Exploring cyclopropylamine containing cyanopyrimidines as LSD1 inhibitors: Design, synthesis, ADMET, MD analysis and anticancer activity profiling.

In this series we report the structure-based design, synthesis and anticancer activity evaluation of a series of eighteen cyclopropylamine containing cyanopyrimidine derivatives. The computational predictions of ADMET properties revealed appropriate aqueous solubility, high GI absorption, no BBB permeability, no Lipinski rule violations, medium total clearance and no mutagenic, tumorigenic, irritant and reproductive toxic risks for most of the compounds. Compounds VIIb, VIIi and VIIm emerged as the most potent anticancer agents among all compounds evaluated against 60 cancer cell lines through the one-dose (10 µM) sulforhodamine B assay. Further, the multiple dose cell viability studies against cancer cell lines MOLT-4, A549 and HCT-116 revealed results consistent with the one-dose assay, besides sparing normal cell line HEK-293. The three potent compounds also displayed potent LSD1 inhibitory activity with IC50 values of 2.25, 1.80 and 6.08 µM. The n-propyl-thio/isopropyl-thio group bonded to the pyrimidine ring and unsubstituted/ electron donating group (at the para- position) attached to the phenyl ring resulted in enhanced anticancer activity. However, against leukemia cancer, the electron donating isopropyl group remarkably enhanced anti-cancer activity. Our findings provide important leads, which merit further optimization to result in better cancer therapeutics.

Deciphering Campylobacter jejuni DsbA1 protein dynamics in the presence of anti-virulent compounds: a multi-pronged computer-aided approach.

The current study aims to evaluate Asinex library compounds against Campylobacter jejuni DsbA1 protein, a thiol disulfide oxidoreductase enzyme that plays a major role in the oxidative folding of bacterial virulence proteins, making it a promising anti-viral drug target. By employing several techniques of computer-aided drug design, BDC25697459, BDD33601083, and BDC30129064 were identified with binding energy scores of -8.8 kcal/mol, -8.8 kcal/mol, and -8.3 kcal/mol, respectively. However, the control molecule, tetraethylene glycol, exhibited a binding energy score of -7.0 kcal/mol. The control, BDD33601083, and BDC30129064 were unveiled to bind the same co-crystallized binding site (pocket 1), while BDC25697459 interacted with a new binding pocket (pocket 2) adjacent to the control binding region. The molecular dynamics simulation showed that complexes exhibit stable dynamics without significant global or residue-level fluctuations. The average RMSD values were in the range of 2.07 Å-2.45 Å. Similarly, mean RMSF was recorded between 1.30 and 1.42 Å. The C. jejuni DsbA1 was also observed as compact in the presence of the compounds, showing a mean RoG value in the range of 16.42 Å-16.55 Å. In terms of MM/PBSA binding energy, the BDC30129064 complex was ranked top with -44.88 ± 4.14 kcal/mol, whereas the positive control molecule exhibited -22.22 ± 3.33 kcal/mol. From a pharmacokinetic perspective, the compounds are suitable candidates for clinical trial investigation. Preliminary computational analysis of these virtual hits indicates that these compounds have a low potential for ADME and toxicity-associated liabilities. In summary, the compounds displayed a high affinity for the C. jejuni DsbA1 protein, indicating potential efficacy that requires further investigation.Communicated by Ramaswamy H. Sarma.

Effectiveness of estrogen and its derivatives over dexamethasone in the treatment of COVID-19.

Coronavirus disease (COVID-19) is an infectious disease caused by the SARS-CoV-2 virus and dexamethasone is a glucocorticoid widely used for its treatment. Dexamethasone is not used in non-severe cases due to its immunosuppressant action. So, considering this, Estrogen and Estetrol were tested for the treatment of COVID-19 as they all possess a common steroid ring and dislike dexamethasone, they are immunoenhancer. Virtual screening of test ligands was performed through molecular docking, MM-GBSA, simulations, in silico ADMET and drug-likeness prediction to identify their potential to inhibit the effects of SARS-CoV-2. Results showed that test ligands possess drug-like properties and they are safe as drug candidates. The protein-ligand interaction study revealed that they bind with the amino acid residues at the active site of the target proteins and the test ligands possess better binding potential than Dexamethasone. With protein Mpro, Estetrol and Estrogen showed docking score of -7.240 and -5.491 kcal/mol, and with protein ACE2, Estetrol and Estrogen showed docking score of -5.269 and -4.732 kcal/mol, respectively. Further, MD Simulation was carried out and most of the interactions of molecular docking are preserved during simulation. The prominent interactions that our test ligands showed during MD Simulation are similar to drugs that possess in vitro anticovid activity as shown in recent studies. Hence, our test ligands possessed potential for anticovid activity and they should be further tested through in vitro and in vivo studies for their activity against COVID-19.Communicated by Ramaswamy H. Sarma.

Eucalyptus-derived essential oils alleviate microbes and modulate inflammation by suppressing superoxide and elastase release.

The Eucalyptus tree, belonging to the myrtle family, grows all over the world for its pharmaceutical and industrial benefits. In this article, we present a comparative analysis of the chemical composition of the hydrodistilled oils obtained from three different Eucalyptus species growing in Egypt viz. E. citriodora, E. camaldulensis, and E. ficifolia. Gas Chromatography-Mass Spectrometric guided analysis resulted in the identification of a total of 20 metabolites in E. citriodora oil with citronellal (54.9%) and citronellol (25.4%) being the most dominant components. ß-cymene (12.7%) and 1,8-cineole (11.7%) were the major volatile constituents identified in E. camaldulensis oil, while trans-ß-ocimene (22.4%), 1,8-cineole (13.5%), and L-trans-pinocarveol (12.5%) were the dominating components in the oil of E. ficifolia. The essential oils of the studied species were evaluated for their in vitro anti-inflammatory, antiviral including anti-SARS-CoV-2 (severe acute respiratory syndrome corona virus 2), antibacterial, and antifungal activities. E. citriodora oil displayed the highest inhibitory activity on the release of the superoxide radical (32%) and elastase enzyme (31%) in human neutrophils, while E. ficifolia oil had enhancing effects on elastase. The latter showed significant antiviral effects against hepatitis A, herpes simplex, and coxsackie viruses with IC50 values at 2.1, 2.5, and 5.6 µg/mL, respectively. Moderate antibacterial and antifungal activities were observed for Eucalyptus oils with Staphylococcus aureus being the most susceptible bacterial strain. E. ficifolia oil, similarly, displayed the best antibacterial activity with minimum inhibitory concentration (MIC) value at ca. 25 µg/mL (for S. aureus). On the contrary, E. camaldulensis oil was the most active against Candida albicans with an MIC value at 45 µg/mL. In silico studies were performed with a number of macromolecular drug targets for confirming the biological activities of the identified compounds and for interpreting their ADME (absorption-distribution-metabolism-elimination) parameters.

Synthesis, molecular docking, and in vivo antidiabetic evaluation of new benzylidene-2,4-thiazolidinediones as partial PPAR-γ agonists.

Peroxisome proliferator-activated receptor-γ (PPAR-γ) partial agonists or antagonists, also termed as selective PPAR-γ modulators, are more beneficial than full agonists because they can avoid the adverse effects associated with PPAR-γ full agonists, such as weight gain and congestive heart disorders, while retaining the antidiabetic efficiency. In this study, we designed and synthesized new benzylidene-thiazolidine-2,4-diones while keeping the acidic thiazolidinedione (TZD) ring at the center, which is in contrast with the typical pharmacophore of PPAR-γ agonists. Five compounds (5a-e) were designed and synthesized in moderate to good yields and were characterized using spectral techniques. The in vivo antidiabetic efficacy of the synthesized compounds was assessed on streptozotocin-induced diabetic mice using standard protocols, and their effect on weight gain was also studied. Molecular docking and molecular dynamics (MD) simulation studies were performed to investigate the binding interactions of the title compounds with the PPAR-γ receptor and to establish their binding mechanism. Antidiabetic activity results revealed that compounds 5d and 5e possess promising antidiabetic activity comparable with the standard drug rosiglitazone. No compound showed considerable effect on the body weight of animals after 21 days of administration, and the findings showed statistical difference (p < 0.05 to p < 0.0001) among the diabetic control and standard drug rosiglitazone groups. In molecular docking study, compounds 5c and 5d exhibited higher binding energies (- 10.1 and - 10.0 kcal/mol, respectively) than the native ligand, non-thiazolidinedione PPAR-γ partial agonist (nTZDpa) (- 9.8 kcal/mol). MD simulation further authenticated the stability of compound 5c-PPAR-γ complex over the 150 ns duration. The RMSD, RMSF, rGyr, SASA, and binding interactions of compound 5c-PPAR-γ complex were comparable to those of native ligand nTZDpa-PPAR-γ complex, suggesting that the title compounds have the potential to be developed as partial PPAR-γ agonists.

Identification of potential inhibitors of HER2 targeting breast cancer-a structure-based drug design approach.

Breast cancer is one of the most prevalent and malignant cancers in women. Most breast cancer patients show overexpression of the HER2 protein. The current study focused on identifying potent inhibitors of HER2 using a structure-based drug design approach. Prefiltered compounds from the Drugbank and the ZINC database were docked on HER2 protein using the FlexX docking tool of LeadIT. The docking study identified the 12 best molecules that interacted strongly with the active site of HER2 and also fulfilled the ADMET parameters. The complexes of these compounds with HER2 were further subjected to molecular dynamics simulation using GROMACS 2021.4, followed by the end-state MMGBSA binding energy calculations. The RMSD analysis was conducted to study the conformational changes, which revealed stability throughout the 100 ns simulation period. The local flexibility and dynamics of the simulated ligand-protein complexes were studied using RMSF analysis. The values of the radius of gyration were computed to analyze the compactness of HER2. The MMGBSA analysis provided insights into the energetic aspects of the system. The compound DB15187 emerged as the most potent candidate, showing MMGBSA-computed binding energy of -63.60 ± 3.39 kcal/mol. The study could help develop targeted therapies for HER2-positive breast cancer.Communicated by Ramaswamy H. Sarma.

An immuno-informatics approach for annotation of hypothetical proteins and multi-epitope vaccine designed against the Mpox virus.

A worrying new outbreak of Monkeypox (Mpox) in humans is caused by the Mpox virus (MpoxV). The pathogen has roughly 28 hypothetical proteins of unknown structure, function, and pathogenicity. Using reliable bioinformatics tools, we attempted to analyze the MpoxV genome, identify the role of hypothetical proteins (HPs), and design a potential candidate vaccine. Out of 28, we identified seven hypothetical proteins using multi-server validation with high confidence for the occurrence of conserved domains. Their physical, chemical, and functional characterizations, including molecular weight, theoretical isoelectric point, 3D structures, GRAVY value, subcellular localization, functional motifs, antigenicity, and virulence factors, were performed. We predicted possible cytotoxic T cell (CTL), helper T cell (HTL) and linear and conformational B cell epitopes, which were combined in a 219 amino acid multiepitope vaccine with human ß defensin as a linker. This multi-epitopic vaccine was structurally modelled and docked with toll-like receptor-3 (TLR-3). The dynamical stability of the vaccine-TLR-3 docked complexes exhibited stable interactions based on RMSD and RMSF tests. Additionally, the modelled vaccine was cloned in-silico in an E. coli host to check the appropriate expression of the final vaccine built. Our results might conform to an immunogenic and safe vaccine, which would require further experimental validation.Communicated by Ramaswamy H. Sarma.

Chemotherapy-induced cardiotoxicity: a new perspective on the role of Digoxin, ATG7 activators, Resveratrol, and herbal drugs.

Cancer is a major public health problem, and chemotherapy plays a significant role in the management of neoplastic diseases. However, chemotherapy-induced cardiotoxicity is a serious side effect secondary to cardiac damage caused by antineoplastic's direct and indirect toxicity. Currently, there are no reliable and approved methods for preventing or treating chemotherapy-induced cardiotoxicity. Understanding the mechanisms of chemotherapy-induced cardiotoxicity may be vital to improving survival. The independent risk factors for developing cardiotoxicity must be considered to prevent myocardial damage without decreasing the therapeutic efficacy of cancer treatment. This systematic review aimed to identify and analyze the evidence on chemotherapy-induced cardiotoxicity, associated risk factors, and methods to decrease or prevent it. We conducted a comprehensive search on PubMed, Google Scholar, and Directory of Open Access Journals (DOAJ) using the following keywords: "doxorubicin cardiotoxicity", "anthracycline cardiotoxicity", "chemotherapy", "digoxin decrease cardiotoxicity", "ATG7 activators", retrieving 59 articles fulfilling the inclusion criteria. Therapeutic schemes can be changed by choosing prolonged infusion application over boluses. In addition, some agents like Dexrazoxane can reduce chemotherapy-induced cardiotoxicity in high-risk groups. Recent research found that Digoxin, ATG7 activators, Resveratrol, and other medical substances or herbal compounds have a comparable effect on Dexrazoxane in anthracycline-induced cardiotoxicity.

The role of Aedes aegypti in inducing/aggravating IgE-mediated allergic airway disease: extensive computational studies for identification of allergenic proteins.

Respiratory allergies have become a major public health concern and affect one-third of the world's population. Several factors like environmental changes, industrialization, and immunologic interactions are reported to contribute to allergic respiratory diseases. Immunological reactions because of mosquito bite (allergic proteins) have been reported to have a high contribution to IgE-mediated allergic airway disease but they are largely ignored. In this study, we aim to predict the potential allergens (proteins) from Aedes aegypti that might play a role in the reactions of IgE-mediated allergic airway diseases. The allergens are identified from an extensive literature search and the 3D structures were prepared using the SwissDock server. Computational studies were performed to identify the potential allergens that might be responsible for IgE-mediated allergies. Our docking and molecular dynamics (MD) simulation results suggest that ADE-3, an allergen from Aedes aegypti, has the highest docking score and is predicted to be responsible for IgE-mediated allergic reaction(s). Overall, this study highlights the importance of immunoinformatics, and the obtained information can be used for designing prophylactic peptide vaccine candidates and inhibitors for controlling IgE-mediated inflammations.Communicated by Ramaswamy H. Sarma.

In vitro and in silico evaluations of actinomycin X2and actinomycin D as potent anti-tuberculosis agents.

Background: Multidrug-resistant tuberculosis (MDR-TB) is one of the world's most devastating contagious diseases and is caused by the MDR-Mycobacterium tuberculosis (MDR-Mtb) bacteria. It is therefore essential to identify novel anti-TB drug candidates and target proteins to treat MDR-TB. Here, in vitro and in silico studies were used to investigate the anti-TB potential of two newly sourced actinomycins, actinomycin-X2 (act-X2) and actinomycin-D (act-D), from the Streptomyces smyrnaeus strain UKAQ_23 (isolated from the Jubail industrial city of Saudi Arabia). Methods: The anti-TB activity of the isolated actinomycins was assessed in vitro using the Mtb H37Ra, Mycobacterium bovis (BCG), and Mtb H37Rv bacterial strains, using the Microplate Alamar Blue Assay (MABA) method. In silico molecular docking studies were conducted using sixteen anti-TB drug target proteins using the AutoDock Vina 1.1.2 tool. The molecular dynamics (MD) simulations for both actinomycins were then performed with the most suitable target proteins, using the GROningen MAchine For Chemical Simulations (GROMACS) simulation software (GROMACS 2020.4), with the Chemistry at HARvard Macromolecular Mechanics 36m (CHARMM36m) forcefield for proteins and the CHARMM General Force Field (CGenFF) for ligands. Results: In vitro results for the Mtb H37Ra, BCG, and Mtb H37Rv strains showed that act-X2 had minimum inhibitory concentration (MIC) values of 1.56 ± 0.0, 1.56 ± 0.0, and 2.64 ± 0.07 µg/mL and act-D had MIC values of 1.56 ± 0.0, 1.56 ± 0.0, and 1.80 ± 0.24 µg/mL respectively. The in silico molecular docking results showed that protein kinase PknB was the preferred target for both actinomycins, while KasA and pantothenate synthetase were the least preferred targets for act-X2and act-D respectively. The molecular dynamics (MD) results demonstrated that act-X2 and act-D remained stable inside the binding region of PknB throughout the simulation period. The MM/GBSA (Molecular Mechanics/Generalized Born Surface Area) binding energy calculations showed that act-X2 was more potent than act-D. Conclusion: In conclusion, our results suggest that both actinomycins X2 and D are highly potent anti-TB drug candidates. We show that act-X2is better able to antagonistically interact with the protein kinase PknB target than act-D, and thus has more potential as a new anti-TB drug candidate.

Non-alcoholic fatty liver disease: relation to juvenile obesity, lipid profile, and hepatic enzymes.

The prevalence of juvenile obesity is increasing, reaching epidemic proportions, presenting a link not only to NAFLD (non-alcoholic fatty liver disease) but to abnormal lipid profiles and liver enzyme abnormalities. Liver ultrasonography is a sensitive and specific tool for the recognition of NAFLD. This study aims to assess the association between NAFLD and juvenile obesity and to determine the other related changes in a set of indicators, including lipid profile abnormalities and serum transaminases. The sample included 470 obese and 210 non-obese individuals aged 6-16. Anthropometric measures were assessed, with the serum lipid profile and liver transaminases, and abdominal ultrasonography was used to detect NAFLD. Fatty liver was found in 38% of the obese subjects and none of the non-obese subjects. Within obese subjects, mean body mass index (BMI) and waist circumference increased significantly in patients with NAFLD compared to those without fatty liver. Moreover, LDL (low-density lipoprotein), CHOL (cholesterol), and serum liver enzymes were significantly higher in the presence of NAFLD. In conclusion, NAFLD commonly associates with juvenile obesity, relating to obesity and the abnormal lipid profile (including elevated CHOL and LDL) among obese people, reflecting elevated liver transaminases, which increase the risk of cirrhosis.

Development and Evaluation of Novel Encapsulated Isoeugenol-Liposomal Gel Carrier System for Methicillin-Resistant Staphylococcus aureus.

In recent years, methicillin-resistant Staphylococcus aureus (MRSA) bacteria have seriously threatened the health and safety of the world's population. This challenge demands the development of alternative therapies based on plant origin. This molecular docking study ascertained the orientation and intermolecular interactions of isoeugenol within penicillin-binding protein 2a. In this present work, isoeugenol as an anti-MRSA therapy was selected by encapsulating it into a liposomal carrier system. After encapsulation into the liposomal carrier, it was evaluated for encapsulation efficiency (%), particle size, zeta potential, and morphology. The percentage entrapment efficiency (% EE) was observed to be 57.8 ± 2.89% with a particle size of 143.31 ± 7.165 nm, a zeta potential of (-)25 mV, and morphology was found to be spherical and smooth. After this evaluation, it was incorporated into a 0.5% Carbopol gel for a smooth and uniform distribution on the skin. Notably, the isoeugenol-liposomal gel was smooth on the surface with a pH of 6.4, suitable viscosity, and spreadability. Interestingly, the developed isoeugenol-liposomal gel was safe for human use, with more than 80% cell viability. The in vitro drug release study shows promising results with 75.95 ± 3.79% of drug release after 24 h. The minimum inhibitory concentration (MIC) was 8.236 µg/mL. Based on this, it can be concluded that encapsulating isoeugenol into the liposomal gel is a potential carrier for MRSA treatment.

The Enhanced Affinity of WRKY Reinforces Drought Tolerance in Solanum lycopersicum L.: An Innovative Bioinformatics Study.

In the scenario of global climate change, understanding how plants respond to drought is critical for developing future crops that face restricted water resources. This present study focuses on the role of WRKY transcription factors on drought tolerance in tomato, Solanum lycopersicum L., which is a significant vegetable crop. WRKY transcription factors are a group of proteins that regulate a wild range of growth and developmental processes in plants such as seed germination and dormancy and the stress response. These transcription factors are defined by the presence of a DNA-binding domain, namely, the WRKY domain. It is well-known that WRKY transcription factors can interact with a variety of proteins and therefore control downstream activities. It aims to simulate the effect of curcumin, a bioactive compound with regulatory capacity, on the protein-protein interaction events by WRKY transcription factors with an emphasis on drought stress. It was found that curcumin binds to WRKY with an energy of -11.43 kcal/mol with inhibitory concentration (Ki) 0.12 mM and has the potential to improve fruit quality and reinforce drought tolerance of S. lycopersicum, according to the results based on bioinformatics tools. The root means square deviation (RMSD) of the C-α, the backbone of 2AYD with ligand coupled complex, displayed a very stable structure with just a little variation of 1.89 Å. MD simulation trajectory of Cα atoms of 2AYD bound to Curcumin revealed more un-ordered orientation in PC1 and PC10 modes and more toward negative correlation from the initial 400 frames during PCA. Establishing the binding energies of the ligand-target interaction is essential in order to characterize the compound's binding affinity to the drought transcription factor. We think we have identified a phyto-agent called curcumin that has the potential to enhance the drought tolerance. Compared to the part of the mismatch repair-base technique that can be used to fix drought related genes, curcumin performed better in a drop-in crop yield over time, and it was suggested that curcumin is a potential candidate factor for improving drought tolerance in tomatoes, and it needs future validation by experiments in laboratory and field.

Formulation, In Vitro and In Silico Evaluations of Anise (Pimpinella anisum L.) Essential Oil Emulgel with Improved Antimicrobial Effects.

Over the past decade, researchers have made several efforts to develop gel-based formulations that provide an alternative to traditional hydrogels and emulgel. Due to its excellent antibacterial properties, anise, the main constituent of Pimpinella anisum L., widely used in pharmaceuticals, was selected as the active ingredient in this study. Since many bacteria have developed considerable antibiotic resistance, this research aimed to develop an herbal emulgel for treating skin infections caused by bacteria. Given these obstacles, we developed and evaluated a new, cost-effective topical emulgel solution containing anise essential oil against Escherichia coli (E. coli). Anise-based emulgels, potential drug delivery platforms, have been evaluated for various parameters, including physical properties, viscosity, pH, rheology, encapsulation efficiency, and in vitro release research. The AEOs emulgel demonstrated remarkable colloidal stability, with a zeta potential of 29 mV, a size of 149.05 nm, and considerable polydispersity. The efficacy of anise-loaded emulgels as antibacterial formulations was evaluated in vitro. E. coli was used as a model microbial organism for the antibacterial study. Human keratinocytes (HaCaT) were used to examine the biocompatibility of the emulgel. Molecular docking revealed that the essential oil components of Pimpinella anisum L. possess a high affinity for the bacterial adhesin protein FimH of E. coli. These findings indicate that the developed AEOs have the potential to be analyzed using E. coli as a model organism.

Dynamic and thermodynamic impact of L94A, W100A, and W100L mutations on the D2 dopamine receptor bound to risperidone.

DRD2 is an important receptor in the mediation of antipsychotic drugs but also in Parkinson medication, hyperprolactinemia, nausea and vomiting. Recently, crystallographic studies of the DRD2-risperidone complex have provided important information about risperidone recognition in wild-type and different stabilizing DRD2-risperidone residues. Using the crystallographic structure of the DRD2-risperidone complex as a starting point, we undertook molecular dynamics (MD) simulations to investigate the structural and thermodynamic basis of molecular recognition by risperidone at the ligand-binding sites of wild-type and mutant DRD2. A solvated phospholipid bilayer was used to construct DRD2-risperidone complexes, which were then subjected to several microsecond (µs) MD simulations in order to obtain realistic receptor-ligand conformations under the equilibrated simulation time. Risperidone had a higher affinity for wild-type and L94A mutant DRD2 than the W100L and W100A mutants, according to binding free energy calculations using the Molecular Mechanics Generalized-Born Surface Area (MMGBSA) method, explaining the experimental differences in ligand residence times. Principal component (PC) analysis revealed important conformational mobility upon molecular recognition of risperidone for the L94A mutant compared to the wild type, indicating an unfavorable entropic component that may contribute to improving risperidone affinity in the L94A DRD2 mutant.

Synthesis, DFT Analyses, Antiproliferative Activity, and Molecular Docking Studies of Curcumin Analogues.

With 19.3 million new cases and almost 10 million deaths in 2020, cancer has become a leading cause of death today. Curcumin and its analogues were found to have promising anticancer activity. Inspired by curcumin's promising anticancer activity, we prepared three semi-synthetic analogues by chemically modifying the diketone function of curcumin to its pyrazole counterpart. The curcumin analogues (3a−c) were synthesized by two different methods, followed by their DFT analyses to study the HOMO/LUMO configuration to access the stability of compounds (∆E = 3.55 to 3.35 eV). The curcumin analogues (3a−c) were tested for antiproliferative activity against a total of five dozen cancer cell lines in a single (10 µM) and five dose (0.001 to 100 µM) assays. 3,5-Bis(4-hydroxy-3-methoxystyryl)-1H-pyrazole-1-yl-(phenoxy)ethanone (3b) and 3,5-bis(4-hydroxy-3-methoxystyryl)-1H-pyrazole-1-yl-(2,4-dichlorophenoxy)ethanone (3c) demonstrated the most promising antiproliferative activity against the cancer cell lines with growth inhibitions of 92.41% and 87.28%, respectively, in a high single dose of 10 µM and exhibited good antiproliferative activity (%GIs > 68%) against 54 out of 56 cancer cell lines and 54 out of 60 cell lines, respectively. The compound 3b and 3c demonstrated the most potent antiproliferative activity in a 5-dose assay with GI50 values ranging between 0.281 and 5.59 µM and 0.39 and 0.196 and 3.07 µM, respectively. The compound 3b demonstrated moderate selectivity against a leukemia panel with a selectivity ratio of 4.59. The HOMO-LUMO energy-gap (∆E) of the compounds in the order of 3a > 3b > 3c, was found to be in harmony with the anticancer activity in the order of 3c ≥ 3b > 3a. Following that, all of the curcumin analogues were molecular docked against EGFR, one of the most appealing targets for antiproliferative activity. In a molecular docking simulation, the ligand 3b exhibited three different types of interactions: H-bond, π-π-stacking and π-cationic. The ligand 3b displayed three H-bonds with the residues Met793 (with methoxy group), Lys875 (with phenolic group) and Asp855 (with methoxy group). The π-π-stacking interaction was observed between the phenyl (of phenoxy) and the residue Phe997, while π-cationic interaction was displayed between the phenyl (of curcumin) and the residue Arg841. Similarly, the ligand 3c displayed five H-bonds with the residue Met793 (with methoxy and phenolic groups), Lys845 (methoxy group), Cys797 (phenoxy oxygen), and Asp855 (phenolic group), as well as a halogen bond with residue Cys797 (chloro group). Furthermore, all the compound 3a−c demonstrated significant binding affinity (−6.003 to −7.957 kcal/mol) against the active site of EGFR. The curcumin analogues described in the current work might offer beneficial therapeutic intervention for the treatment and prevention of cancer. Future anticancer drug discovery programs can be expedited by further modifying these analogues to create new compounds with powerful anticancer potentials.

The Structural, Biological, and In-Silico Profiling of Novel Capryloyl Tetra-Glucoside and Aliphatic Ester Constituents from the Abutilon indicum Offers New Perspectives on the Treatment of Pain and Inflammation.

Abutilon indicum L. (Malvaceae), more often referred to as Peeli booti, Kanghi, and Kakhi, is a perennial shrub found in many countries of Asia. Traditionally, this plant is used as a diuretic to treat inflammation, discomfort, urethral infections, and gout. Inflammation and pain are key topics of interest for researchers throughout the globe, since they are linked to almost every illness that could affect humans or animals. The present study was conducted to isolate the phytoconstituents from the methanolic extract of Abutilon indicum collected from the Bihar state Koshi river belt in India, and to evaluate the isolated phytoconstituents' ability to reduce nociception and inflammation. Furthermore, molecular docking was performed to investigate the molecular interaction profile, with possible therapeutic targets for anti-inflammatory medicines. A. indicum methanolic extract yielded two novel phytocompounds identified as 5'-hydroxyhexyl n-hexadecanoate (AB-01) and n-octanoyl-ß-D-glucopyranosyl-(2'-1'')-ß-D-glucopyranosyl-(2''-1''')-ß-D-glucopyranosyl-(2'''-1'''')-ß-D-glucopyranoside (AB-05), together with three previously recognized phytocompounds such as ester glucoside. All isolated molecules were tested for the efficacy of analgesic and anti-inflammatory characteristics at doses of 5 and 10 mg/kg body weight. The isolated compound's molecular interaction profile with anti-inflammatory drug targets cyclooxygenase-2 and tumor necrosis factor-alpha possessed high potential energy in molecular docking. These findings may aid in developing anti-inflammatory and analgesic drugs from A. indicum.

Microsecond MD Simulations to Explore the Structural and Energetic Differences between the Human RXRα-PPARγ vs. RXRα-PPARγ-DNA.

The heterodimeric complex between retinoic X receptor alpha (RXRα) and peroxisome proliferator-activated receptor gamma (PPARγ) is one of the most important and predominant regulatory systems, controlling lipid metabolism by binding to specific DNA promoter regions. X-ray and molecular dynamics (MD) simulations have revealed the average conformation adopted by the RXRα-PPARγ heterodimer bound to DNA, providing information about how multiple domains communicate to regulate receptor properties. However, knowledge of the energetic basis of the protein-ligand and protein-protein interactions is still lacking. Here we explore the structural and energetic mechanism of RXRα-PPARγ heterodimer bound or unbound to DNA and forming complex with co-crystallized ligands (rosiglitazone and 9-cis-retinoic acid) through microsecond MD simulations, molecular mechanics generalized Born surface area binding free energy calculations, principal component analysis, the free energy landscape, and correlated motion analysis. Our results suggest that DNA binding alters correlated motions and conformational mobility within RXRα-PPARγ system that impact the dimerization and the binding affinity on both receptors. Intradomain correlated motions denotes a stronger correlation map for RXRα-PPARγ-DNA than RXRα-PPARγ, involving residues at the ligand binding site. In addition, our results also corroborated the greater role of PPARγ in regulation of the free and bound DNA state.

An Insight into the Structural Requirements and Pharmacophore Identification of Carbonic Anhydrase Inhibitors to Combat Oxidative Stress at High Altitudes: An In-Silico Approach.

Carbonic anhydrases (CA) inhibitory action could be linked to the treatment of a number of ailments, including cancer, osteoporosis, glaucoma, and several neurological problems. For the development of effective CA inhibitors, a variety of heterocyclic rings have been investigated. Furthermore, at high altitudes, oxygen pressure drops, resulting in the formation of reactive oxygen and nitrogen species, and CA inhibitors having role in combating this oxidative stress. Acetazolamide contains thiadiazole ring, which has aroused researchers' interest because of its CA inhibitory action. In the present study, we used a number of drug design tools, such as pharmacophore modeling, 3D QSAR, docking, and virtual screening on twenty-seven 1,3,4-thiadiazole derivatives that have been described as potential CA inhibitors in the literature. An atom-based 3D-QSAR analysis was carried out to determine the contribution of individual atoms to model generation, while a pharmacophore mapping investigation was carried out to find the common unique pharmacophoric properties required for biological activity. The coefficient of determination for both the training and test sets were statistically significant in the generated model. The best QSAR model was chosen based on the values of R2 (0.8757) and Q2 (0.7888). A molecular docking study was also conducted against the most potent analogue 4m, which has the highest SP docking score (-5.217) (PDB ID: 6g3v). The virtual screening revealed a number of promising compounds. The screened compound ZINC77699643 interacted with the amino acid residues, Pro201 and Thr199, in the virtual screening study (PDB ID: 6g3v). These interactions demonstrated the significance of the CA inhibitory activity of the compound. Furthermore, ADME study revealed useful information regarding compound's drug-like properties. Therefore, the findings of the present investigation could aid in the development of more potent CA inhibitors, which could benefit the treatment of oxidative stress at high altitudes.

Toward the Discovery of a Novel Class of Leads for High Altitude Disorders by Virtual Screening and Molecular Dynamics Approaches Targeting Carbonic Anhydrase.

For decades, carbonic anhydrase (CA) inhibitors, most notably the acetazolamide-bearing 1,3,4-thiadiazole moiety, have been exploited at high altitudes to alleviate acute mountain sickness, a syndrome of symptomatic sensitivity to the altitude characterized by nausea, lethargy, headache, anorexia, and inadequate sleep. Therefore, inhibition of CA may be a promising therapeutic strategy for high-altitude disorders. In this study, co-crystallized inhibitors with 1,3,4-thiadiazole, 1,3-benzothiazole, and 1,2,5-oxadiazole scaffolds were employed for pharmacophore-based virtual screening of the ZINC database, followed by molecular docking and molecular dynamics simulation studies against CA to find possible ligands that may emerge as promising inhibitors. Compared to the co-crystal ligands of PDB-1YDB, 6BCC, and 6IC2, ZINC12336992, ZINC24751284, and ZINC58324738 had the highest docking scores of -9.0, -9.0, and -8.9 kcal/mol, respectively. A molecular dynamics (MD) simulation analysis of 100 ns was conducted to verify the interactions of the top-scoring molecules with CA. The system's backbone revealed minor fluctuations, indicating that the CA-ligand complex was stable during the simulation period. Simulated trajectories were used for the MM-GBSA analysis, showing free binding energies of -16.00 ± 0.19, -21.04 ± 0.17, and -19.70 ± 0.18 kcal/mol, respectively. In addition, study of the frontier molecular orbitals of these compounds by DFT-based optimization at the level of B3LYP and the 6-311G(d,p) basis set showed negative values of the HOMO and LUMO, indicating that the ligands are energetically stable, which is essential for forming a stable ligand-protein complex. These molecules may prove to be a promising therapy for high-altitude disorders, necessitating further investigations.