Biomacromolecular quantitative structure–activity relationship (BioQSAR): a proof-of-concept study on the modeling, prediction and interpretation of protein–protein binding affinity

Quantitative structure–activity relationship (QSAR), a regression modeling methodology that establishes statistical correlation between structure feature and apparent behavior for a series of congeneric molecules quantitatively, has been widely used to evaluate the activity, toxicity and property of various small-molecule compounds such as drugs, toxicants and surfactants. However, it is surprising to see that such useful technique has only very limited applications to biomacromolecules, albeit the solved 3D atom-resolution structures of proteins, nucleic acids and their complexes have accumulated rapidly in past decades. Here, we present a proof-of-concept paradigm for the modeling, prediction and interpretation of the binding affinity of 144 sequence-nonredundant, structure-available and affinity-known protein complexes (Kastritis et al. Protein Sci 20:482–491, 2011) using a biomacromolecular QSAR (BioQSAR) scheme. We demonstrate that the modeling performance and predictive power of BioQSAR are comparable to or even better than that of traditional knowledge-based strategies, mechanism-type methods and empirical scoring algorithms, while BioQSAR possesses certain additional features compared to the traditional methods, such as adaptability, interpretability, deep-validation and high-efficiency. The BioQSAR scheme could be readily modified to infer the biological behavior and functions of other biomacromolecules, if their X-ray crystal structures, NMR conformation assemblies or computationally modeled structures are available.     

A functional feature analysis on diverse protein–protein interactions: application for the prediction of binding affinity

Protein–protein interactions (PPIs) play crucial roles in diverse cellular processes. There are different types of PPIs based on the composition, affinity and whether the association is permanent or transient. Analyzing the diversity of PPIs at the atomic level is crucial for uncovering the key features governing the interactions involved in PPI. A systematic physico-chemical and conformational studies were implemented on interfaces involved in different PPIs, including crystal packing, weak transient heterodimers, weak transient homodimers, strong transient heterodimers and homodimers. The comparative analysis shows that the interfaces tend to be larger, less planar, and more tightly packed with the increase of the interaction strength. Meanwhile the strong interactions undergo greater conformational changes than the weak ones involving main chains as well as side chains. Finally, using 18 features derived from our analysis, we developed a support vector regression model to predict the binding affinity with a promising result, which further demonstrate the reliability of our studies. We believe this study will provide great help in more thorough understanding the mechanism of diverse PPIs.     

Probing the protein–nanoparticle interface: the role of aromatic substitution pattern on affinity

A new class of cationic gold nanoparticles (NPs) has been synthesised bearing benzyl moieties featuring –NO₂ and –OMe groups to investigate the regioisomeric control of aromatic NP–protein recognition. In general, NPs bearing electron-withdrawing groups demonstrated higher binding affinities towards green fluorescent protein (GFP) than NPs bearing electron-donating groups. Significantly, a ～7.5- and ～4.3-fold increase in binding with GFP was observed for –NO₂ groups in meta-position and para-position, respectively, while ortho-substitution showed binding similar to the unsubstituted ring. These findings demonstrated that the NP–protein interaction can be controlled by tuning the spatial orientation and the relative electronic properties of the aromatic substituents. This improved biomolecular recognition provides opportunities for enhanced biosensing and functional protein delivery to the cells.     

A promising in silico protocol to develop novel PPARγ antagonists as potential anticancer agents: Design,synthesis and experimental validation via PPARγ protein activity and competitive binding assay

Peroxisome proliferator-activated receptor gamma (PPARγ), a member of the nuclear receptor superfamily is an excellent example of targets that orchestrates cancer, inflammation, lipid and glucose metabolism. We report a protocol for the development of novel PPARγ antagonists by employing 3D QSAR based virtual screening for the identification of ligands with anticancer properties. The models are generated based on a large and diverse set of PPARγ antagonist ligands by the HYPOGEN algorithm using Discovery Studio 2019 drug design software. Among the 10 hypotheses generated, Hypotheses 2 showed the highest correlation coefficient values of 0.95 with less RMS deviation of 1.193. Validation of the developed pharmacophore model was performed by Fischer’s randomization and screening against test and decoy set. The GH score or goodness score was found to be 0.81 indicating moderate to a good model. The selected pharmacophore model Hypo 2 was used as a query model for further screening of 11,145 compounds from the PubChem, sc-PDB structure database, and designed novel ligands. Based on fit values and ADMET filter, the final 10 compounds with the predicated activity of ≤ 3 nM were subjected for docking analysis. Docking analysis revealed the unique binding mode with hydrophobic amino acid that can cause destabilization of the H12 which is an important molecular mechanism to prove its antagonist action. Based on high CDocker scores, Cpd31 was synthesized, purified, analyzed and screened for PPARγ competitive binding by TR-FRET assay. The biochemical protein binding results matched the predicted results. Further, Cpd31 was screened against cancer cells and validated the results.     

Prediction of protein–ligand binding affinity by free energy simulations: assumptions,pitfalls and expectations

Many limitations of current computer-aided drug design arise from the difficulty of reliably predicting the binding affinity of a small molecule to a biological target. There is thus a strong interest in novel computational methodologies that claim predictions of greater accuracy than current scoring functions, and at a throughput compatible with the rapid pace of drug discovery in the pharmaceutical industry. Notably, computational methodologies firmly rooted in statistical thermodynamics have received particular attention in recent years. Yet free energy calculations can be daunting to learn for a novice user because of numerous technical issues and various approaches advocated by experts in the field. The purpose of this article is to provide an overview of the current capabilities of free energy calculations and to discuss the applicability of this technology to drug discovery.     

Temperature effects in carbon monoxide and methanol electrooxidation on platinum–ruthenium: influence of grain boundaries

The temperature dependence of methanol and CO monolayer oxidation is studied on carbon-supported PtRu (1:1 atomic ratio) electrodes with different metal percentages (5, 30, and 60 wt.%) in an aqueous H₂SO₄ electrolyte. High-resolution transmission microscopy confirms that at high (30 or 60 wt.%) metal percentage PtRu nanostructures with a high concentration of intercrystalline boundaries are formed. These nanostructures comprise multiple-twinned particles, particles with intersecting randomly oriented intergrain boundaries, or particles with parallel intergrain boundaries. Formation of such nanostructures leads to a decrease of the apparent activation energy of the methanol and CO monolayer oxidation, while the Tafel slope and the reaction order in methanol show minor dependence on the type of nanostructure. Materials with a high concentration of grain boundary regions may be of interest for practical applications in direct methanol or proton exchange fuel cells fed with reformate.     

Iron porphyrin-modified electrodes: influence of the method of modification on the stability and electroactivity in oxidation of sulfite or hydrogensulfite in ethanol–water solutions

The aim of this work is to study four types of modification of a glassy carbon electrode by Fe(III)-tetrakis(p-tetraaminophenyl)porphyrin and determine the influence of the method of immobilization of the complex on glassy carbon in electrocatalytic properties for the sulfite and hydrogensulfite oxidation in ethanol–water. The first modification was deposition of a drop of solution containing the porphyrin on a glassy carbon electrode and evaporation of the solvent (dry-drop method). The second method was immersion of the electrode at 54°C in a solution of dimethylformamide containing the porphyrin for 2 h. The third method consisted of the same heating treatment but after formation of a chemical bond of 4-aminopyridine on the glassy carbon surface, which acts as an axial ligand for the first layer of porphyrin. The fourth method involves electropolymerization of the porphyrin on the electrode surface. Important differences in stability, the potential where the oxidation wave begins and selectivity of the electrode to sulfite or hydrogensulfite were observed. The behavior of the polymer-modified electrode is different in water compared to ethanol–water.     

Junction properties of In2O3:Al2O3 composite on p-type silicon by sol–gel method

Schottky barrier diode based on composite of In₂O₃ and Al₂O₃ was fabricated using sol–gel spin coating method. The electrical properties of the diode were studied using current–voltage, capacitance–voltage and resistance–voltage characteristics. The non-linear I–V characteristics suggest the formation of Schottky barrier diode. The I–V characteristics of the diode were analyzed using the thermionic emission model. The electrical properties of the diode were investigated in the temperature range of 303–243 K. It was observed that the barrier height of the diode increases with increase in temperature. The capacitance of the diode was measured at various frequencies and temperatures. It was seen that the capacitance of the diode is decreased with increase in frequency. On the other hand, the capacitance was observed to increase with increasing temperature.     

In situ DRIFTS investigation on CeO2/TiO2–ZrO2–SO42− catalyst for NH3–SCR: the influence of surface acidity and reducibility

Research on Chemical Intermediates - A series of CeO2-modified TiO2–ZrO2–SO42? catalysts were employed to the selective catalytic reduction (SCR) of NOx by NH3. The obtained...     

Substituted salen–Ru(II) complexes as catalysts in the asymmetric cyclopropanation of styrene by ethyl diazoacetate: the influence of substituents and achiral additives on activity and enantioselectivity

A series of alkyl-, halogen- and nitro-substituted salen ligands, 1, have been employed in the asymmetric cyclopropanation of styrene with ethyl diazoacetate by its ruthenium(II) complex with [RuCl₂(p-cymene)]₂ or RuCl₂(PPh₃)₃ as precursors. The introduction of appropriate electron withdrawing groups in the salen ligands benefited the enantioselectivity of the reaction. Some additives, including O-donor, N-donor and P-donor ligands, were added to the reaction to improve the enantioselectivity and activity, and e.e.s of up to 80% were achieved. In the salen/[RuCl₂(p-cymene)]₂ system, the (1R,2S)-isomer was obtained in 80.2% e.e. by using the salen ligand 1f derived from 3,5-dibrominated salicylaldehyde with Et₃N as additive. E.e.s of up to 81.3% for (1S,2R)-isomers were achieved by using the complex 2 synthesized from the nitro-substituted ligand 1m and RuCl₂(PPh₃)₃. A possible mechanism was also discussed.     

Preparation of calibration materials for microanalysis of Ti minerals by direct fusion of synthetic and natural materials: Experience with LA–ICP–MS analysis of some important minor and trace elements in ilmenite and rutile

Calibration materials for microanalysis of Ti minerals have been prepared by direct fusion of synthetic and natural materials by resistance heating in high-purity graphite electrodes. Synthetic materials were FeTiO₃ and TiO₂ reagents doped with minor and trace elements; CRMs for ilmenite, rutile, and a Ti-rich magnetite were used as natural materials. Problems occurred during fusion of Fe₂O₃-rich materials, because at atmospheric pressure Fe₂O₃ decomposes into Fe₃O₄ and O₂ at 1462?°C. An alternative fusion technique under pressure was tested, but the resulting materials were characterized by extensive segregation and development of separate phases. Fe₂O₃-rich materials were therefore fused below this temperature, resulting in a form of sintering, without conversion of the materials into amorphous glasses. The fused materials were studied by optical microscopy and EPMA, and tested as calibration materials by inductively coupled plasma mass spectrometry, equipped with laser ablation for sample introduction (LA–ICP–MS). It was demonstrated that calibration curves based on materials of rutile composition, within normal analytical uncertainty, generally coincide with calibration curves based on materials of ilmenite composition. It is, therefore, concluded that LA–ICP–MS analysis of Ti minerals can with advantage be based exclusively on calibration materials prepared for rutile, thereby avoiding the special fusion problems related to oxide mixtures of ilmenite composition. It is documented that sintered materials were in good overall agreement with homogeneous glass materials, an observation that indicates that in other situations also sintered mineral concentrates might be a useful alternative for instrument calibration, e.g. as alternative to pressed powders.     

Electrochemical detection of cystatin C by oriented antibody immobilization on streptococcal protein G–modified ZIF-8-Cu1−xNix(OH)2@Cu core-shell nanostructured electrode

Herein, we prepared a novel nanostructure involving Cu shell on Zeolitic imidazolate frameworks (ZIF-8) and Cu_1?xNi_x(OH)₂ composite (ZIF-8-Cu_1?xNi_x(OH)₂@Cu) combining sol-gel and co-precipitation method. The morphology, stoichiometry, and structure of the nanocomposite were elucidated by various physicochemical analyses. A poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) coated indium tin oxide (ITO) was modified with the synthesized ZIF-8-Cu_1?xNi_x(OH)₂@Cu nanoparticles (NPs) to obtain an efficient electrode for further antibody immobilization. The ZIF-8-Cu_1?xNi_x(OH)₂@Cu/PEDOT:PSS/ITO was applied for the detection of cystatin C, a promising biomarker of chronic kidney disease (CKD). The electrode was functionalized by streptococcal protein G (SPG) to bind the Fc region of anti-cystatin C in an oriented manner. The synergistic catalytic activities, high surface coverage, enhanced electroactive sites, and excellent redox properties of the proposed electrode lead to excellent electrochemical sensing. The proposed sensor obtained a much lower detection limit (33 pg/mL) for a linear range of 0.1 ng/mL to 1,000 ng/mL with high selectivity, stability, and reproducibility compared with bare ZIF-8/PEDOT:PSS/ITO-based immunosensor. The clinical feasibility of the sensor was confirmed by measuring the human serum in the presence of different concentrations of cystatin C. This work demonstrates a new and facile approach to fabricating a metal-organic framework (MOF) –based nanoimmunosensor for cystatin C, which has significant importance in diagnosing the renal failure.     

TiO<Subscript>2</Subscript> thin films on soda-lime and borosilicate glass prepared by sol–gel processing: influence of the substrates

TiO₂ films were deposited on soda-lime and borosilicate glass substrates, their optical and microstructural properties were investigated. X-ray diffraction showed significant differences between the sample series. Films deposited on the upper surface of soda-lime glass substrates showed higher indices of refraction than those prepared on the lower surface that had been in contact with the tin bath during float glass production. Results indicate that these differences not only result from different optical properties of the TiO₂ backbone material due to alkali contamination but that also different film porosities can measured by ellipsometric porosimetry.     

Supported organometallic complexes: Part XXX. Hydroformylation of 1-hexene in interphases — the influence of different kinds of inorganic–organic hybrid co-condensation agents on the catalytic activity

A novel mono-T-silyl functionalized triphenylphosphine ligand was prepared by a simple coupling reaction of (p-aminophenyl)diphenylphosphine and 3-triethoxysilylpropylisocyanate. The corresponding carbonylchlorobisphosphinerhodium(I) complex ClRh(CO)[PPh₂C₆H₄NHCONH(CH₂)₃Si(OEt)₃]₂ was synthesized in order to be sol–gel processed with various amounts of different D- and T-silyl bifunctionalized co-condensation agents. The polysiloxane matrices and the active rhodium centers were investigated by means of multinuclear solid state NMR (¹³C, ²⁹Si, ³¹P) and dynamic NMR measurements. The rhodium containing xerogels were applied in the hydroformylation of 1-hexene. These stationary phases show remarkable catalytic activities independent on the solvent. An enhancement of the activities is achieved when T-silyl bifunctionalized co-condensation agents are used to build up the carrier matrix.