Chemistry, Volume 4, Issue 3 (September 2022) – 29 articles

The paper presents results of studies on the possibility of using the ultrafiltration method supported by sorption on low-cost, easily accessible aluminosilicates to purify water contaminated with radionuclides. An aqueous solution contaminated with radionuclides in the form of cations at different oxidation states—Cs(I)-137, Co(II)-60 and Am(III)-241—as well as pertechnetate anions—TcO₄⁻-99m—was treated by the proposed hybrid method. In the presented work, the influence of the important process parameters (i.e., pH, sorbent dosage, temperature and feed flow rate) on the removal efficiency of radionuclides was studied. The obtained results showed that hazardous impurities, both in the form of cations and anions, may be effectively removed from water by the application of sorption-assisted UF (SAUF) using the clay-salt slimes as a sorbent. As a final stage of the work, we treated the simulated liquid radioactive waste using the SAUF method, also showing satisfactory results in its purification efficiency. Full article

Ni(CO)₄, Cr(CO)₆, Co(CO)₃NO are some of the most common precursors used for focused electron beam induced deposition. Some of the compounds, even though extensively used have high requirements when it comes to handling being, explosives, highly flammable and with high toxicity levels, as is the case of Ni(CO)₄. We are employing simulations to determine values hard to determine experimentally, and compare them with DFT calculations and experimental data where available. The use of Quantemol-N cross section simulations for dissociative electron attachment (DEA) at low electron energy in the range of 0–20 eV, gives valuable information on the fragmentation of the molecules, based on their bond dissociation energies, electron affinities and incident electron energies. The values obtained for the cross sections are 0.12 × 10⁻¹⁸ cm² for Ni(CO)₄, 4.5 × 10⁻¹⁶ cm² for Co(CO)₃NO DEA cross-sections and 4.3 × 10⁻¹⁵ cm² for Cr(CO)₆. Full article

In this study, we used the FP-LAPW technique based on density functional theory applied in WIEN2k code to examine the structural, electronic, elastic, and thermoelectric properties of cubic double perovskite Rb₂InBiX₆ (X = Cl, Br) compounds. The structural stability was confirmed from the tolerance factor, formation energy, and phonon dispersion. The exchange-correlation potentials LDA, GGA, mBJ, and HSE were used to estimate the electronic properties. According to the band structure computed band gap using mBJ, the HSE are 1.61 eV, 1.81 eV for Rb₂InBiCl₆ and 1.22 eV, 1.32 eV for Rb₂InBiBr₆ compounds, respectively. The mechanical stability of the materials under examination were reflected by the calculated elastic constants. The estimated bulk modulus-to-shear modulus ratios for Rb₂InBiX₆ (X = Cl, Br) are 2.13 and 3.65, respectively. This indicates that the examined compounds were ductile in nature. The optical properties in terms of real and imaginary dielectric functions, refractive index, and absorption coefficient were computed, indicating that they might be employed in optoelectronic and photovoltaic applications. In the temperature range 200–800 K, the electrical conductivity, Seebeck coefficient, thermal conductivity, and power factor (PF) were analysed. Relatively high PFs of about 2.7 × 10¹⁰ W/K² ms and 3.1 × 10¹⁰ W/K² ms were obtained for Rb₂InBiX₆ (X = Cl, Br) suggesting that these compounds are viable for usage in thermoelectric devices. Both the compounds showed strong absorption patterns and excellent PF signifying that these are suitable materials for photovoltaic and thermoelectric applications. Full article

In consideration of the issues of drug delivery systems, the artificial vesicle structures composed of block copolymers called polymersomes recently gained considerable attention. The possibility of tuning the mechanical parameter and increasing the scale-up production of polymersomes led to its wide application in healthcare. Bearing in mind the disease condition, the structure and properties of the polymersomes could be tuned to serve the purpose. Furthermore, specific ligands can be incorporated on the vesicular surface to induce smart polymersomes, thus improving targeted delivery. The synthesis method and surface functionalization are the two key aspects that determine the versatility of biological applications as they account for stability, specific targeting, degradability, biocompatibility, and bioavailability. A perfectly aligned polymer vesicle can mimic the cells/organelles and function by avoiding cytotoxicity. This supramolecular structure can carry and deliver payloads of a wide range, including drugs, proteins, and genes, contributing to the construction of next-generation therapeutics. These aspects promote the potential use of such components as a framework to approach damaged tissue while maintaining healthy environments during circulation. Herein, this article concentrates specifically on the drug delivery applications of polymersomes. Full article

The photodynamic therapy (PDT) represents a non-invasive method with good results in the treatment of superficial tumors. PDT is based on a combination of two factors, namely, a non-toxic photosensitizing molecule and a light source; the photosensitizer absorbs a photon of radiation, leading to a series of reactions that cause irreversible damage to the affected tissue. The present paper investigates the photosensitization properties of nine substituted metal-phthalocyanines (the central metals being iron, nickel, and zinc). In addition, the interactions between the aforementioned compounds and four fullerenes are investigated by means of molecular docking studies in order to verify their potential as delivery systems for phthalocyanines. Our results outline that the properties of metal-phthalocyanines are mainly influenced by the type of substituent and to a lesser extent by the nature of the metal. The binding energies of the metal-phthalocyanines towards the fullerenes suggest a slight increased affinity for the fullerene C₅₂ as compared to the three nitrogen- and phosphorus-doped C₄₆N₃P₃ fullerenes. Full article

The human myeloid leukemia cell differentiation protein (hMcl-1) is an anti-apoptotic multi-partner protein, belonging to the B-cell lymphoma-2 (Bcl-2) family of proteins. Studies have linked hMcl-1 alleviated expression with resistance to hemopoietic chemotherapeutics, which makes it a key drug target in blood cancers. However, most of the developed small- to medium-sized hMcl-1 inhibitors have typical off-target activity towards other members of the Bcl-2 family. To improve the hMcl-1 inhibitor design, especially exploring a suitable scaffold with pharmacophoric features, we focused on natural hMcl-1 inhibitors. To date, seven classes of natural compounds have been isolated, which display a low micromolar affinity for hMcl-1 and have limited biophysical studies. We screened hMcl-1 co-crystal structures, and identified nine co-crystal structures of hMcl-1 protein, which were later evaluated by multiple receptor conformations (which indicates that the differences between hMcl-1 in crystal structures are low (RMSD values between 0.52 and 1.13 Å, average RMSD of 0.638–0.888 Å, with a standard deviation of 0.102–0.185Å)), and multiple ligand conformations (which led to the selection of the PDB structure, 3WIX (RMSD value = 0.879 Å, standard deviation 0.116 Å), to accommodate various Mcl-1 ligands from a range of co-crystal PDB files) methods. Later, the three adopted docking methods were assessed for their ability to reproduce the conformation bound to the crystal as well as predict trends in Ki values based on calculated RMSD and docking energies. Iterative docking and clustering of the docked pose within ≤1.0 Å was used to evaluate the reproducibility of the adopted docking methods and compared with their experimentally determined hMcl-1 affinity data. Full article

Quinazolinone and isoxazoline systems have attracted much attention due to their interesting pharmacological properties. The association of these two pharmacophores in a single hybrid structure can boost the biological activity or bring a new one. Inspired by this new paradigm, in the present work we report the synthesis and spectroscopic characterization of new quinazolinone–isoxazoline hybrids. The target compounds were obtained via 1,3-dipolar cycloaddition reactions of arylnitriloxides and N-allylquinazolinone. The synthesized compounds were characterized using spectroscopic techniques such as IR, 1D NMR (1H and 13C), 2D NMR (COSY and HSQC), and high-resolution mass spectrometry (HRMS). The spectral data show that this reaction leads only to the 3,5-disubstituted isoxazoline regioisomer, and that the observed regiochemistry is not affected by the nature of the substituents in the phenyl ring of the dipole. In addition, a theoretical study was performed using density functional theory (DFT) to support the experimental results in regard to the regiochemistry of the studied reactions. The computational mechanistic study was in good agreement with the experimental data. Full article

Pyrazole-containing compounds represent one of the most influential families of N-heterocycles due to their proven applicability and versatility as synthetic intermediates in preparing relevant chemicals in biological, physical-chemical, material science, and industrial fields. Therefore, synthesizing structurally diverse pyrazole derivatives is highly desirable, and various researchers continue to focus on preparing this functional scaffold and finding new and improved applications; this review highlights some of the most recent and strategic examples regarding the synthesis and properties of different pyrazole derivatives, mainly reported from 2017–present. The discussion involves strategically functionalized rings (i.e., amines, carbaldehydes, halides, etc.) and their use in forming various fused systems, predominantly bicyclic cores with 5:6 fusion taking advantage of our experience in this field and the more recent investigations of our research group. Full article

Antimicrobial properties of silver have been known for a long time, but there is also cytotoxicity of high concentrations of silver. Therefore, it is important to select the concentration and shape of silver depending on the goals. The ideal wound dressing should ensure that the wound remains optimally moist, protected from infections, has no toxic compounds, and stimulates regeneration. In the present work, we obtained a series of polycaprolactone-based nanomaterials fabricated by electrospinning and incorporated with silver ions (up to 0.6 at.%). By adjusting the magnetron current (0.3 A) and implanter voltage (5 kV), the deposition of TiO₂ and Ag⁺ implantation into PCL/PEO nanofibers was optimized to achieve implantation of Ag⁺ without damaging the nanofibrous structure of the biodegradable nanofibers. The obtained results allow us to predict significant protection properties of the developed material not only from mechanical influence but also thanks to the antimicrobial effect due to silver ions, which is important for chronic wounds and injuries with a large area of damage and can activate host cells proliferation. Full article

Magnetic nanoparticles (MNPs) have evolved tremendously during recent years, in part due to the rapid expansion of nanotechnology and to their active magnetic core with a high surface-to-volume ratio, while their surface functionalization opened the door to a plethora of drug, gene and bioactive molecule immobilization. Taming the high reactivity of the magnetic core was achieved by various functionalization techniques, producing MNPs tailored for the diagnosis and treatment of cardiovascular or neurological disease, tumors and cancer. Superparamagnetic iron oxide nanoparticles (SPIONs) are established at the core of drug-delivery systems and could act as efficient agents for MFH (magnetic fluid hyperthermia). Depending on the functionalization molecule and intrinsic morphological features, MNPs now cover a broad scope which the current review aims to overview. Considering the exponential expansion of the field, the current review will be limited to roughly the past three years. Full article

A well-defined virus-like cage hybrid (VCH) with 24 covalent organic cages (COCs) attached to one metal organic cage (MOC) is presented here. The quantitative assembly of VCH was completed through coordination between soluble anisotropic COC bearing one bipyridine moiety and Pd(II) ions. The obtained VCH exhibited discrete, uniform and stable structures with good solubility and was well characterized by NMR, FT-IR, TEM, AFM, DLS, TGA, and so on. This designable cage hybrid promotes a new strategy to expand the structural and functional complexities of porous molecular cages. Full article

Considering the wide interest in (benz)imidazolium-based drugs, we here report our study on a benzimidazolium-based organic cage as potential antimicrobial and antifungal agent. Cytotoxicity studies on a human derived cell line, SH-SY5Y, showed that the cage is not cytotoxic at all at the investigated concentrations. Anion binding studies demonstrated that the cage can bind anions (chloride and nitrate, in particular) both in organic solvent and 20%v D₂O/CD₃CN mixture. The cage was also tested as anionophore, showing a weak but measurable transport of chloride and nitrate across LUVs vesicles. Nonetheless, the compounds have antimicrobial activity towards Staphylococcus aureus (Gram-positive bacteria). This is probably the first organic cage studied as anionophore and antimicrobial agent. Full article

Infrared spectroscopy is a widely used method of analysis to monitor various characteristics in the honey products analysis, to highlight these changes and to detect fraudulent modifications. In this way honey products could not be avoided. This article reviews some of the most important applications of these spectroscopic procedures in order to discriminate different types of honey and other products published between 2015–2022. Full article

Biominerals are extraordinary materials that provide organisms with a variety of functions to support life. The synthesis of biominerals and organization at the macroscopic level is a consequence of the interactions of these materials with proteins. The association of biominerals and proteins is very ancient and has sparked a wealth of research across biological, medical and material sciences. Calcium carbonate, hydroxyapatite, and silica represent widespread natural biominerals. The atomic details of the interface between macromolecules and these biominerals is very intriguing from a chemical perspective, considering the association of chemical entities that are structurally different. With this review I provide an overview of the available structural studies of biomineralization proteins, explored from the Protein Data Bank (wwPDB) archive and scientific literature, and of how these studies are inspiring the design and engineering of proteins able to synthesize novel biominerals. The progression of this review from classical template proteins to silica polymerization seeks to benefit researchers involved in various interdisciplinary aspects of a biomineralization project, who need background information and a quick update on advances in the field. Lessons learned from structural studies are exemplary and will guide new projects for the imaging of new hybrid biomineral/protein superstructures at the atomic level. Full article

In the present study, the conversion performance of hydrogen sulfide (H₂S) to elemental sulfur in ionic-liquid-incorporated transition metals (ILTMs) is predicted using a conductor-like screening model for realistic solvents (COSMO-RS). The predictions were made via the establishment of a correlation between the conversion performance and solubility of H₂S in ionic liquids (ILs). All molecules involved were optimized at the DFT/TZVP/M06 computational level and imported on the COSMOtherm program at equimolar conditions. For validation purposes, the solubility of ILs was predicted at 1 bar pressure. Simple regression analysis was used to establish a relationship between the solubility and conversion performance of H₂S. The results indicate that the solubility prediction of ILs is accurate (R² = 93.40%) with a p-value of 0.0000000777. Additionally, the conversion performance is generally found to be dependent on the solubility value. Furthermore, 1-butyl-3-methylimidazolium chloride [bmim][Cl] was chosen as the base IL for incorporating the transition metal, owing to its solubility and selectivity to H₂S. The solubility trend of ILTMs is found to follow the following order: [bmim][NiCl₃] > [bmim][FeCl₄] > [bmim][CoCl₃] > [bmim][CuCl₃]. According to the viscosity measurements of ILTMs, [bmim][NiCl3] and [bmim][FeCl4] exhibited the highest and lowest viscosity values, respectively. Therefore, [bmim][FeCl₄] is a promising ILTM owing to its higher solubility and low viscosity for the application studied. Full article

Zero-dimensional (0D), mono-dimensional (1D), or two-dimensional (2D) nanostructures with well-defined properties fabricated directly on surfaces are of growing interest. The fabrication of covalently bound nanostructures on non-metallic surfaces is very promising in terms of applications, but the lack of surface assistance during their synthesis is still a challenge to achieving the fabrication of large-scale and defect-free nanostructures. We discuss the state-of-the-art approaches recently developed in order to provide covalently bounded nanoarchitectures on passivated metallic surfaces, semiconductors, and insulators. Full article

Two new ruthenium complexes with chelating-ether benzylidene ligands bearing a furan moiety were synthesized and characterized, including X-ray crystallography. They initiated fast, also at 0 °C, and were found to be highly active in a variety of ring-closing, ene-yne, and cross-metathesis reactions, including an active pharmaceutical ingredient (API) model, which makes them good candidates for the transformation of complex polyfunctional compounds that require mild reaction conditions. Full article

Highly reactive decomposition products of deuterated chloroform can deteriorate samples dissolved in this commonly used solvent for nuclear magnetic resonance (NMR) spectroscopy. Samples for metabolomics studies often contain a complex mixture of sensitive substances such as phospholipids, peptides, unsaturated fatty acids or vitamins. If these react with decomposition products (of chloroform), abnormal NMR spectra could result, e.g., signal shifts depending on pH, attenuation of signals over time due to chemical changes of analytes or new signals from reaction products. Such irreproducibly influenced spectra are especially problematic for non-targeted analysis methods using automated chemometrical data evaluation. To prevent these artefacts, chlorine, phosgene and hydrochloric acid need to be eliminated from deuterated chloroform before its use. Since the common stabilisation methods have proven to be insufficient for sensitive NMR samples, another purging method has been tested: Mitigation is easily and reliably achieved by washing the deuterated chloroform with concentrated disodium carbonate solution and subsequent desiccation with oven-dried disodium carbonate. Full article

Enhancing photocarrier separation is a key step of photocatalysis, and in situ constructed composition interface is an advanced method to achieve this aim. Therefore, we report a face-to-face Bi₂WO₆/BiOCl (BWOC) which was synthesized via the continuous in situ ion-exchange method. As UV light is harmful to the human body, BWOC exhibits excellent photocatalytic activity only in visible light, and this is an important feature because visible light is a human-friendly operating condition. Under 50 W visible LED lamp illumination, unexcited BiOCl (BOC) only extracts electrons of excited Bi₂WO₆ (BWO), and holes remain on BWO, resulting in excellent photocarrier spatial separation efficiency through the face-to-face interface. This is why BWOC can be safe to use for the removal of hazardous substances. Compared with BWO and BOC, BWOC possesses 2.6 and 5.6 times higher photodegradation activity than RhB. This work provides a novel insight of efficient visible light photocatalytic system for environmental remediation. Full article

Supramolecular self-assembly in water resulting in polymeric structures is emerging because of its potential in the preparation of adaptive materials with applications in biology and medicine. Here, we report the first example of host molecules based on glycoluril dimers, which self-associate into linear oligomers in water. The degree of polymerization for the resulting supramolecular aggregates was calculated using the isodesmic model and the Carothers equation. The model compound was prepared to enable a deeper understanding of the forces responsible for the self-association of the glycoluril dimer-based monomers in water. Full article

The higher-order cycloaddition (HOCA) reaction of tropone with cyclopentadiene (Cp) has been studied within the Molecular Electron Density Theory. The Electron Localization Function (ELF) analysis of the electronic structure of tropone and Cp characterizes the structural behaviors of the two conjugated unsaturated systems, while the conceptual DFT reactivity indices classify tropone as a strong electrophile and Cp as a strong nucleophile participating in polar cycloaddition reactions of reverse electron density flux. Eight competitive reaction paths have been characterized for this cycloaddition reaction. The most favorable one allowing the formation of the formal out [6 + 4] cycloadduct has an activation enthalpy of 16.2 kcal·mol⁻¹, and the reaction is exothermic by −21.4 kcal·mol⁻¹. This HOCA reaction, which takes place through a non-concerted two-stage one-step mechanism, presents high stereo-, pseudocyclic- and regioselectivities, explaining the exclusive formation of the experimental [6 + 4] cycloadduct. While the most favorable nucleophilic attack of Cp on most electrophilic C2 positions of tropone accounts for regioselectivities, the favorable electrostatic interactions present between the Cp framework and the negatively charged O8 oxygen of tropone account for the stereo- and pseudocyclic selectivities. Despite the symmetry of the two reagents, this HOCA reaction takes place via a highly asynchronous transition state structure as a consequence of the most favorable two-center interactions taking place between the electrophilic C2 center of tropone and the nucleophilic C9 center of Cp. Full article

Electron donor–acceptor (EDA) complexes are characterized by charge-transfer (CT) processes between electron-rich and electron-poor counterparts, typically resulting in a new absorption band at a higher wavelength. In this paper, we report a series of novel 2,6-di(imino)pyridine ligands with different electron-rich aromatic substituents and their 1:2 (metal/ligand) complexes with zinc(II) in which the formation of a CT species is promoted by the metal ion coordination. The absorption properties of these complexes were studied, showing the presence of a CT absorption band only in the case of aromatic substituents with donor groups. The nature of EDA interaction was confirmed by crystallographic studies, which disclose the electron-poor and electron-rich moieties involved in the CT process. These moieties mutually belong to both the ligands and are forced into a favorable spatial arrangement by the coordinative preferences of the metal ion. Full article

Dye-sensitized solar cells transform solar light into electricity. One commonly used dye is a ruthenium complex. However, the use of ruthenium has been shown to have several disadvantages. In this study, via singular spectrum analysis using HypSpec software, we determined the formation constants and calculated individual electronic spectra of species of iron(III) with several ligands (1,2-diaminoethane, 1,3-diaminopropane, 1,4-diaminobutane, 2,2′-bipyridyl, 5,5-dimethyl-2,2′-bipyridyl, 4,4′-di-tert-butyl-2,2′-bipyridyl, 1,10-phenanthroline, and 3,4,7,8-tetramethyl-1,10-phenanthroline) in methanol solution. We present a spectral comparison of the complexes reported here to the ruthenium complex: tris-(2,2′-bipyridyl)ruthenium(II). Full article

Thermo-responsive (TR) gels of the LCST (lower critical solution temperature) type swell in water at temperatures below their volume phase transition temperature $T_{\mathrm{c}}$ and collapse above the critical temperature. When water is partially replaced with an organic liquid, these materials demonstrate three different types of equilibrium solvent uptake diagrams at temperatures below, above, in the close vicinity of $T_{\mathrm{c}}$. A model is developed for equilibrium swelling of TR gels in binary mixtures of solvents. It takes into account three types of phase transitions in TR gels driven by (i) aggregation of hydrophobic side groups into clusters from which solvent molecules are expelled, (ii) replacement of water with cosolvent molecules in cage-like structures surrounding these groups, and (iii) replacement of water with cosolvent as the main element of hydration shells around backbone chains. The model involves a relatively small number of material constants that are found by matching observations on covalently cross-linked poly(N-isopropylacrylamide) macroscopic gels and microgels. Good agreement is demonstrated between the experimental data and results of numerical analysis. Classification is provided of the phase transition points on equilibrium swelling diagrams. Full article

The geological nature of the territory of the Republic of Cuba has favoured the formation of large and varied deposits of volcanic tuffs enriched by various species of zeolites. Today, new zeolite deposits continue to be discovered in the country. This work aims to present the results of a study carried out in an unexplored area that is located approximately 1.2 km east of the Loma Blanca deposit, outside the mining operation limits. To carry out this research and to establish a qualitative comparison between both sample populations, four samples were taken from the study area, and another four were taken from the Loma Blanca deposit. The characterisation of the samples was performed by XRD, SEM, and XRF. The pozzolan quality was determined by the pozzolanicity test (PT) and quality chemical analysis (QCA). Finally, a study of the mechanical strength (MST) was performed at 7, 28, and 90 days, using mortar specimens made with PC/ZT: 75–25% and PC/ZT: 70–30%, respectively. The results of the studies using XRD, SEM, and XRF indicated that both groups of samples had a similar complex mineralogical composition, consisting mainly of mordenite and clinoptilolite accompanied by secondary phases such as quartz and amorphous materials in the form of altered glass. The pozzolanicity test showed that both the samples from the study area and those from the Loma Blanca deposit behaved like typical pozzolans, which is a trend that can be seen in the high values of mechanical strength to compression up to 72 MPa for the PC/ZT: 75–25% formulation and 66 MPa for the PC/ZT: 70–30%. The results obtained establish that the zeolite varieties detected in the study area are similar to those of the Loma Blanca deposit, which could have a positive impact on the increase in current reserves, especially for manufacturing pozzolanic cements with properties that contribute to the preservation of the environment. Full article

Piperine (1-piperoylpiperidine) is the major pungent component of black pepper (Piper nigrum) and exhibits a spectrum of pharmacological activities. The molecular bases for many of piperine’s biological effects are incompletely defined. We noted that the chemical structure of piperine generally conforms to a pharmacophore model for small bioactive molecules that activate mitofusin (MFN)-mediated mitochondrial fusion. Piperine, but not its isomer chavicine, stimulated mitochondrial fusion in MFN-deficient cells with EC₅₀ of ~8 nM. We synthesized piperine analogs having structural features predicted to optimize mitofusin activation and defined structure-activity relationships (SAR) in live-cell mitochondrial elongation assays. When optimal spacing was maintained between amide and aromatic groups the derivatives were potent mitofusin activators. Compared to the prototype phenylhexanamide mitofusin activator, 2, novel molecules containing the piperidine structure of piperine exhibited markedly enhanced passive membrane permeability with no loss of fusogenic potency. Lead compounds 5 and 8 enhanced mitochondrial motility in cultured murine Charcot-Marie-Tooth disease type 2A (CMT2A) neurons, but only 8 improved mitochondrial transport in sciatic nerve axons of CMT2A mice. Piperine analogs represent a new chemical class of mitofusin activators with potential pharmaceutical advantages. Full article

A new synthesis strategy towards gold-coated silica nanoparticles is presented. The method provides an efficient, reliable and facile-coating process of well-defined star-shaped shell structures, characterized by UV-Vis, TEM, PXRD, DLS and zeta-potential measurements. A marked red shift of the Au-based plasmonic band to the region of the first biological window is observed offering great potential for future research of biological applications. Full article

The human ether-a-go-go-related gene (hERG) potassium channel is a well-known contributor to drug-induced cardiotoxicity and therefore is an extremely important target when performing safety assessments of drug candidates. Ligand-based approaches in connection with quantitative structure active relationships (QSAR) analyses have been developed to predict hERG toxicity. The availability of the recent published cryogenic electron microscopy (cryo-EM) structure for the hERG channel opened the prospect of using structure-based simulation and docking approaches for hERG drug liability predictions. In recent times, the idea of combining structure- and ligand-based approaches for modeling hERG drug liability has gained momentum offering improvements in predictability when compared to ligand-based QSAR practices alone. The present article demonstrates uniting the structure-based SILCS (site-identification by ligand competitive saturation) approach in conjunction with physicochemical properties to develop predictive models for hERG blockade. This combination leads to improved model predictability based on Pearson’s R and percent correct (represents rank-ordering of ligands) metric for different validation sets of hERG blockers involving a diverse chemical scaffold and wide range of pIC50 values. The inclusion of the SILCS structure-based approach allows determination of the hERG region to which compounds bind and the contribution of different chemical moieties in the compounds to the blockade, thereby facilitating the rational ligand design to minimize hERG liability. Full article