and propargylic chlorides; (3) trifluoromethylselenolation of allylic bromides, vinyl halides, α‐bromo‐α,β‐unsaturated carbonyl compounds, and acyl chlorides; (4) trifluoromethylselenolation of diazo compounds; and (5) synthesis of trifluoromethyl selenides from selenocyanates and fluoroform.     

Influence of stereoelectronic effects on the 1JC─F spin–spin coupling constant in fluorinated heterocyclic compounds

The Perlin effect and its analog for fluorinated compounds (the fluorine Perlin-like effect) manifest on one-bond C─H (C─F for the fluorine Perlin-like effect) spin–spin coupling constants (SSCCs) in six-membered rings. These effects can be useful to probe the stereochemistry (axial or equatorial) of the C─H and C─F bonds, respectively. The origin of these effects has been debatable in the literature as being due to hyperconjugative interactions, dipolar effects, and induced current density. Accordingly, a variety of model compounds has been used to probe such effects since the cyclohexanone carbonyl group and the endocyclic heteroatom lone pairs play different roles on the above-mentioned effects. Thus, the ¹J_C─F SSCC in fluorinated lactams and lactones were theoretically studied to gain further insight on the nature of the fluorine Perlin-like effect. In addition, because the intramolecular α-effect has recently gained attention for its importance in the reactivity and stereoelectronic interactions in peroxide compounds, some fluorinated 1,2-dioxanes and 1,2-dithianes were studied to evaluate the role of the α-effect on the behavior of ¹J_C─F SSCCs. Differently from fluorinated ketones and ethers, the fluorine Perlin-like effect in the amides and esters cannot be explained by hyperconjugative or dipolar interactions alone, because the resonance in these groups affect the ¹J_C─F values. The O─O and S─S-containing systems exhibit a strong fluorine Perlin-like effect, but unlike the α-effect, this behavior cannot be explained neither by hyperconjugation nor by dipolar interactions alone; the spatial proximity of the C─F and O─O/S─S bonds is proposed to affect the magnitude of the ¹J_C─F SSCC.     

Spectroscopic elucidation (FT-IR,FT-Raman and UV-visible) with NBO,NLO, ELF,LOL, drug likeness and molecular docking analysis on 1-(2-ethylsulfonylethyl)-2-methyl-5-nitro-imidazole: An antiprotozoal agent

1-(2-ethylsulfonylethyl)-2-methyl-5-nitro-imidazole (1EMI) C₈H₁₃N₃O₄S also known as Tinidazole, selected for its antiprotozoal property is extensively used for spectroscopic elucidations and computational aspects using density functional methods. Along with spectral conclusions, further investigations on fundamental reactive properties such as electrical, optical, nonlinear combined with DFT simulations were performed. Molecular docking procedure supports the results of chosen appropriate antiprotozoal agent based on ligand-protein interactions. Experimental and simulated (B3LYP/6-311++G (d,p)) IR and Raman spectra showed concurrence. NLO analysis through first order hyperpolarizability parameter helps in finding the potential of 1EMI as a good NLO candidate. Charge delocalization and the stability of the compound were discussed using natural bond orbital (NBO) analysis. Furthermore, Electron localization function (ELF), local orbital locator (LOL), and Frontier molecular orbitals (FMO) were studied. Besides, Mulliken population analysis on atomic charges, Energy gap, chemical potential, global hardness, softness, ionization potential, electronegativity, electrophilicity index along thermodynamic parameters (enthalpy, entropy and heat capacity) have been calculated. Drug likeness parameters and molecular docking approach enabled to check pharmaceutical potential and biological activity of 1EMI. The biological activity of 1EMI through ligand and protein interactions have been confirmed theoretically for the treatment of Malaria, Invasive aspergillosis and Mycobacterium tuberculosis with respect to chosen proteins. Three different activity targets and protein interactions are quite successful revealing the bond distances, intermolecular energy, binding energy and inhibition constant. 2D interaction profile image of the two maximum interacted proteins and also Ramachandran plot used to show stereochemistry of selected protein. The activities of 1EMI were studied in accordance with literature survey and the results were presented.     

Biotechnical potential of natural products

The potential of natural products has been recognized since antiquity. They continue to contribute a great deal to modern industries by providing a wide range of chemicals; many of them now vital to modern life, such as antibiotics, cardiac drugs and insecticides, were discovered from living organisms.Traditionally, natural product research has primarily centred around the structural elucidation of compounds. However, in recent years, research has been directed towards the physiological and ecological significance of these chemicals. We have just begun to understand the role of naturally occurring chemicals in the biological interactions of organisms with their ecosystems. The study of natural products not only provides novel bioactive compounds, but also helps in the understanding of nature's way of tackling environmental problems. These processes, which may be called “Natural Technology”, might provide us with totally new means and agents for combating diseases, controlling pests or improving agricultural productivity.The extension of research to marine natural products has paid rich dividends. Polyoxygenated compounds such as tetrodotoxins, palytoxins and halichondrins show novel bioelectric properties which influence the ionic permeability of biological membranes. Some of these compounds show remarkable antitumour and immunomodulatory activities. So far, only a small proportion of the known flora has been subjected to chemical or biological investigations; the vast unexplored biotechnical potential of flora awaits discovery and exploitation.     

The Equilibrium Structure of Methyl Fluoride

The equilibrium structure of CH₃F has been determined using new sets of accurate rotational constants that have been determined by taking into account all the interactions between the excited vibrational states. This experimental structure is in excellent agreement with the equilibrium geometry calculated at the CCSD(T) level of theory with the cc-pV(5, Q)Z basis set (including corrections for the core correlation and for the effect of diffuse functions on fluorine). Finally, the experimental and ab initio structures have been combined by a least-squares analysis. The results are , and L _e(HCH) = 110.2 (1)°, where the uncertainties shown in parentheses correspond to three standard deviations.     

酪氨酸激酶抑制剂的柔性原子受体模型方法研究

用柔性原子受体模型方法对一系列嘧啶类衍生物酪氨酸激酶抑制剂进行了3D－ QSAR研究，建立了相关性很好的模型，这些模型对测试集中化合物活性的预测结果 表明其具有较强的预测能力。柔性原子受体模型方法还给出了虚拟的受体模型，表 明了受体和配体之间可能的相互作用，包括两个氢键相互作用、一个疏水作用和一 个硫－芳香相互作用，这与Novartis的药效团模型非常一致。