Quantitative Molecular Analysis Research Articles

Per- and polyfluoroalkyl substances inhibit human and rat 17β-hydroxysteroid dehydrogenase 1: Quantitative structure-activity relationship and molecular docking analysis

Per- and polyfluoroalkyl (PFAS) substances are enduring industrial materials. 17β-Hydroxysteroid dehydrogenase isoform 1 (17β-HSD1) is an estrogen metabolizing enzyme, which transforms estrone into estradiol in human placenta and rat ovary. Whether PFAS inhibit 17β-HSD1 and what the structure-activity relationship (SAR) remains unexplored. We screened 18 PFAS for inhibiting human and rat 17β-HSD1 in microsomes and studied their SAR and mode of action(MOA). Of the 11 perfluorocarboxylic acids (PFCAs), C8-C14 PFCAs at a concentration of 100 μM substantially inhibited human 17β-HSD1, with order of C11 (half-maximal inhibition concentration, IC50, 8.94 μM) > C10 (10.52 μM) > C12 (14.90 μM) > C13 (30.97 μM) > C9 (43.20 μM) > C14 (44.83 μM) > C8 (73.38 μM) > others. Of the 7 per- and poly-fluorosulfonic acids (PFSAs), the potency was C8S (IC50, 14.93 μM) > C7S (80.70 μM) > C6S (177.80 μM) > others. Of the PFCAs, C8-C14 PFCAs at 100 μM markedly reduced rat 17β-HSD1 activity, with order of C11 (IC50, 9.11 μM) > C12 (14.30 μM) > C10 (18.24 μM) > C13 (25.61 μM) > C9 (67.96 μM) > C8 (204.39 μM) > others. Of the PFSAs, the potency was C8S (IC50, 37.19 μM) > C7S (49.38 μM) > others. In contrast to PFOS (C6S), the partially fluorinated compound 6:2 FTS with an equivalent number of carbon atoms demonstrated no inhibition of human and rat 17β-HSD1 activity at a concentration of 100 μM. The inhibition of human and rat enzymes by PFAS followed a V-shaped trend from C4 to C14, with a nadir at C11. Moreover, human 17β-HSD1 was more sensitive than rat enzyme. PFAS inhibited human and rat 17β-HSD1 in a mixed mode. Docking analysis revealed that they bind to the NADPH and steroid binding site of both 17β-HSD1 enzymes. The 3D quantitative SAR (3D-QSAR) showed that hydrophobic region, hydrogen bond acceptor and donor are key factors in binding to 17β-HSD1 active sites. In conclusion, PFAS exhibit inhibitory effects on human and rat 17β-HSD1 depending on factors such as carbon chain length, degree of fluorination, and the presence of carboxylic acid or sulfonic acid groups, with a notable V-shaped shift observed at C11.

Solvent-induced dual nucleophiles and the α-effect in the SN2 versus E2 competition.

We have quantum chemically investigated how microsolvation affects the various E2 and SN2 pathways, their mutual competition, and the α-effect of the model reaction system HOO-(H2O)n + CH3CH2Cl, at the CCSD(T) level. Interestingly, we identify the dual nature of the α-nucleophile HOO- which, upon solvation, is in equilibrium with HO-. This solvent-induced dual appearance gives rise to a rich network of competing reaction channels. Among both nucleophiles, SN2 is always favored over E2, and this preference increases upon increasing microsolvation. Furthermore, we found a pronounced α-effect, not only for SN2 substitution but also for E2 elimination, i.e., HOO- is more reactive than HO- in both cases. Our activation strain and quantitative molecular orbital analyses reveal the physical mechanisms behind the various computed trends. In particular, we demonstrate that two recently proposed criteria, required for solvent-free nucleophiles to display the α-effect, must also be satisfied by microsolvated HOO-(H2O)n nucleophiles.

Understanding the Retro‐Cope Elimination Reaction of Linear Alkynes

AbstractThe bioorthogonal retro‐Cope elimination reaction of linear alkynes R3C−C≡C−X (R3 = combinations of H, MeO, F; X = H, F, Cl, Br, I) with N,N‐dimethylhydroxylamine was quantum chemically investigated using relativistic density functional theory at ZORA‐BP86/TZ2P. This novel reaction can be tuned through judicious substitution of the alkyne at both the terminal and propargylic position to render second‐order kinetics that rival and out‐compete strain‐promoted variants. Activation strain and quantitative molecular orbital analyses reveal that, both upon terminal or propargylic substitution of propyne, the main effect of substituting H for X is a lowering of the propyne LUMO which stabilizes the HOMO–LUMO interactions and thus the transition state. In the case of terminal substitution with larger halogens (X = Cl, Br, I), a secondary effect interferes: steric repulsion with these larger halogens is absorbed into a longer forming C⋯N bond leading to a more asynchronous reaction accompanied by less (not more) steric Pauli repulsion.

Multidimensional quantitative phenotypic and molecular analysis reveals neomorphic behaviors of p53 missense mutants

Mutations in the TP53 tumor suppressor gene occur in >80% of the triple-negative or basal-like breast cancer. To test whether neomorphic functions of specific TP53 missense mutations contribute to phenotypic heterogeneity, we characterized phenotypes of non-transformed MCF10A-derived cell lines expressing the ten most common missense mutant p53 proteins and observed a wide spectrum of phenotypic changes in cell survival, resistance to apoptosis and anoikis, cell migration, invasion and 3D mammosphere architecture. The p53 mutants R248W, R273C, R248Q, and Y220C are the most aggressive while G245S and Y234C are the least, which correlates with survival rates of basal-like breast cancer patients. Interestingly, a crucial amino acid difference at one position—R273C vs. R273H—has drastic changes on cellular phenotype. RNA-Seq and ChIP-Seq analyses show distinct DNA binding properties of different p53 mutants, yielding heterogeneous transcriptomics profiles, and MD simulation provided structural basis of differential DNA binding of different p53 mutants. Integrative statistical and machine-learning-based pathway analysis on gene expression profiles with phenotype vectors across the mutant cell lines identifies quantitative association of multiple pathways including the Hippo/YAP/TAZ pathway with phenotypic aggressiveness. Further, comparative analyses of large transcriptomics datasets on breast cancer cell lines and tumors suggest that dysregulation of the Hippo/YAP/TAZ pathway plays a key role in driving the cellular phenotypes towards basal-like in the presence of more aggressive p53 mutants. Overall, our study describes distinct gain-of-function impacts on protein functions, transcriptional profiles, and cellular behaviors of different p53 missense mutants, which contribute to clinical phenotypic heterogeneity of triple-negative breast tumors.

Prediction of cosolvent effect on solvation free energies and analysis of intermolecular forces of tizanidine hydrochloride in ethyl acetate + methanol / ethanol mixtures

The solubility of small molecule drug in solvents can be dramatically affected by addition of a suitable cosolvent, which makes the screening of the best-suited cosolvent an important task for the purification and preparation. The present work aims to improve the fundamental understanding of tizanidine hydrochloride (TIZ HC) solvation by cosolvent. Solubility experimental data from TIZ HCl in mixtures of ethyl acetate + alcohols were obtained at different temperatures with the method of isothermal equilibrium. In the system of ethyl acetate + methanol, the solubility data increased firstly and then decreased with an increase in ethyl acetate content, however, the strictly monotonic decreasing of solubility in ethyl acetate + ethanol mixtures was observed. The solubility correlation fitting was performed with the Jouyban-Acree model and CNIBS/R-K model. The solvent effect analysis indicates that the hydrogen bond acidity, the polarity / polarizability and the cohesive forces of the solvent have a greater influence on the solubility, which was further validated by the local quantitative molecular surface analysis results of electrostatic potential (ESP). The dissolution process of TIZ HCl in systems with different solvent compositions was analyzed in the form of preferential solvation parameters, it was found that methanol is the preferred solvent in the solvation shell of TIZ HCl in methanol-rich and ethyl acetate-rich mixtures but the ethanol is preferred in intermediate compositions and ethyl acetate-rich mixtures. Moreover, the types of intermolecular solute–solvent interactions were discussed on the basis of the structural characteristics of TIZ HCl. The solvation free energy is a key parameter describing solvent effects, which is extremely important for understanding solution chemistry. For this part, with the aid of density functional theory (DFT) and molecular dynamics (MD) simulations, it was found that the cosolvent effect is consistent with the prediction trend of solvation free energy of TIZ HCl in each systems. The effect of the cavity formed by the solvent molecules and dipole moment of solute was calculated accordingly by the solvation model based on density (SMD) for explaining the former behavior.

Study on the microcosmic mechanism of inhibition of coal spontaneous combustion by antioxidant diphenylamine

Diphenylamine has been applied to suppress coal spontaneous combustion with good results, but its microscopic reaction mechanism is not clear. In this paper, the free radical reaction process of coal spontaneous combustion is calculated more systematically, and the quantum chemical method is applied to analyze in detail the process of diphenylamine depletion of reactive free radicals in coal from three perspectives: hydrogen atom transfer, direct radical capture, and regeneration cycle chain. By destroying the molecular structure of coal to generate free radicals as the initial condition of coal spontaneous combustion, the oxidation process of the free radical chain reaction was analyzed, the thermodynamic data of all reactions were calculated, the microscopic mechanism of free radical capture by diphenylamine was revealed, and the transition state structure model of the reaction process was given. The active sites of each reactant were determined by quantitative molecular surface analysis, the spontaneity of the reaction was measured by the free energy change, and the interaction relationship between different conformations was graphically represented by applying the IRI (interaction region indicator) method. The results show that most of the free radical reactions during the spontaneous combustion of coal are exothermic, and they provide heat for the spontaneous combustion of coal, which can react directly with oxygen when accumulated to a certain temperature. Diphenylamine can break the N-H bond, allowing hydroxyl radicals and carbon radicals to obtain hydrogen atoms to form stable compounds, and the generated diphenylamine radicals can reduce the content of free radicals in coal by direct capture. In addition, the process of diphenylamine inhibition of coal spontaneous combustion has a circular regeneration chain, which can indeed effectively reduce the content of reactive radicals and inhibit the spontaneous combustion of coal, which is reflected in the macroscopic level of reducing the generation of coal spontaneous combustion indicator gas, which is consistent with the experimental results.

Ajay Kumar Parida (1963-2022), an eminent plant biotechnologist with a passion for mangrove biology.

We remember Dr Ajay Parida, a leading plant biotechnologist, whose premature passing has deprived the Indian plant science community of a committed scientist and an able administrator. Born on 12 December 1963 in Bhagabanpur, Cuttack District (now Jajpur district), Odisha, he passed away in Guwahati on 19 July 2022. A collegial scientist, his down-to-earth and approachable nature, as well as his resourcefulness were instrumental in advancing the cause of Indian science and harnessing frontier biotechnological tools as vehicles of social consciousness. His expertise in quantitative DNA variation and molecular marker analysis, paved the way for subsequent research on mangrove molecular diversity at the M. S. Swaminathan Research Foundation (MSSRF), Chennai. His contributions to mangrove biology, genetics and genomics as well as extremophile plant species in the Indian context over two decades are a benchmark in his field. He also provided commendable leadership in his capacity as Director, Institute of Life Sciences (ILS), Bhubaneshwar during the COVID-19 pandemic.

Revealing a notable interaction in the binding of type II statins to HMG‐CoA reductase: Stacked cation–π interaction

AbstractThis study has centered on potentially important enzyme‐ligand interaction currently not incorporated: stacked cation–π interaction between the guanidinium group of arginine 590 residues in the HMG‐CoA reductase active site and the 4‐fluorophenyl group of type II statins. The geometry of interaction between these planar groups has been considered based on the X‐ray crystallographic structures already available in the protein data bank (PDB) archive. Electronic interaction energies between this residue and statins have been acquired by M06 and MP2 methods. In addition, stacking interaction and hydrogen bonding as two important investigated interactions are verified through prominent analyses: (1) quantum theory of atoms in molecules (QTAIM) analysis; (2) plotting and quantitative molecular surface analyses such as electrostatic potential (ESP) analysis, Hirshfeld surface (HS) and Becke surface (BS) analyses; (3) visual study methods such as noncovalent interaction (NCI), independent gradient model (IGM) analyses; and (4) localized orbital locator integrated pi over plane (LOLIPOP) index.The results indicate the absolute binding energy for type II statins is overall more than for type I statins.

Redescription and molecular characterization of Mothocya parvostis Bruce, 1986 (Crustacea: Isopoda: Cymothoidae) parasitic on Japanese halfbeak, Hyporhamphus sajori (Temminck & Schlegel, 1846) (Hemiramphidae) with Mothocya sajori Bruce, 1986 placed into synonymy.

Two species of Mothocya have previously been recorded from Hyporhamphus sajori: M. parvostis Bruce, 1986 and M. sajori Bruce, 1986. Mothocya parvostis is re-described based on the ovigerous female type and additional materials collected from the host from in and around the type locality. Morphological re-examination of fresh specimens and the type materials together with genetic data show that the M. sajori and M. parvostis are the same species, differing primarily in size, therefore we have placed Mothocya sajori Bruce, 1986 into a junior synonym of Mothocya parvostis Bruce, 1986. Mothocya parvostis is characterized by the following combinations of characters: 1) body slightly to moderately twisted to one side; 2) pereonite 7 posterior margin moderately to deeply recessed; 3) uropodal rami extending to pleotelson posterior margin; and 4) uropod rami bluntly rounded, exopod 1.5 times as long as peduncle. The differences of four morphological features for M. parvostis and M. sajori was quantified. Furthermore, a total of 635 isopods infesting H. sajori were collected from all over Japan to conduct quantitative morphological and molecular sequence analyses (mitochondrial cytochrome c oxidase subunit I and 16S rRNA). Although the four quantitative features did not overlap between the two species in type specimens, all quantitative morphological values of newly collected specimens in this study did not display a bimodal distribution. In addition, our molecular analyses found only a single clade for our newly collected specimens in neighbor-joining tree.

Interface engineering of LDH-based material as efficient anti-corrosive system via synergetic performance of host, interlayers, and morphological features of nature-mimic architectures

High-performance hybrid materials with special features are desired to meet the requirements of more complex cutting-edge applications. However, the self-assembly of layered double hydroxides (LDH) with organic frameworks is hampered by a lack of understanding of the formation mechanism and the effects of the self-assembled architecture on anticorrosion activity remain a major challenge. Herein, we put forward how the honeycomb-like network would architecturally upgraded on the pre-existing hierarchical floral structure with Trimesic acid (TMA) compound resulting in a promising layer-by-layer (LBL) material. This nature-inspired network is realized to offer an ideal approach not only endows with excellent properties but also exploits the power of layered coating materials as a bastion in the fields of nanotechnology, without limiting conditions, taking advantage of the synergy beneficial effects of the self-assembled honeycomb-like TMA and the anion-exchange ability of the layered coating material. In this work, a three-dimensional assembly with an architecture closely resembling interconnected micro-petals was successfully deposited on the defective surface obtained via plasma electrolytic oxidation (PEO) of Mg alloy, where TMA compound was used for supramolecular self-assembly. The MgO layer was first formed on AZ31Mg alloy via PEO treatment and the Mg-Al LDH micro-petals were synthesized on the MgO surface in the presence of a chelating agent [diethylenetriaminepentaacetic acid (DTPA)]. In a typical synthesis, TMA compound was used as an appropriate linker for the formation of well-organized multidimensional layered materials taking advantage of the synergy beneficial effects of the self-assembled honeycomb-like TMA and the anion-exchange ability of the Mg-Al LDH coating. The results indicate that Mg alloy coated with the self-assembled TMA@LDH-MgO materials presents excellent anti-corrosion performance as compared to the bare Mg. The use of such system would open a brand-new possibility to correct, in a targeted way, the inevitable defects of the layered coating morphology while retaining its exceptional potential. First-principles calculations, quantitative molecular surface analyses and independent gradient model framework further verify the self-assembly and adsorption behavior of TMA over the Mg-Al LDH layer. The improved performance of the TMA@Mg-Al LDH film is attributed to the synergistic effects of different interactions that occurred around active sites in the hierarchical network.

Change of Campylobacter, Escherichia coli and Salmonella counts in packaged broiler breast meat stored under modified atmosphere and vacuum conditions at 4 and 10 °C based on cultural and molecular biological quantification

Poultry on the European market is offered primarily as fresh meat and is usually sold at the retail level packed under either a modified atmosphere (MAP) or vacuum. Packaging is meant to retain product quality during retail offering and influences microbiological changes during storage. The focus of this study was to determine the influence of routinely used broiler meat packaging technologies on the change of Campylobacter , Salmonella and Escherichia coli counts on chicken breast meat. Chicken breast meat was inoculated with Campylobacter (5 log 10 cfu/g), Salmonella and E. coli (each at 4 log 10 cfu/g), packaged under MAP or vacuum conditions and stored at 4 and 10 °C over a period of 13 days. Cultural microbiological analysis was used together with quantitative viability real time PCR (v-qPCR) to assess the development of inoculated bacteria as well as the general hygiene and spoilage microbiota. The results showed a reduction of thermophilic Campylobacter spp. of about 2 log 10 cfu at the end of storage for MAP meat as compared to vacuum packed meat. However, this reduction was not observed by v-qPCR, where viable Campylobacter spp. counts remained almost at inoculation level. No change in cfu was observed for either Salmonella or E. coli . The results indicate that examination by culturing alone can lead to an underestimation of the Campylobacter spp. load on fresh broiler meat. Quantitative molecular biological analysis with live/dead differentiation is applicable for overcoming the limitations of culturing methods and therefore requires further verification through additional studies under retail conditions on different matrices. • MAP storage at 4 °C resulted in a 2 log reduction of cultured Campylobacter . • Reduction of Campylobacter count of cultural examination was not confirmed by qPCR. • No significant differences found for E. coli comparing qPCR and cultural results. • Storage temperature influenced the change in Salmonella counts.

Qualitative and Quantitative Molecular Analysis of Epstein-Barr Virus in Iraqi Patients with Relapsing-Remitting Multiple Sclerosis

Multiple sclerosis (MS) is a neuro-inflammatory disorder in which the Epstein-Barr virus (EBV) is proposed to have a pathogenic role. Therefore, a case-control study was performed (93 patients with relapsing-remitting MS and 113 healthy controls (HC) to analyze the prevalence and viral load of EBV infection using real time-polymerase chain reaction. Prevalence of EBV infection was lower in patients compared to HC but the difference was not significant (12.9 vs. 21.2%; probability [p] = 0.187). EBV-positive MS cases were more common in females than in males (83.3 vs. 16.7%), while an opposite distribution was observed in HC (37.5 vs. 62.5%), and the difference was significant (p = 0.041). Blood group O frequency was higher in EBV-positive patients compared to the corresponding HC but the difference was not significant (33.3 vs. 20.8%; p = 0.443). EBV-positive MS cases showed similar frequency in the two groups of the expanded disability status scale (EDSS: < 3.0 and ≥ 3.0; 50% each). EBV load was significantly elevated in EBV-positive MS cases compared to EBV-positive HC (94.6 ± 84.2 vs. 17.0 ± 16.3 DNA copy/100 cells; p = 0.009). When EBV-positive MS cases were classified by gender, EDSS groups or ABO blood groups, there were no significant differences between EBV loads in each stratum. However, a significant correlation between EBV load and EDSS was found (correlation coefficient = 0.620; p = 0.031). In conclusion, the prevalence of EBV infection showed no significant differences between MS patients and HC, while EBV load was significantly higher in patients.

Methods for the Assessment of NET Formation: From Neutrophil Biology to Translational Research.

Several studies have indicated that a neutrophil extracellular trap (NET) formation, apart from its role in host defense, can contribute to or drive pathogenesis in a wide range of inflammatory and thrombotic disorders. Therefore, NETs may serve as a therapeutic target or/and a diagnostic tool. Here, we compare the most commonly used techniques for the assessment of NET formation. Furthermore, we review recent data from the literature on the application of basic laboratory tools for detecting NET release and discuss the challenges and the advantages of these strategies in NET evaluation. Taken together, we provide some important insights into the qualitative and quantitative molecular analysis of NETs in translational medicine today.

Demonstration of intracellular real-time molecular quantification via FRET-enhanced optical microcavity

Single cell analysis is crucial for elucidating cellular diversity and heterogeneity as well as for medical diagnostics operating at the ultimate detection limit. Although superbly sensitive biosensors have been developed using the strongly enhanced evanescent fields provided by optical microcavities, real-time quantification of intracellular molecules remains challenging due to the extreme low quantity and limitations of the current techniques. Here, we introduce an active-mode optical microcavity sensing stage with enhanced sensitivity that operates via Förster resonant energy transferring (FRET) mechanism. The mutual effects of optical microcavity and FRET greatly enhances the sensing performance by four orders of magnitude compared to pure Whispering gallery mode (WGM) microcavity sensing system. We demonstrate distinct sensing mechanism of FRET-WGM from pure WGM. Predicted lasing wavelengths of both donor and acceptor by theoretical calculations are in perfect agreement with the experimental data. The proposed sensor enables quantitative molecular analysis at single cell resolution, and real-time monitoring of intracellular molecules over extended periods while maintaining the cell viability. By achieving high sensitivity at single cell level, our approach provides a path toward FRET-enhanced real-time quantitative analysis of intracellular molecules.

Characterization of the RAS/RAF/ERK Signal Cascade as a Novel Regulating Factor in Alpha-Amanitin-Induced Cytotoxicity in Huh-7 Cells

The well-known hepatotoxicity mechanism resulting from alpha-amanitin (α-AMA) exposure arises from RNA polymerase II (RNAP II) inhibition. RNAP Ⅱ inhibition occurs through the dysregulation of mRNA synthesis. However, the signaling pathways in hepatocytes that arise from α-AMA have not yet been fully elucidated. Here, we identified that the RAS/RAF/ERK signaling pathway was activated through quantitative phosphoproteomic and molecular biological analyses in Huh-7 cells. Bioinformatics analysis showed that α-AMA exposure increased protein phosphorylation in a time-dependent α-AMA exposure. In addition, phosphorylation increased not only the components of the ERK signaling pathway but also U2AF65 and SPF45, known splicing factors. Therefore, we propose a novel mechanism of α-AMA as follows. The RAS/RAF/ERK signaling pathway involved in aberrant splicing events is activated by α-AMA exposure followed by aberrant splicing events leading to cell death in Huh-7 cells.

Micro-injection Molded Droplet Generation System for Digital PCR Application.

Sensitive, effective, and quantitative analysis of infectious pathogens is an important task for the prevention of human health threats. Herein, we present an advanced approach to producing gene-encapsulated microdroplets for quantitative analysis using a micropatterned metal mold and injection molding technique with an automatically operated system. An injection molded microdroplet generation device was successfully fabricated with a minimum channel width of 30 μm and optimized to produce 100 μm diameter droplets. The optimized microchannel design and flow rate also enable the production of stable numbers of microdroplets (~ 16,000 droplets). To verify the applicability of our device and system to droplet-based digital PCR analysis, Escherichia coli (E. coli) O157:H7 was selected as a model bacterial pathogen, and the stx2 gene was amplified in the microdroplets. The generated microdroplets exhibit both chemical and mechanical stability, and our results are similar to those obtained by a commercially available method. Accordingly, the usefulness of the microdroplet generative device and system is confirmed as a simple, fast, and reliable tool for the quantitative molecular analysis of infectious diseases.

Quantitative Structure Activity Relationship (QSAR) Investigations and Molecular Docking Analysis of Plasmodium Protein Farnesyltransferase Inhibitors as Potent Antimalarial Agents

The development of farnesyltransferase inhibitors based on the benzophenone scaffold directed against Plasmodium falciparum is considered a strategy in malaria treatment. In this work, quantitative structure–activity relationship (QSAR) was performed to predict the protein farnesyltransferase (PFT) inhibitory activities for a series of 36 benzophenone derivatives. The data set was divided into two subsets of training and test sets, and the best model using multiple linear regression (MLR), with the values of internal and external validity (R2 = 0.884, R2adj = 0.865, R2pred = 0.821, Q2cv =0.822 and R2p=0.811) was found in agreement with the Tropsha and Golbraikh criteria. The applicability domain (AD) was determined using the Williams plot to describe the chemical space for the model used in this study. The model shows that antimalarial activities of benzophenone depend on logP, bpol, MAXDn, and FMF descriptors. These indications prompted us to design new benzophenones PFT inhibitors and predict the value of their anti-malarial activities based on the MLR equation. Docking results reveal that the newly designed benzophenones bind to the hydrophobic pocket and polar contact with high affinity. The predicted results from this study can help to design novel benzophenone as inhibitors of human PFT with high antimalarial activities.

3D-QSAR, molecular docking and ADMET studies of thioquinazolinone derivatives against breast cancer

Breast cancer is a deadly disease and the second largest cause of mortality on a worldwide platform. Despite the availability of several cancer treatments, life expectancies stay relatively poor. Consequently, the medicinal chemistry community prioritizes the quick discovery of novel anticancer drugs. In recent years, computational approaches have been widely used to accelerate the drug development process. In light of this, in the current work, we performed three-dimensional quantitative structure-activity relationships (3D-QSAR) and molecular docking analyses on thioquinazolinone derivatives with aromatase enzyme (PDB: 3S7S). External validation was used to validate the prediction capabilities of the generated model. The best CoMSIA (comparative molecular similarity indices analysis) model exhibited the significant values of Q2, R2andRpred2. These findings suggested that the electrostatic, hydrophobic and hydrogen bond donor and acceptor fields have a significant effect on inhibition of breast cancer. Thus, a number of innovative potent aromatase inhibitors were designed and their biological activities were predicted based on the best model. Furthermore, molecular docking studies were carried out for the designed compounds against breast cancer. Additionally, ADMET proprieties were used to evaluate drug-likeness of these novel drug candidates. The most active compounds found by these computational studies could be helpful for synthesis and testing as prospective future anti-cancer treatments.

Inter-/intra-molecular interactions, preferential solvation, and dissolution and transfer property for tirofiban in aqueous co-solvent mixtures

Using Hirshfeld surface, interaction region indicator and quantitative molecular surface analysis, the microscopic electrostatic features of basicity and acidity of the tirofiban molecule were clearly demonstrated. Both the O atoms in >SO2 and H atom in –COOH serve as primary electrophilic site and nucleophilic site, respectively. Utilizing solubility data for tirofiban in four different water-based co-solvent mixtures {isopropanol/ethylene glycol (EG)/methanol/ethanol (1) + water (2)}, the inverse Kirkwood–Buff integral method was utilized to determine the preferred solvent for the tirofiban solvation according to the results of preferential solvation analysis. In water-rich composition ranges, the drug is surrounded by water, whereas in isopropanol/methanol/ethanol-intermediate and -rich composition ranges, the drug is surrounded by ethanol/methanol/isopropanol. Isopropanol solutions had the largest magnitude of preferential solvation. Alcohols may have a greater basicity that enhances interactions with the Lewis acidic function groups of tirofiban, giving rise to selective solvation of this drug. The linear solvation energy relationships were used to determine the relative impact of solvent-solvent and solvent-solute interactions in determining the variation of solubility magnitudes. The properties of dissolution and transfer, such as entropy, enthalpy and Gibbs energy change were computed. Entropy-driven and enthalpy-driven mechanisms were shown to be responsible for the change in tirofiban solubility in the four aqueous solutions, according to the enthalpy–entropy compensation analysis.

Through-Space Stabilization of an Imidazolium Cation by Aromatic Rings

Imidazole-based compounds are widely found in natural products, synthetic molecules, and biomolecules. Noncovalent interactions between the imidazole ring and other functional groups play an important role in determining the function of diverse molecules. However, there is a limited understanding of the underlying noncovalent interactions between imidazoles and aromatic systems. In this work, we report physical-organic chemistry studies on 2-(2,6-diarylphenyl)-1H-imidazoles and their protonated forms to investigate the noncovalent interactions between the central imidazole ring and two flanking aromatic rings possessing substituents at the para/meta position. Hammett analysis revealed that pKa values and proton affinities correlate well with Hammett σ values of para-substituents at the flanking rings. Additional quantitative Kohn-Sham molecular orbital and energy decomposition analyses reveal that through-space π-π interactions and NH-π interactions contribute to the intramolecular stabilization of the imidazolium cation. The results are important because they clearly demonstrate that the imidazolium cation forms energetically favorable noncovalent interactions with aromatic rings via the through-space effect, a knowledge that can be used in rational drug and catalyst design.