Molecular Operating Environment Research Articles

Assessment of Nucleobase Protomeric and Tautomeric States in Nucleic Acid Structures for Interaction Analysis and Structure-Based Ligand Design.

With increasing interest in RNA as a therapeutic and a potential target, the role of RNA structures has become more important. Even slight changes in nucleobases, such as modifications or protomeric and tautomeric states, can have a large impact on RNA structure and function, while local environments in turn affect protonation and tautomerization. In this work, the application of empirical tools for pKa and tautomer prediction for RNA modifications was elucidated and compared with ab initio quantum mechanics (QM) methods and expanded toward macromolecular RNA structures, where QM is no longer feasible. In this regard, the Protonate3D functionality within the molecular operating environment (MOE) was expanded for nucleobase protomer and tautomer predictions and applied to reported examples of altered protonation states depending on the local environment. Overall, observations of nonstandard protomers and tautomers were well reproduced, including structural C+G:C(A) and A+GG motifs, several mismatches, and protonation of adenosine or cytidine as the general acid in nucleolytic ribozymes. Special cases, such as cobalt hexamine-soaked complexes or the deprotonation of guanosine as the general base in nucleolytic ribozymes, proved to be challenging. The collected set of examples shall serve as a starting point for the development of further RNA protonation prediction tools, while the presented Protonate3D implementation already delivers reasonable protonation predictions for RNA and DNA macromolecules. For cases where higher accuracy is needed, like following catalytic pathways of ribozymes, incorporation of QM-based methods can build upon the Protonate3D-generated starting structures. Likewise, this protonation prediction can be used for structure-based RNA-ligand design approaches.

A New Insight Into Toxicity of Database Compounds from Ginger (Zingiber officinale) by Modelling Study

Dengue haemorrhagic fever (DHF) is an infectious disease caused by the dengue virus. The dengue virus is transmitted through female mosquitoes, especially Aedes aegypti and Aedes albopictus. Indonesia is a dengue endemic country, and almost all provinces in Indonesia are infected with dengue. However, targeted antiviral drugs against dengue virus (DENV) are not yet available. This study aimed to determine the potential of three compounds isolated from ginger (Zingiber officinale) as dengue NS2B/NS3 inhibitors, and to predict the physicochemical properties (drug-likeness) and potential toxicity of drug candidates. Ginger isolates in the form of [8]-gingerol, [6]-paradol, shogaol were obtained from the Natural Discovery Database (NADI). Toxicity and drug-likeness predictions were performed using ProTox-II and SwissADME, and Molecular Operating Environment (MOE) 2022.0901 was used for the molecular docking process. Results: The results showed that the ginger compound (Zingiber officinale), [8]-Gingerol, [6]-Paradol, and Shogaol, had binding free energy of -7.18, -7.10 and -6.88 kcal/mol, respectively. It is indicated that three compounds had potentiality to inhibit the NS2B/NS3 protein complex with a binding free energy that was almost equivalent to that of the positive control, panduratin A, and similar to that of the positive control, which can be seen in superimposition. In addition, three compounds isolated from ginger met the drug-likeness parameters. Based on the analysis of in silico toxicity studies, the three compounds isolated from ginger showed different levels of toxicity. Therefore, based on the safety level of oral use, the [8]-gingerol compound is safer to develop as a dengue antiviral drug, where the LD50 value of [8]-gingerol is 2.580 mg/kg with a class V toxicity level that is practically nontoxic.

Exploring active ingredients and mechanisms of Coptidis Rhizoma-ginger against colon cancer using network pharmacology and molecular docking.

Colon cancer is the most prevalent and rapidly increasing malignancy globally. It has been suggested that some of the ingredients in the herb pair of Coptidis Rhizoma and ginger (Zingiber officinale), a traditional Chinese medicine, have potential anti-colon cancer properties. This study aimed to investigate the molecular mechanisms underlying the effects of the Coptidis Rhizoma-ginger herb pair in treating colon cancer, using an integrated approach combining network pharmacology and molecular docking. The ingredients of the herb pair Coptidis Rhizoma-ginger, along with their corresponding protein targets, were obtained from the Traditional Chinese Medicine System Pharmacology and Swiss Target Prediction databases. Target genes associated with colon cancer were retrieved from the GeneCards and OMIM databases. Then, the protein targets of the active ingredients in the herb pair were identified, and the disease-related overlapping targets were determined using the Venn online tool. The protein-protein interaction (PPI) network was constructed using STRING database and analyzed using Cytoscape 3.9.1 to identify key targets. Then, a compound-target-disease-pathway network map was constructed. The intersecting target genes were subjected to Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses for colon cancer treatment. Molecular docking was performed using the Molecular Operating Environment (MOE) software to predict the binding affinity between the key targets and active compounds. Besides 1922 disease-related targets, 630 targets associated with 20 potential active compounds of the herb pair Coptidis Rhizoma-ginger were collected. Of these, 229 intersection targets were obtained. Forty key targets, including STAT3, Akt1, SRC, and HSP90AA1, were further analyzed using the ClueGO plugin in Cytoscape. These targets are involved in biological processes such as miRNA-mediated gene silencing, phosphatidylinositol 3-kinase (PI3K) signaling, and telomerase activity. KEGG enrichment analysis showed that PI3K-Akt and hypoxia-inducible factor 1 (HIF-1) signaling pathways were closely related to colon cancer prevention by the herb pair Coptidis Rhizoma-ginger. Ten genes (Akt1, TP53, STAT3, SRC, HSP90AA1, JAK2, CASP3, PTGS2, BCl2, and ESR1) were identified as key genes for validation through molecular docking simulation. This study demonstrated that the herb pair Coptidis Rhizoma-ginger exerted preventive effects against colon cancer by targeting multiple genes, utilizing various active compounds, and modulating multiple pathways. These findings might provide the basis for further investigations into the molecular mechanisms underlying the therapeutic effects of Coptidis Rhizoma-ginger in colon cancer treatment, potentially leading to the development of novel drugs for combating this disease.

Biological evaluation of levofloxacin and its thionated derivatives: antioxidant activity, aldehyde dehydrogenase enzyme inhibition, and cytotoxicity on A549 cell line.

Levofloxacin (LVX) is among the fluoroquinolones antibiotics that has also been studied in vitro and in vivo for its anticancer effects. In this study, we used LVX and novel LVX thionated derivatives; compounds 2 and 3, to evaluate their antioxidant activity, aldehyde dehydrogenase (ALDH) enzymes activity inhibition, and anticancer activity. Combination treatments with doxorubicin (DOX) were investigated as well. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay was used to determine the antioxidant activity. The NADH fluorescence spectrophotometric activity assay was used to determine the ALDH inhibitory effects. Resazurin dye method was applied for cell viability assays. Molecular Operating Environment software was used for the molecular docking experiments. Compared to ascorbic acid, DPPH assay showed that compound 3 had the highest antioxidant activity among the tested compounds with approximately 35% scavenging activity. On ALDH enzymes, compound 3 showed a significant ALDH activity inhibition compared to compound 2 at 200 µM. The IC50 values for the tested compounds were approximately 100 µM on A549 cell line, a non-small cell lung cancer (NSCLC) cell line. However, significant enhancement of cytotoxicity and reduction of IC50 values were observed by combining DOX and synergism was achieved with LVX with a combination index value of 0.4. The molecular docking test showed a minimum binding energy with a good affinity for compound 3 towards ALDH enzymes. Thionated LVX derivatives, may be repurposed for NSCLC therapy in combination with DOX, taking into account the antioxidant activity, ALDH activity inhibition, and the molecular docking results of compound 3.

Powerful Approach for New Drugs as Antibacterial Agents via Molecular Docking and In Vitro Studies of Some New Cyclic Imides and Quinazoline-2,5-diones.

We generated novel elven 1,2,3,6-tetrahydrophthalimides and tetrahydroquinazoline derivatives from 1,2,3,6-tetrahydrophthalic anhydride (1) in response to our interest in using the anhydrides to produce heterocyclic nitrogen compounds. The elemental and spectral analyses of the produced compounds validated the recommended configurations and MOE 2014.09 (Molecular Operating Environment) computations were used to perform their in silico analysis. The synthesized compounds have been analyzed and put through various experiments, including in vitro and in silico methods to assess their biological activity against Escherichia coli Penicillin-Binding Protein 3 (PBP3) and Staphylococcus aureus Penicillin-Binding Protein 2 (PBP2), among these compounds showing promising data as antibacterial drugs.

Cytotoxic Activity of Cambodian Leaves Extract (Plumeria acuminate) on Breast Cancer Cells and COX-2 Targeted Prediction of Its Chemical Contents

Cambodian leaves are suspected to contain stigma sterol which may target Cyclo-Oxygenase-2 (COX-2) or Estrogen Receptor (ER) to contribute to its cytotoxic activity on breast cancer cells. This study aimed to determine the potential of Cambodian leaf compounds and extracts as chemopreventive agents for luminal breast cancer with a molecular target of COX-2. Ethanol was used to extract the active compound of Cambodian leaves. The study on chemical activity against COX-2 employed molecular docking with Molecular Operating Environment (MOE) and the cytotoxic property of Cambodian leaf extract (CLE) on T47D was determined using the trypan blue exclusion method. The extraction yielded as 4.87% w/w CLE. Thin layer chromatography showed that Cambodian leaves contain sterol. Molecular docking confirmed that several sterol compounds have greater affinity to COX-2 than native ligands indicating that they are potent as COX-2 inhibitors. They are Stigmast-7-en-3-ol, Lupeol Acetate, and Lupeol carboxylic acid with docking scores of -14.3874, -13.8098, and -14.1045 kcal/mol respectively. The CLE exhibited cytotoxic activity on T47D cells with an IC50 value of 18 μg/mL. Therefore, CLE has a potential effect as a chemopreventive agent for breast cancer and potentially as a COX-2 inhibitor.Keywords: Cambodian leaf extract, breast cancer, COX-2 inhibitor, chemopreventive.

Network pharmacology analysis and experimental validation to explore the mechanism of kaempferol in the treatment of osteoporosis

Osteoporosis (OP) is a prevalent global disease characterized by bone mass loss and microstructural destruction, resulting in increased bone fragility and fracture susceptibility. Our study aims to investigate the potential of kaempferol in preventing and treating OP through a combination of network pharmacology and molecular experiments. Kaempferol and OP-related targets were retrieved from the public database. A protein–protein interaction (PPI) network of common targets was constructed using the STRING database and visualized with Cytoscape 3.9.1 software. Enrichment analyses for GO and KEGG of potential therapeutic targets were conducted using the Hiplot platform. Molecular docking was performed using Molecular operating environment (MOE) software, and cell experiments were conducted to validate the mechanism of kaempferol in treating OP. Network pharmacology analysis identified 54 overlapping targets between kaempferol and OP, with 10 core targets identified. The primarily enriched pathways included atherosclerosis-related signaling pathways, the AGE/RAGE signaling pathway, and the TNF signaling pathway. Molecular docking results indicated stable binding of kaempferol and two target proteins, AKT1 and MMP9. In vitro cell experiments demonstrated significant upregulation of AKT1 expression in MC3T3-E1 cells (p < 0.001) with kaempferol treatment, along with downregulation of MMP9 expression (p < 0.05) compared to the control group. This study predicted the core targets and pathways of kaempferol in OP treatment using network pharmacology, and validated these findings through in vitro experiments, suggesting a promising avenue for future clinical treatment of OP.

A novel SIK2 inhibitor SIC-19 exhibits synthetic lethality with PARP inhibitors in ovarian cancer

PurposeOvarian cancer patients with HR proficiency (HRP) have had limited benefits from PARP inhibitor treatment, highlighting the need for improved therapeutic strategies. In this study, we developed a novel SIK2 inhibitor, SIC-19, and investigated its potential to enhance the sensitivity and expand the clinical utility of PARP inhibitors in ovarian cancer. MethodsThe SIK2 protein was modeled using a Molecular Operating Environment (MOE), and the most favorable model was selected based on a GBVI/WSA dG scoring function. The Chembridge Compound Library was screened, and the top 20 candidate compounds were tested for their interaction with SIK2 and downstream substrates, AKT-pS473 and MYLK-pS343. SIC-19 emerged as the most promising drug candidate and was further evaluated using multiple assays. ResultsSIC-19 exhibited selective and potent inhibition of SIK2, leading to its degradation through the ubiquitination pathway. The IC50 of SIC-19 correlated inversely with endogenous SIK2 expression in ovarian cancer cell lines. Treatment with SIC-19 significantly inhibited cancer cell growth and sensitized cells to PARP inhibitors in vitro, as well as in ovarian cancer organoids and xenograft models. Mechanistically, SIK2 knockdown and SIC-19 treatment reduced RAD50 phosphorylation at Ser635, prevented nuclear translocation of RAD50, disrupted nuclear filament assembly, and impaired DNA homologous recombination repair, ultimately inducing apoptosis. These findings highlight the crucial role of SIK2 in the DNA HR repair pathway and demonstrate the significant PARP inhibitor sensitization achieved by SIC-19 in ovarian cancer. ConclusionsSIC-19, a novel SIK2 inhibitor, effectively inhibits tumor cell growth in ovarian cancer by interfering with RAD50-mediated DNA HR repair. Furthermore, SIC-19 enhances the efficacy of PARP inhibitors, providing a promising therapeutic strategy to improve outcomes for ovarian cancer patients.

Molecular Dynamics of Outer Membrane-Embedded Polysaccharide Secretion Porins Reveals Closed Resting-State Surface Gates Targetable by Virtual Fragment Screening for Drug Hotspot Identification.

Recent advances in iterative neural network analyses (e.g., AlphaFold2 and RoseTTA fold) have been revolutionary for protein 3D structure prediction, especially for difficult-to-manipulate α-helical/β-barrel integral membrane proteins. These model structures are calculated based on the coevolution of amino acids within the protein of interest and similarities to existing protein structures; the local effects of the membrane on folding and stability of the calculated model structures are not considered. We recently reported the discovery, 3D modeling, and characterization of 18-β-stranded outer-membrane (OM) WzpX, WzpS, and WzpB β-barrel secretion porins for the exopolysaccharide (EPS), major spore coat polysaccharide (MASC), and biosurfactant polysaccharide (BPS) pathways (respectively) in the Gram-negative social predatory bacterium Myxococcus xanthus DZ2. However, information was not obtained regarding the dynamic behavior of surface-gating WzpX/S/B loop domains or on potential treatments to inactivate these porins. Herein, we developed a molecular dynamics (MD) protocol to study the core stability and loop dynamism of neural network-based integral membrane protein structure models embedded in an asymmetric OM bilayer, using the M. xanthus WzpX, WzpS, and WzpB proteins as test candidates. This was accomplished through integration of the CHARMM-graphical user interface (GUI) and Molecular Operating Environment (MOE) workflows to allow for a rapid simulation system setup and facilitate data analysis. In addition to serving as a method of model structure validation, our molecular dynamics simulations revealed a minimal movement of extracellular WzpX/S/B loops in the absence of an external stimulus as well as druggable cavities between the loops. Virtual screening of a commercial fragment library against these cavities revealed putative fragment-binding hotspots on the cell-surface face of each β-barrel, along with key interacting residues, and identified promising hits for the design of potential binders capable of plugging the β-barrels and inhibiting polysaccharide secretion.

A novel isatin Schiff based cerium complex: synthesis, characterization, antimicrobial activity and molecular docking studies

In this work, a novel isatin-Schiff base L2 had been synthesized through a simple reaction between isatin and 2-amino-5-methylthio-1,3,4-thiadiazole. The produced Schiff base L2 was then subjected to a hydrothermal reaction with cerium chloride to produce the cerium (III)-Schiff base complex C2. Several spectroscopic methods, including mass spectra, FT-IR, elemental analysis, UV–vis, 13C-NMR, 1H-NMR, Thermogravimetric Analysis, HR-TEM, and FE-SEM/EDX, were used to completely characterize the produced L2 and C2. A computer simulation was performed using the MOE software program to find out the probable biological resistance of studied compounds against the proteins in some types of bacteria or fungi. To investigate the interaction between the ligand and its complex, we conducted molecular docking simulations using the molecular operating environment (MOE). The docking simulation findings revealed that the complex displayed greater efficacy and demonstrated a stronger affinity for Avr2 effector protein from the fungal plant pathogen Fusarium oxysporum (code 5OD4) than the original ligand. The antibacterial activity of the ligand and its Ce3+ complex were applied in vitro tests against different microorganism. The study showed that the complex was found to be more effective than the ligand.

In Silico Investigation of Novel Compounds as Inhibitors of Acetylcholinesterase Enzyme for the Treatment of Alzheimer's Diseases.

Alzheimer's disease (AD) is a "progressive, neurodegenerative disease that occurs when nerve cells in the brain die." There are only 4 drugs approved by the United States Food and Drug Administration (FDA). Three (donepezil, rivastigmine, and galantamine) out of these four drugs are anticholinesterase inhibitors, while the fourth one memantine is an N-methyl-D-aspartate (NMDA) receptor inhibitor. Currently, two immunotherapy drugs that target amyloid protein (donanemab and lecanemab) are being considered for the treatment of Alzheimer's disease at an early stage. All these drug molecules are still not the complete answer to the treatment of Alzheimer's disease. A recent report from the Office of National Statistics showed that AD is the leading cause of death in 2022. Therefore, there is an urgency to develop more drugs that can treat AD. Based on this urgency, we aim to investigate how bioactive and already approved drugs could be repurposed for inhibiting the anticholinesterase enzyme using computational studies. To achieve this, the data science tool-Python coding was compiled on Jupyter Notebook to mine bioactive compounds from the ChEMBL database. The most bioactive compounds obtained were further investigated using Molecular Operating Environment (MOE) software to carry out molecular docking and ligand analysis, and this was followed by molecular dynamics simulation production at 35 ns using GROMACS 2022.4 on Archer 2 machine. The molecular dynamic analysis was carried out using HeroMDanalysis software. Data mining of the ChEMBL database was carried out for lipase inhibitors, and this gave CHEMBL-ID 1240685, a peptide molecule, the most active compound at the time of data mining. Further literature studies gave Zoladex an FDA-approved drug for the treatment of breast cancer as another compound of interest. The in silico studies were carried out against the anticholinesterase enzyme using two FDA-approved drugs donepezil and galantamine as a template for comparing the in silico activities of the repurposed drugs. A very useful receptor for this study was PDB-1DX6, a cocrystallized galantamine inhibitor of acetylcholinesterase enzyme. The molecular docking analysis (using ligand interactions) and molecular dynamic analysis (root mean square deviation (RMSD) and root mean square fluctuation (RMSF)) showed that the two peptide molecules CHEMBL-1240685 and Zoladex gave the best binding energy and stability when compared to the FDA-approved drugs (donepezil and galantamine). Finally, further literature studies revealed that Zoladex affects memory reduction; therefore, it was dropped as a possible repurposed drug. Our research showed that CHEMBL-1240685 is a potential compound that could be investigated for the inhibition of anticholinesterase enzyme and might be another drug molecule that could be used to treat Alzheimer's disease.

Synthesis and antimicrobial activity of thiophene-based heterocycles derived from thiophene-2-carbohydrazide.

Aim: Thiophene-based heterocycles were synthesized and evaluated for their antimicrobial activity against methicillin-resistant Staphylococcus aureus, Escherichia coli, Clostridium difficile and Candida albicans strains. Methods: Antimicrobial activity was determined using the broth microdilution method. Results: Spiro-indoline-oxadiazole 17 displayed the highest activity against C. difficile while having no effects against other bacterial strains. Compounds 8 and 16 displayed strong effects against TolC, an outer membrane protein, mutant E. coli. The results of computational chemical study and outcomes of experiments were in good agreement. A molecular docking study was conducted using a molecular operating environment to simulate the binding energies of the potent compounds with D-alanine ligase protein. Conclusion: This study suggests that spiro-indoline-oxadiazole 17 could be a good anticlostridial agent.

Synthesis and Biological Evaluation of 2-Azolylmethylene-3-(2H)-benzofuranone Derivatives as Potent Monoamine Oxidases Inhibitors.

A series of 2-azolylmethylene-3-(2H)-benzofuranone derivatives, 2-indolylmethylene-3-(2H)-benzofuranone and 2-pyrrolylmethylene-3-(2H)-benzofuranone derivatives, were synthesized, and their monoamine oxidase (MAO) A and B inhibitory activities were evaluated. Compounds 1b, 3b, 6b, 7b, and 10b showed strong inhibitory activity against MAO-A, and compound 3b showed the highest potency and selectivity, with an IC50 value of 21 nM and a MAO-A selectivity index of 48. Compounds 3c, 4c, 9a, 9c, 10c, 11a, and 11c showed strong inhibitory activity against MAO-B, and compound 4c showed the highest potency and selectivity, with an IC50 value of 16 nM and a MAO-B selectivity index of >1100. Further analysis of these compounds indicated that compound 3b for MAO-A and compound 4c for MAO-B were competitive inhibitors, with Ki values of 10 and 6.1 nM, respectively. Furthermore, computational analyses, such as quantitative structure-activity relationship (QSAR) analysis of the 2-azolylmethylene-3-(2H)-benzofuranone derivatives conducting their pIC50 values with the Molecular Operating Environment (MOE) and Mordred, and molecular docking analysis using MOE-Dock supported that the 2-azolylmethylene-3-(2H)-benzofuranone derivatives are a privileged scaffold for the design and development of novel MAO inhibitors.

Synthesis, Corrosion Inhibition Efficiency in Acidic Media, and Quantum Chemical Studies of Some Hydrazine Derivatives

In this work, four hydrazone Schiff base derivatives N-(2,4-Dinitro-phenyl)-N’-(1H-pyrrol-2-ylmethylene)-hydrazine (1a), N-Benzo [1,3] dioxol-5-ylmethylene-N’-(2,4-dinitro-phenyl)-hydrazine (1b), (E)-5-((2-(2,4-dinitrophenyl)hydrazono)methyl)-2-hydroxybenzoic acid (1c) and (E)-1-(2,4-dinitrophenyl)-2-(2-methoxybenzylidene)hydrazine (1d) were synthesized by reaction of four aldehydes namely pyrrole-2-carboxaldehyde, piperonal, 5-formylsalicylic acid, and o-vanillin with 2,4-dinitrophenyl hydrazine to produce the final compounds 1a, 1b, 1c, and 1d, respectively. These four compounds were investigated as corrosion inhibitors in aqueous mild acidic static solution. FTIR, HNMR, and elemental analysis were used to elucidate the chemical structure of the synthesized inhibitors. Using potential dynamic polarization measurements, these inhibitors’ efficiency in preventing C-steel corrosion in 1.00 M HCl was studied. The results of the experiments revealed that 1×10−3 M is the ideal concentration for 1a, 1b, 1c, and 1d, and that the corresponding inhibition efficiencies for these subunits were 80.70%, 91.30%, 91.34, and 88.80%, respectively. The best corrosion inhibitors were compounds 1b and 1c. Furthermore, studies suggested that these substances are mixed-type inhibitors and that the efficiency of the inhibition is strongly correlated with their quantity. Quantum paraments included Dipole moment, energy band gap (ΔE), value of energy of lowermost unoccupied molecular orbital (ELUMO), and energy of high most occupied molecular orbital (EHOMO) using Molecular Operating Environment MOE, Gaussian, and HyperChem software packages were determined which demonstrated strong agreement between algorithmic and practical findings.

Chemical profile and radical scavenging of the Psidium guajava flower’s essential oil: Molecular docking study on the human cytochrome P450 CYP2C9

Psidium guajava L. plant is frequently utilized as therapeutic plant due to its nutritional benefits and bioactive metabolites. The current study intends to identify the chemical characterization and antioxidant activity of essential oil (EO) of freshly harvested P. guajava flowers. The EO was analyzed using GC with flame-ionization detection (FID), gas chromatography-mass spectrometry (GC-MS) along with chemometric analysis. With 98.87% of overall oil mass, 37 volatile constituents were assigned. All identified compounds were categorized into two classes including mono-(30.34%) and sesquiterpenes (68.53%). The d-limonene (26.10%), trans-β-caryophyllene (17.24%), trans-nerolidol (11.01%), and ledol (5.12%) served as predominant compounds. Using three separate methods, DPPH, ABTS, and reducing power, the free radical scavenging activity of P. guajava flower oil was assessed in comparison with ascorbic acid as a reference antioxidant. The net results revealed that EO has considerable activities with respective IC50 values of 224.53, 125.78, and 231.78 mg L−1. All main compounds (> 3.00%) were in silico studied by Molecular Operating Environment (MOE) software on human cytochrome P450 CYP2C9. The net findings showed that the tested compounds have good binding affinity ranging from ΔG at −4.43 to −5.65 kcal/mol, while ascorbic acid exhibits binding affinity with ΔG = −4.58 kcal/mol. Cubenol revealed the best binding affinity with ΔG = −5.65 kcal/ mol. The present findings verified the guava flower EO’s powerful functions. For a better knowledge of the action pathways both in vitro and in vivo, more scientific studies on this oil’s antioxidant and/or its main components in pure form were advised.

Homology Modeling of Alpha-Glucosidase from Candida albicans: Sequence Analysis and Structural Validation Studies in silico

The alpha-glucosidase enzyme of Candida albicans plays a vital role in the pathogenesis of candidiasis, a serious fatal disease in immune-compromised patients. The unavailability of the threedimensional crystallographic structure of this enzyme creates a hindrance in developing novel and potent inhibitors. Here, an attempt has been made to design a stable three-dimensional conformer of alpha-glucosidase through in silico analysis which may be helpful for the designing of effective drugs. For this purpose, the oligo-1-6-glucosidase enzyme is used as a template for homology modeling of the alpha-glucosidase structure by Molecular Operating Environment 2011-12 software. The generated model was validated through ERRAT and Ramachandran tools, whereas its stability was studied through the molecular dynamics simulation technique. The obtained results indicate that model of alpha-glucosidase has stable secondary and tertiary arrangements. This finding may spur new directions for the rational designing and development of new antifungal inhibitors. Nevertheless, additional experimental investigations and validation are needed to confirm the in silico results of this study.

An In Silico Investigation of the Molecular Interactions between Volatile Anesthetics and Actin.

Volatile anesthetics (VAs) are medicinal chemistry compounds commonly used to enable surgical procedures for patients who undergo painful treatments and can be partially or fully sedated, remaining in an unconscious state during the operation. The specific molecular mechanism of anesthesia is still an open issue, but scientific evidence supports the hypothesis of the involvement of both putative hydrophobic cavities in membrane receptors as binding pockets and interactions between anesthetics and cytoplasmic proteins. Previous studies demonstrated the binding of VAs to tubulin. Since actin is the other major component of the cytoskeleton, this study involves an investigation of its interactions with four major anesthetics: halothane, isoflurane, sevoflurane, and desflurane. Molecular docking was implemented using the Molecular Operating Environment (MOE) software (version 2022.02) and applied to a G-actin monomer, extrapolating the relative binding affinities and root-mean-square deviation (RMSD) values. A comparison with the F-actin was also made to assess if the generally accepted idea about the enhanced F-to-G-actin transformation during anesthesia is warranted. Overall, our results confirm the solvent-like behavior of anesthetics, as evidenced by Van der Waals interactions as well as the relevant hydrogen bonds formed in the case of isoflurane and sevoflurane. Also, a comparison of the interactions of anesthetics with tubulin was made. Finally, the short- and long-term effects of anesthetics are discussed for their possible impact on the occurrence of mental disorders.

Computational exploration of allosteric inhibitors targeting CDK4/CDK6 proteins: a promising approach for multi-target drug development

Cyclin-dependent kinases (CDKs) play a pivotal role in orchestrating the intricate regulation of the cell cycle, a fundamental process governing cell growth and division. In particular, CDK4 and CDK6 are critical for the transition from the G1 phase to the S phase, where Deoxyribonucleic acid (DNA) replication occurs, and their dysregulation is linked to various diseases, notably cancer. While ATP-binding site inhibitors for CDKs are well-documented, this study focuses on uncovering allosteric inhibitors, providing a fresh perspective on CDK inhibition. Computational techniques were employed in this investigation, utilizing Molecular Operating Environment (MOE) for virtual screening of a drug-like compound library. Moreover, the stability of the most promising binding inhibitors was assessed through Molecular Dynamics (MD) simulations and MMPBSA/MMGBSA analyses. The outcome reveals that three inhibitors (C1, C2, and C3) exhibited the strongest binding affinity for CDK4/CDK6, as corroborated by docking and simulation analyses. The computed binding energies ranged from −6.1 to −7.6 kcal/mol, underscoring the potency of these allosteric inhibitors. Notably, this study identifies key residues (PHE31, HIS95, HIS100, VAL101, ASP102, ASP104, and THR107) that play pivotal roles in mediating inhibitor binding within the allosteric sites. Among the findings, the C1–CDK4 complex and C2–CDK6 complex emerge as particularly promising inhibitors, exhibiting high binding energies, favorable interaction patterns, and sustained presence within the active site. This study contributes significantly to the pursuit of multi-target drugs against CDK4/CDK6 proteins, with potential implications for the development of innovative therapies across various disorders, including cancer and other cell cycle-related conditions. Communicated by Ramaswamy H. Sarma

Oleic acid and linoleic acid nanosomes boost immunity and provoke cell death via the upregulation of beta-defensin-4 at genetic and epigenetic levels

Abstract Host defense peptides (HDPs) are encouraged as anticancer and antimicrobial agents. Thus, this study aimed to investigate the effect of oleic acid (OA)- and linoleic acid (LA)-loaded nanosomes on the gene expression of beta-defensin-4 (BD-4) as a member of HDPs. The OA and LA nanosomes were prepared and characterized in terms of particle size and surface charge as lymphatic delivery systems. Afterwards, the effect of fatty acid (FA)-loaded nanosomes on BD-4 gene expression in mice dermal cells was investigated using polymerase chain reaction at 6, 12, and 24 h intervals. The epigenetic effect of OA and LA on histone deacetylase-6 (HDAC6) was studied using the molecular operating environment (MOE) docking. Moreover, the cytotoxic effect of free and FA-loaded nanosomes was investigated using 375 cell lines. The present results indicated that the prepared OA and LA nanosomes have a nanosize range (258–275 nm), negative zeta potential (−26 to −32 mV), and are homogenous polydispersity index (0.200–0.400). Moreover, free, and FA-loaded nanosomes induced significant upregulation of BD-4 mRNA expression after 6 and 12 h compared to the control mice BD-4 gene expression by several folds. However, after 24 h, the BD-4 mRNA expression significantly decreased compared to 12 h. Molecular docking studies revealed that OA and LA inhibit HDAC6 by binding with the active site. Treating the melanoma cell line with free or OL- and LA-loaded nanosomes induced significant cell death compared to negative control. This study suggests new insight into the effect of OA and LA on HDPs production. Consequently, the consumption of oils enriched with OL and LA stimulates the host immune system to fight microbial invasion and cancer. Moreover, Nanosomes are suggested as influential tactics for the specific lymphatic delivery of cytotoxic medicines.

Hydrodynamic Control of Alzheimer Aβ Fibrillation with Glucosaminic Acid Containing Click-Cyclized β-Bodies.

It is well established that the dynamic hydration shell plays a vital role in macromolecular functions such as protein-ligand, protein-protein, protein-DNA, and protein-lipid interactions. Here we investigate how the water modality affects conformational changes, solubility, and motion of fibrillar proteins. The hypothesis is that the introduction of a poly hydroxyl amino acid would increase solvation of the fibril forming peptides, preventing their misfolding and aggregation. For the amyloid β (Aβ) peptide, which is considered to be connected with nervous system diseases, including dementia and cognitive decline in Alzheimer's disease, the formation of β-sheet fibrils always occurs with a conformational change and a decrease in the dynamic hydration shell around Aβ(1-42). We present novel cyclic d-amino acid peptides that effectively inhibit fibrillation through affecting the dynamic hydration shell of Aβ(1-42) in vitro. Using de novo design within the software Molecular Operating Environment (MOE), five different peptides that recognize Alzheimer's fibrils were designed and synthesized. Three of them were cyclic all-d-amino acid peptides incorporating the same polyhydroxy building block derived from d-glucosaminic acid (GA). One peptide was the parent cyclic all d-amino acid inhibitor with no GA incorporated, and another was an all l-amino acid linear fibrillation inhibitor. The GA-containing peptides were found to show significantly improved inhibition of Aβ(1-42) aggregation. The inhibition was dramatically improved by the synergistic application of two GA peptides targeting each end of the growing fibril. The present study may facilitate future developments of intervention strategies for Alzheimer's disease and similar neurodegenerative diseases.