QSAR,Molecular Docking,MD Simulation and MMGBSA Calculations Approaches to Recognize Concealed Pharmacophoric Features Requisite for the Optimization of ALK Tyrosine Kinase Inhibitors as Anticancer Leads

ALK tyrosine kinase ALK TK is an important target in the development of anticancer drugs. In the present work, we have performed a QSAR analysis on a dataset of 224 molecules in order to quickly predict anticancer activity on query compounds. Double cross validation assigns an upward plunge to the genetic algorithm–multi linear regression (GA-MLR) based on robust univariate and multivariate QSAR models with high statistical performance reflected in various parameters like, fitting parameters; R² = 0.69–0.87, F = 403.46–292.11, etc., internal validation parameters; Q²_LOO = 0.69–0.86, Q²_LMO = 0.69–0.86, CCC_cv = 0.82–0.93, etc., or external validation parameters Q²_F1 = 0.64–0.82, Q²_F2 = 0.63–0.82, Q²_F3 = 0.65–0.81, R²_ext = 0.65–0.83 including RMSE_tr < RMSE_cv. The present QSAR evaluation successfully identified certain distinct structural features responsible for ALK TK inhibitory potency, such as planar Nitrogen within four bonds from the Nitrogen atom, Fluorine atom within five bonds beside the non-ring Oxygen atom, lipophilic atoms within two bonds from the ring Carbon atoms. Molecular docking, MD simulation, and MMGBSA computation results are in consensus with and complementary to the QSAR evaluations. As a result, the current study assists medicinal chemists in prioritizing compounds for experimental detection of anticancer activity, as well as their optimization towards more potent ALK tyrosine kinase inhibitor.     

Oxy-Polybrominated Diphenyl Ethers from the Indonesian Marine Sponge,Lamellodysidea herbacea: X-ray,SAR, and Computational Studies

Polybrominated diphenyl ether (PBDE) compounds, derived from marine organisms, originate from symbiosis between marine sponges and cyanobacteria or bacteria. PBDEs have broad biological spectra; therefore, we analyzed structure and activity relationships of PBDEs to determine their potential as anticancer or antibacterial lead structures, through reactions and computational studies. Six known PBDEs (1–6) were isolated from the sponge, Lamellodysdiea herbacea; ¹³C NMR data for compound 6 are reported for the first time and their assignments are confirmed by their theoretical ¹³C NMR chemical shifts (RMSE < 4.0 ppm). Methylation and acetylation of 1 (2, 3, 4, 5-tetrabromo-6-(3′, 5′-dibromo-2′-hydroxyphenoxy) phenol) at the phenol functional group gave seven molecules (7–13), of which 10, 12, and 13 were new. New crystal structures for 8 and 9 are also reported. Debromination carried out on 1 produced nine compounds (1, 2, 14, 16–18, 20, 23, and 26) of which 18 was new. Debromination product 16 showed a significant IC₅₀ 8.65 ± 1.11; 8.11 ± 1.43 µM against human embryonic kidney (HEK293T) cells. Compounds 1 and 16 exhibited antibacterial activity against Gram-positive Staphylococcus aureus and Gram-negative Klebsiella pneumoniae with MID 0.078 µg/disk. The number of four bromine atoms and two phenol functional groups are important for antibacterial activity (S. aureus and K. pneumoniae) and cytotoxicity (HEK293T). The result was supported by analysis of frontier molecular orbitals (FMOs). We also propose possible products of acetylation and debromination using analysis of FMOs and electrostatic charges and we confirm the experimental result.     

Novel Coumarin Glycosides from Daphne oleoides

`Dimeric' coumarin glycoside 1 and `trimeric' coumarin fucosides 2 and 3 were isolated from Daphne oleoides. Their structures were established by means of different spectroscopic techniques, including 2D‐NMR spectroscopy.     

QSAR Evaluations to Unravel the Structural Features in Lysine-Specific Histone Demethylase 1A Inhibitors for Novel Anticancer Lead Development Supported by Molecular Docking,MD Simulation and MMGBSA

Using 84 structurally diverse and experimentally validated LSD1/KDM1A inhibitors, quantitative structure–activity relationship (QSAR) models were built by OECD requirements. In the QSAR analysis, certainly significant and understated pharmacophoric features were identified as critical for LSD1 inhibition, such as a ring Carbon atom with exactly six bonds from a Nitrogen atom, partial charges of lipophilic atoms within eight bonds from a ring Sulphur atom, a non-ring Oxygen atom exactly nine bonds from the amide Nitrogen, etc. The genetic algorithm–multi-linear regression (GA-MLR) and double cross-validation criteria were used to create robust QSAR models with high predictability. In this study, two QSAR models were developed, with fitting parameters like R² = 0.83–0.81, F = 61.22–67.96, internal validation parameters such as Q²_LOO = 0.79–0.77, Q²_LMO = 0.78–0.76, CCC_cv = 0.89–0.88, and external validation parameters such as, R2ext = 0.82 and CCCex = 0.90. In terms of mechanistic interpretation and statistical analysis, both QSAR models are well-balanced. Furthermore, utilizing the pharmacophoric features revealed by QSAR modelling, molecular docking experiments corroborated with the most active compound’s binding to the LSD1 receptor. The docking results are then refined using Molecular dynamic simulation and MMGBSA analysis. As a consequence, the findings of the study can be used to produce LSD1/KDM1A inhibitors as anticancer leads.     

3-(((1S,3S)-3-((R)-Hydroxy(4-(trifluoromethyl)phenyl)methyl)-4-oxocyclohexyl)methyl)pentane-2,4-dione: Design and Synthesis of New Stereopure Multi-Target Antidiabetic Agent

The chiral drug candidates have more effective binding affinities for their specific protein or receptor site for the onset of pharmacological action. Achieving all carbon stereopure compounds is not trivial in chemical synthesis. However, with the development of asymmetric organocatalysis, the synthesis of certain vital chiral drug candidates is now possible. In this research, we have synthesized 3-(((1S,3S)-3-((R)-hydroxy(4-(trifluoromethyl)phenyl)methyl)-4-oxocyclohexyl)methyl)pentane-2,4-dione (S,S,R-5) and have evaluated it potential as multi-target antidiabetic agent. The stereopure compound S,S,R-5 was synthesized with a 99:1 enantiomeric ratio. The synthesized compound gave encouraging results against all in vitro antidiabetic targets, exhibiting IC₅₀ values of 6.28, 4.58, 0.91, and 2.36 in α-glucosidase, α-amylase, PTP1B, and DPPH targets, respectively. The molecular docking shows the binding of the compound in homology models of the respective enzymes. In conclusion, we have synthesized a new chiral molecule (S,S,R-5). The compound proved to be a potential inhibitor of the tested antidiabetic targets. With the observed results and molecular docking, it is evident that S,S,R-5 is a potential multitarget antidiabetic agent. Our study laid the baseline for the animal-based studies of this compound in antidiabetic confirmation.     

Securing Cloud Storage by Remote DataIntegrity Check with Secured Key Generation

In recent decades, a number of protocols for Remote data integrity checking (RDIC) have been proposed.Identity (ID) based RDIC protocols are constructed to guarantee cloud data integrity and data privacy. The known protocols for RDIC always assume that the Private key generator (PKG) is a trusted one, but in real-world applications by corrupt PKG, malicious Cloud server (CS) can easily cheat the third party auditor that the data owner's outsourced data are kept safe through the data has been deleted or altered. In this paper, we explore the novel model of RDIC with untrusted PKG and malicious CS, by employing the partial key method and Authentication, authorization, accounting (AAA) service. We construct a new ID-based RDIC, which provides the ID revocation and key updation. The experimental evaluations show that our scheme is more efficient than known ones.     

Can the SARS-CoV-2 Omicron Variant Confer Natural Immunity against COVID-19?

The coronavirus disease 2019 (COVID-19) pandemic is still ongoing, with no signs of abatement in sight. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the causative agent of this pandemic and has claimed over 5 million lives, is still mutating, resulting in numerous variants. One of the newest variants is Omicron, which shows an increase in its transmissibility, but also reportedly reduces hospitalization rates and shows milder symptoms, such as in those who have been vaccinated. As a result, many believe that Omicron provides a natural vaccination, which is the first step toward ending the COVID-19 pandemic. Based on published research and scientific evidence, we review and discuss how the end of this pandemic is predicted to occur as a result of Omicron variants being surpassed in the community. In light of the findings of our research, we believe that it is most likely true that the Omicron variant is a natural way of vaccinating the masses and slowing the spread of this deadly pandemic. While the mutation that causes the Omicron variant is encouraging, subsequent mutations do not guarantee that the disease it causes will be less severe. As the virus continues to evolve, humans must constantly adapt by increasing their immunity through vaccination.     

In Silico and Ex Vivo Studies on the Spasmolytic Activities of Fenchone Using Isolated Guinea Pig Trachea

Fenchone is a bicyclic monoterpene found in a variety of aromatic plants, including Foeniculum vulgare and Peumus boldus, and is used in the management of airways disorders. This study aimed to explore the bronchodilator effect of fenchone using guinea pig tracheal muscles as an ex vivo model and in silico studies. A concentration-mediated tracheal relaxant effect of fenchone was evaluated using isolated guinea pig trachea mounted in an organ bath provided with physiological conditions. Sustained contractions were achieved using low K⁺ (25 mM), high K⁺ (80 mM), and carbamylcholine (CCh; 1 µM), and fenchone inhibitory concentration–response curves (CRCs) were obtained against these contractions. Fenchone selectively inhibited with higher potency contractions evoked by low K⁺ compared to high K⁺ with resultant EC₅₀ values of 0.62 mg/mL (0.58–0.72; n = 5) and 6.44 mg/mL (5.86–7.32; n = 5), respectively. Verapamil (VRP) inhibited both low and high K⁺ contractions at similar concentrations. Pre-incubation of the tracheal tissues with K⁺ channel blockers such as glibenclamide (Gb), 4-aminopyridine (4-AP), and tetraethylammonium (TEA) significantly shifted the inhibitory CRCs of fenchone to the right towards higher doses. Fenchone also inhibited CCh-mediated contractions at comparable potency to its effect against high K⁺ [6.28 mg/mL (5.88–6.42, n = 4); CCh] and [6.44 mg/mL (5.86–7.32; n = 5); high K⁺]. A similar pattern was obtained with papaverine (PPV), a phosphodiesterase (PDE), and Ca²⁺ inhibitor which inhibited both CCh and high K⁺ at similar concentrations [10.46 µM (9.82–11.22, n = 4); CCh] and [10.28 µM (9.18–11.36; n = 5); high K⁺]. However, verapamil, a standard Ca²⁺ channel blocker, showed selectively higher potency against high K⁺ compared to CCh-mediated contractions with respective EC₅₀ values of 0.84 mg/mL (0.82–0.96; n = 5) 14.46 mg/mL (12.24–16.38, n = 4). The PDE-inhibitory action of fenchone was further confirmed when its pre-incubation at 3 and 5 mg/mL potentiated and shifted the isoprenaline inhibitory CRCs towards the left, similar to papaverine, whereas the Ca²⁺ inhibitory-like action of fenchone pretreated tracheal tissues were authenticated by the rightward shift of Ca²⁺ CRCs with suppression of maximum response, similar to verapamil, a standard Ca²⁺ channel blocker. Fenchone showed a spasmolytic effect in isolated trachea mediated predominantly by K⁺ channel activation followed by dual inhibition of PDE and Ca²⁺ channels. Further in silico molecular docking studies provided the insight for binding of fenchone with Ca²⁺ channel (−5.3 kcal/mol) and K⁺ channel (−5.7), which also endorsed the idea of dual inhibition.     

Rational Design of a Fluorescent Chromophore as a Calcium Receptor via DFT and Multivariate Approaches

Computational and experimental approaches were adopted to utilize a chromophore diglycolic functionalized fluorescein derivative as a Ca²⁺ receptor. Fluorescein diglycolic acid (Fl-DGA, 1) was synthesized and used in multivariate determination of Ca²⁺ and K⁺. Full-structure computation shows that the complexes of 1 and Ca²⁺ have comparable energies regardless of additional interaction with lactone moiety. The initial formation of diglycolic-Ca²⁺ complex followed by macrocyclization is thermodynamically disfavored. A U-shaped pre-organized 1 allows Ca²⁺ to interact simultaneously with diglycolic and lactone motifs. Both motifs actively participate in Ca²⁺ recognition and the eleven methylene units in the undecyl arm provides excellent flexibility for reorganization and optimum interaction. Principal component analysis (PCA) of computational molecular properties reveals a simple method in evaluating motifs for cation recognition. Fragment models support full-structure results that negative charge causes significant structural changes, but do not reproduce the full extent of C-O bond breaking observed in the latter. Experimental optical responses show that 1 is selective towards Ca²⁺ and discriminates against K⁺ and Mg²⁺. PCA of emission intensities affords distinct clusters of 0.01, 0.1 and 1 mM Ca²⁺ and K⁺, and suggests applicability of this technique for simultaneous determination of cationic plant macronutrients in precision agriculture and a wide variety of other applications.     

Physicochemical Properties of a New Green Honey from Banggi Island,Sabah

Green honey is exclusively available on the island of Banggi in Sabah, and its uniqueness sees the commodity being sold at a high market price. Therefore, green honey is prone to adulteration by unscrupulous individuals, possibly compromising the health of those consuming this food commodity for its curative properties. Moreover, an established standard for reducing sugar in green honey is unavailable. Ipso facto, the study aimed to profile green honey’s physical and chemical properties, such as its pH, moisture content, free acidity, ash content, electroconductivity, hydroxymethylfurfural (HMF), total phenolic content, total flavonoid content, DPPH, colour, total sugar content, total protein content, and heavy metals as well as volatile organic compounds, the data of which are profoundly valuable in safeguarding consumers’ safety while providing information for its quality certification for local consumption and export. The results revealed that the honey’s physicochemical profile is comparable to other reported kinds of honey. The honey’s naturally green colour is because of the chlorophyll from the nectar from various flowers on the island. The raw honey showed free acidity between 28 and 33 Meq/100 g, lower than the standard’s 50 Meq/100 g. The hydroxymethylfurfural content is the lowest compared to other reported honey samples, with the total phenolic content between 16 and 19 mg GAE/100 g. The honey’s reducing sugar content is lower (~37.9%) than processed ones (56.3%) because of water removal. The protein content ranged from 1 to 2 gm/kg, 4- to 6-fold and 2-fold higher than local and manuka honey, respectively. The exceptionally high content of trans-4-hydroxyproline in raw honey is its source of collagen and other healing agents. Interestingly, low levels of arsenic, lead, nickel, cadmium, copper, and cobalt were detected in the honey samples, presumably due to their subterranean hives. Nevertheless, the honey is fit for general consumption as the concentrations were below the maxima in the Codex Alimentarius Commission of 2001.