Binding Affinity Research Articles

Synthesis and Evaluation of 68Ga- and 177Lu-Labeled [Pro14]bombesin(8-14) Derivatives for Detection and Radioligand Therapy of Gastrin-Releasing Peptide Receptor-Expressing Cancer.

The gastrin-releasing peptide receptor (GRPR) is overexpressed in a variety of cancers and represents a promising target for diagnosis and therapy. However, the extremely high accumulation in the pancreas observed for most of the clinically evaluated GRPR-targeted radiopharmaceuticals could limit their applications. In this study, we synthesized one GRPR antagonist (ProBOMB5) and two GRPR agonists (LW02056 and LW02057) by replacing the 4-thiazolidinecarboxylic acid (Thz14) residue in our previously reported GRPR-targeted tracers with Pro14. The 68Ga and 177Lu labeling were conducted in HEPES (2 M, pH 5.0) buffer and acetate (0.1 M, pH 4.5) buffer, respectively, and the radiolabeled products were obtained in a 24-57% decay-corrected radiochemical yield and >92% radiochemical purity. The binding affinities (Ki) of Ga-ProBOMB5, Ga-LW02056, Ga-LW02057, and Lu-ProBOMB5 were measured via in vitro competition binding assays and were 12.2 ± 1.89, 14.7 ± 4.81, 13.8 ± 2.24, and 13.6 ± 0.25 nM, respectively. The PET imaging and ex vivo biodistribution studies were conducted in PC-3 tumor-bearing mice at 1 h post injection. [68Ga]Ga-ProBOMB5, [68Ga]Ga-LW02056, and [68Ga]Ga-LW02057 enabled clear tumor visualization in PET images. The tumor uptake values of [68Ga]Ga-ProBOMB5, [68Ga]Ga-LW02056, and [68Ga]Ga-LW02057 were 12.4 ± 1.35, 8.93 ± 1.96, and 7.64 ± 0.55%ID/g, respectively, and their average pancreas uptake values were minimal (0.60-1.37%ID/g). Longitudinal SPECT imaging and ex vivo biodistribution studies were also conducted for [177Lu]Lu-ProBOMB5 and clinically validated [177Lu]Lu-RM2. Despite comparable tumor uptake at 1 h post injection ([177Lu]Lu-ProBOMB5:8.09 ± 1.70%ID/g; [177Lu]Lu-RM2:7.73 ± 0.96%ID/g), a faster clearance from PC-3 tumor xenografts was observed for [177Lu]Lu-ProBOMB5, leading to a lower radiation-absorbed dose delivered to tumors. Our data demonstrate that [68Ga]Ga-ProBOMB5 is a promising tracer for clinical translation for detecting GRPR-expressing tumor lesions. However, further optimizations are needed for [177Lu]Lu-ProBOMB5 to prolong tumor retention for therapeutic applications.

Essential Oils from the Leaves and Stem Barks of Pluchea Indica (L.) Less.: Chemical Analysis, Cytotoxicity, Anti-inflammation, Antimicrobial Activity, Molecular Docking, and ADMET Profiling.

Pluchea indica (L.) Less. is a medicinal plant native to Asia. Traditionally, it is known for numerous traditional uses, such as treatments for fever, cough, and digestive issues. The present investigation aims to determine the chemical compositions of essential oils from its fresh leaves and stem barks. By using hydro-distillation and the GC-FID/MS (gas chromatography-flame ionization detection/mass spectrometry) analysis, the studied samples were dominated by sesquiterpene hydrocarbons (76.8-82.2 %) and their oxygenated derivatives (8.4-19.0 %). β-Selinene (42.0-43.5 %) and silphinene (21.1-22.9 %) were the main compounds. Significantly, the stem bark essential oil strongly monitored the growth of four cancer cell lines K562, HeLa, HepG2, and MCF-7 with IC50 values of 2.89-7.34 μg/mL. Both studied samples showed strong anti-inflammatory activity against NO (nitric oxide) production with IC50 values of 21.81-23.18 μg/mL. The studied sample also exhibited antimicrobial activity at different levels. The molecular docking study revealed that β-selinene exhibited the strongest binding affinity for all four cancer-related protein targets: epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), Abelson tyrosine-protein kinase 1 (ABL1), and phosphatidylinositol 3-kinase (PI3 K-α). The ADMET profiles of the major compounds were also predicted to provide insights for further research considerations.

Investigating the role of keratin proteins and microbial associations in hereditary and pathogenic alopecia.

The purpose of this research was to identify the role of keratin proteins in causing inherited as well as pathogenic alopecia, pinpoint deleterious SNPs, and predict structural changes affecting protein-protein interactions in hair disorders. To elucidate the role of keratin proteins and genetic mutations in alopecia by analyzing protein structures through bioinformatics and identifying a mutation in the LPAR6 gene. It sought to identify the microorganisms linked to alopecia and conducted a comprehensive bioinformatics analysis of proteins with unknown experimental structures and molecular simulation analysis. The study identified a genetic mutation (c.188A > T, p.Asp63Val) in the LPAR6 gene associated with hereditary hair loss. Pathogenic alopecia was identified to be associated with S. aureus and two ic keratinophilic fungi namely M. canis, and T. violaceum. Additionally, among 14 proteins lacking prior structural information, four proteins namely Keratin, type II cuticular Hb3 (KR1), Keratin, type II cuticular Hb6 (KR2), Keratin, type II cytoskeletal 74 (KR3) and Keratin, type II cuticular Hb1 (KR4) exhibited common 'K-head' and 'F' domains. Docking analysis revealed five distinct binding sites (C1-C5) for each protein. The 'K-head' displayed the highest predicted binding affinities with Vina scores of -5.6 for KR2 and - 4.7 for KR4 whereas the 'F' domain showed Vina scores of -6.0 for KR3 and - 5.7 for KR2. This research underscores the crucial role of keratin proteins in both hereditary and pathogenic alopecia, emphasizing their significance for future investigations.

Pangenome analysis of five representative Tropheryma whipplei strains following multiepitope-based vaccine design via immunoinformatic approaches.

Whipple disease caused by Tropheryma whipplei a gram-positive bacterium is a systemic disorder that impacts not only the gastrointestinal tract but also the vascular system, joints, central nervous system, and cardiovascular system. Due to the lack of an approved vaccine, this study aimed to utilize immunoinformatic approaches to design multiepitope -based vaccine by utilizing the proteomes of five representative T. whipplei strains. The genomes initially comprised a total of 4,844 proteins ranging from 956 to 1012 proteins per strain. We collected 829 nonredundant lists of core proteins, that were shared among all the strains. Following subtractive proteomics, one extracellular protein, WP_033800108.1, a WhiB family transcriptional regulator, was selected for the chimeric-based multiepitope vaccine. Five immunodominant epitopes were retrieved from the WhiB family transcriptional regulator protein, indicating MHC-I and MHC-II with a global population coverage of 70.61%. The strong binding affinity, high solubility, nontoxicity, nonallergenic properties and high antigenicity scores make the selected epitopes more appropriate. Integration of the epitopes into a chimeric vaccine was carried out by applying appropriate adjuvant molecules and linkers, leading to the vaccine construct having enhanced immunogenicity and successfully eliciting both innate and adaptive immune responses. Moreover, the abilityof the vaccine to bind TLR4, a core innate immune receptor, was confirmed. Molecular dynamics simulations have also revealed the promising potential stability of the designed vaccine at 400 ns. In summary, we have designed a potential vaccine construct that has the ability not only to induce targeted immunogenicity for one strain but also for global T. whipplei strains. This study proposes a potential universal vaccine, reducing Whipple's disease risk and laying the groundwork for future research on multi-strain pathogens.

Graph masked self-distillation learning for prediction of mutation impact on protein–protein interactions

Assessing mutation impact on the binding affinity change (ΔΔG) of protein–protein interactions (PPIs) plays a crucial role in unraveling structural-functional intricacies of proteins and developing innovative protein designs. In this study, we present a deep learning framework, PIANO, for improved prediction of ΔΔG in PPIs. The PIANO framework leverages a graph masked self-distillation scheme for protein structural geometric representation pre-training, which effectively captures the structural context representations surrounding mutation sites, and makes predictions using a multi-branch network consisting of multiple encoders for amino acids, atoms, and protein sequences. Extensive experiments demonstrated its superior prediction performance and the capability of pre-trained encoder in capturing meaningful representations. Compared to previous methods, PIANO can be widely applied on both holo complex structures and apo monomer structures. Moreover, we illustrated the practical applicability of PIANO in highlighting pathogenic mutations and crucial proteins, and distinguishing de novo mutations in disease cases and controls in PPI systems. Overall, PIANO offers a powerful deep learning tool, which may provide valuable insights into the study of drug design, therapeutic intervention, and protein engineering.

Deciphering the 4',7-Dihydroxy-3'-Methylflavone from Boerhavia, Agonist/Antagonist Interactions Against 5-HT2 Receptors using Homology Modeling, Molecular Docking, and Dynamic Simulation Studies.

Seizures, depression, and anxiety are neurological disorders that affected innumerable people worldwide. Recent research has revealed that targeting 5-hydroxytryptamine 2 (5-HT2) receptors can help suppress these conditions. An in-depth literature study has identified that phytocompounds from the Boerhavia genus could reduce seizures. Therefore, homology models of 5-HT2 receptors were generated and validated using techniques such as the alignment of amino acid sequences and the Ramachandran plot. Later, a comparison of modeled structures was made with a non-redundant set of PDB structures. The pharmacokinetics, drug-likeness, blood-brain barrier (BBB) permeability, and Lipinski's rule of five shed light on 22 phytocompounds, which are the potential candidates for molecular docking among 127 Boerhavia's bioactive. Notably, molecular docking analysis revealed 4',7-dihydroxy-3'-methylflavone as the most potent lead compound, which has a strong binding affinity to all modeled receptors. Additionally, with a remarkably high docking score of -9.1 kcal/mol, 4',7-dihydroxy-3'-methylflavone showed promising interactions, particularly with 5-HT2A receptor, as seen from the RMSD, SASA, Rg, and number of hydrogen bonds during 100 ns molecular dynamic (MD) simulation. Principal component analysis (PCA) and Molecular Mechanics-Poisson-Boltzmann Surface Area (MM-PBSA) further confirmed that 4',7-dihydroxy-3'-methylflavone is the best novel phytocompound in Boerhavia genus for 5-HT2 receptor as agonist/antagonist activity against seizures.

Structural and free energy landscape analysis for the discovery of antiviral compounds targeting the cap-binding domain of influenza polymerase PB2

Influenza poses a significant threat to global health, with the ability to cause severe epidemics and pandemics. The polymerase basic protein 2 (PB2) of the influenza virus plays a crucial role in the viral replication process, making the CAP-binding domain of PB2 an attractive target for antiviral drug development. This study aimed to identify and evaluate potential inhibitors of the influenza polymerase PB2 CAP-binding domain using computational drug discovery methods. We employed a comprehensive computational approach involving virtual screening, molecular docking, and 500 ns molecular dynamics (MD) simulations. Compounds were selected from the Diverse lib database and assessed for their binding affinity and stability in interaction with the PB2 CAP-binding domain. The study utilized the generalized amber force field (GAFF) for MD simulations to further evaluate the dynamic behaviour and stability of the interactions. Among the screened compounds, compounds 1, 3, and 4 showed promising binding affinities. Compound 4 demonstrated the highest binding stability and the most favourable free energy profile, indicating strong and consistent interaction with the target domain. Compound 3 displayed moderate stability with dynamic conformational changes, while Compound 1 maintained robust interactions throughout the simulations. Comparative analyses of these compounds against a control compound highlighted their potential efficacy. Compound 4 emerged as the most promising inhibitor, with substantial stability and strong binding affinity to the PB2 CAP-binding domain. These findings suggest that compound 4, along with compounds 1 and 3, holds the potential for further development into effective antiviral agents against influenza. Future studies should focus on experimental validation of these compounds and exploration of resistance mechanisms to enhance their therapeutic utility.

Dual Antimicrobial Activity of HTCC and Its Nanoparticles: A Synergistic Approach for Antibacterial and Antiviral Applications Through Combined In Silico and In Vitro Studies

N-(2-hydroxyl) propyl-3-trimethyl ammonium chitosan chloride (HTCC), a quaternized chitosan derivative, has been shown to exhibit a broad spectrum of antimicrobial activity, especially against bacteria and enveloped viruses. Despite this, molecular docking studies showing its atomic-level mechanisms against these microorganisms are scarce. Here, for the first time, we employed molecular docking analyses to investigate the potential antibacterial activity of HTCC against Staphylococcus aureus and its antiviral activity against human immunodeficiency virus 1 (HIV-1). According to the findings, HTCC exhibited promising antibacterial activity with high binding affinities; however, it had limited antiviral activity. To validate these theoretical outcomes, experimental studies were conducted. Different derivatives of HTCC were synthesized and characterized using NMR, XRD, FTIR, and DLS. The in vitro assays validated the potent antibacterial efficacy of HTCC against S. aureus, whereas the antiviral studies did not show good antiviral activity. However, our research also revealed a promising avenue for further exploration of the antimicrobial activity of HTCC nanoparticles (NPs), since, thus far, no studies have been conducted to show the antiviral activity of HTCC NPs against HIV-1. The nanosized HTCC exhibited superior antiviral performance compared to the parent polymers, with complete (100%) inhibition of HIV-1 viral activity at the highest tested concentration (0.33 mg/mL).

Insights into the Therapeutic Potential of Active Ingredients of Citri Reticulatae Pericarpium in Combatting Sarcopenia: An In Silico Approach

Sarcopenia is a systemic medical disorder characterized by a gradual decline in muscular strength, function, and skeletal muscle mass. Currently, there is no medication specifically approved for the treatment of this condition. Therefore, the identification of new pharmacological targets may offer opportunities for the development of novel therapeutic strategies. The current in silico study investigated the active ingredients and the mode of action of Citri Reticulatae Pericarpium (CRP) in addressing sarcopenia. The active ingredients of CRP and the potential targets of CRP and sarcopenia were determined using various databases. The STRING platform was utilized to construct a protein–protein interaction network, and the key intersecting targets were enriched through the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses. Molecular docking was used to determine the binding interactions of the active ingredients with the hub targets. The binding affinities obtained from molecular docking were subsequently validated through molecular dynamics simulation analyses. Five active ingredients and 45 key intersecting targets between CRP and sarcopenia were identified. AKT1, IL6, TP53, MMP9, ESR1, NFKB1, MTOR, IGF1R, ALB, and NFE2L2 were identified as the hub targets with the highest degree node in the protein–protein interaction network. The results indicated that the targets were mainly enriched in PIK3-AKT, HIF-1, and longevity-regulating pathways. The active ingredients showed a greater interaction affinity with the hub targets, as indicated by the results of molecular docking and molecular dynamics simulations. Our findings suggest that the active ingredients of Citri Reticulatae Pericarpium, particularly Sitosterol and Hesperetin, have the potential to improve sarcopenia by interacting with AKT1 and MTOR proteins through the PI3K-AKT signaling pathway.

A Network Pharmacology Study on Mechanism of Total Flavonoids of Hippophae Rhamnoides in Treating Allergic Dermatitis via Regulation of IL-17 Signaling Pathways

Objective: This study aims to investigate the active ingredients and potential mechanisms of Total Flavonoids of Hippophae (TFH) in the treatment of Allergic Dermatitis (AD) using network pharmacology and molecular docking. Methods: The effective components and targets of TFH were identified using the TCMSP, Pub- Chem, and Pharmmapper databases. AD-related targets were screened through GeneCards, OMIM, and TTD databases, leading to the identification of TFH anti-AD related targets. The STRING database was utilized to obtain protein interaction relationships, and Cytoscape 3.9.0 software was employed to construct the protein-protein interaction network. GO and KEGG enrichment analyses were conducted to elucidate the biological processes and pathways involved. Molecular docking between key components and key targets was verified using AutoDock Tools 1.5.6 software. Results: The key components identified for anti-AD activity were Quercetin, Kaempferol, Cianidanol, and Epicatechin, while the key targets included MAPK8, MAPK10, MAPK14, AKT1, SRC, and EGFR. GO analysis indicated that TFH's anti-AD effects are primarily associated with hormone regulation, cellular processes, response to stimuli, organelles, and cytoplasm. KEGG enrichment analysis suggested that the key pathways involved are pathways in cancer, lipid and atherosclerosis, and the IL-17 signaling pathway, with a significant emphasis on the IL-17 signaling pathway. Molecular docking results demonstrated that the key active ingredients exhibited strong binding activity with all the key targets, with the highest binding affinities observed between kaempferol and MAPK14, epicatechin and MAPK14, and quercetin and AKT1. Conclusion: TFH exerts therapeutic effects on atopic dermatitis through multi-component, multitarget, and multi-pathway mechanisms involving inflammatory response, immune regulation, and apoptosis. This study provides valuable insights for the further development of drugs specifically targeting AD.

Structure-based identification of small-molecule inhibitors that target the DIII domain of the Dengue virus glycoprotein E pan-serotypically.

Dengue viral infection is caused by the Dengue virus, which spreads to humans through the bite of infected mosquitos. Dengue affects over half of the global population, with an estimated 500 million infections per year. Despite this, no effective treatment is currently available, however, several promising candidates are undergoing pre-clinical/clinical testing. The existence of four major serotypes is an important challenge in the development of drugs and vaccines to combat Dengue virus infection. Hence, the drug/vaccine thereby developed should neutralize all the four serotypes equally. However, there is no pan-serotype specific treatment for Dengue virus, thereby emphasizing the need for the identification of novel drug-like compounds that can target all serotypes of the Dengue virus equally. To this end, we employed virtual screening methodologies to find drug-like compounds that target the domain III of glycoprotein E. Most importantly, domain III of E protein is involved in viral fusion with the host membrane and is also targeted by neutralizing antibodies. Our study found two small molecule drug-like compounds (out of the 3 million compounds screened) having similar binding affinity with all four serotypes. The compounds thereby identified exhibit favourable drug like properties and can be developed as a treatment for Dengue virus.

Design and development of dual targeting CAR protein for the development of CAR T-cell therapy against KRAS mutated pancreatic ductal adenocarcinoma using computational approaches

Mutant KRAS promotes the proliferation, metastasis, and aggressiveness of various cancers including pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), and colorectal adenocarcinoma (CRC) respectively. Mutant KRAS therapeutics are limited, while Sotorasib and Adagrasib were the only FDA-approved drugs for the treatment of KRASG12C mutated NSCLC. Chimeric antigen receptor (CAR) T-cell therapy has been emerged as an effective strategy against hematological malignancies and being extended towards solid cancers including PDAC. mesothelin (MSLN) and Carcinoembryonic Antigen (CEA) were reported to be highly overexpressed in KRAS-mutated PDAC. Meanwhile, in clinical trials, several CAR T-cell therapy studies are mainly focused towards these two cancer antigens in PDAC, however, the dual targeting of these two neoantigens is not reported. In the present study, we have designed and developed a novel dual-targeting CAR protein by employing various bioinformatics approaches such as functional analysis (antigenicity, allergenicity, antigen binding sites & signalling cascades), qualitative analysis (physicochemical, prediction, refinement & validation of 2D and 3D structures), molecular docking, and in silico cloning. Our results revealed that the designed CAR protein specifically binds with both MSLN & CEA with significant binding affinities, and was predicted to be stable & non-allergenic. Additionally, the protein–protein interaction network reveals the T-cell mediated antitumor responses of each domain in the designed CAR. Conclusively, we have designed and developed a dual targeting (MSLN & CEA) CAR protein towards KRAS-mutated PDAC using computational approaches. Alongside, we further recommend to engineer this designed CAR in T-cells and evaluating their therapeutic efficiency in in vitro and in vivo studies in the near future.

Chemical composition, antioxidant, and enzyme inhibition activities of Crithmum maritimum essential oils: the first chemo-biological study for species grown in North Africa

Crithmum maritimum (sea fennel), is a halophytic plant species found globally in coastal environments. This study is the first investigation into the chemical composition and biological activities of C. maritimum growing wildly in Jebel Akhdar, Libya. Gas Chromatography-Mass Spectrometry (GC-MS) analysis was utilized to identify and profile the plant’s volatile components; it resulted in the identification of twenty-four components, representing 99.17% of the total peaks in the GC-MS chromatogram. The analysis revealed that thymyl methyl ether, γ-terpinene, and ledene oxide, were the major volatile constituents of the plant at relative percentage levels of 56.86, 16.17, and 4.32%, respectively. The analysis also indicated substantial variations in the volatile composition of C. maritimum Libyan species compared to those from various geographic regions. The plant’s volatile oil quality was evaluated by investigating its in vitro antioxidant activity and the oil’s ability to inhibit acetylcholinesterase (AChE) and tyrosinase enzymes. The oil markedly scavenged the free radicals and reduced the ferric ions in the DPPH and FRAP assays at levels of 34.30 ± 0.10 and 38.90 ± 0.51 Trolox equivalents, respectively. The plant’s volatile oil has substantially reduced the AChE at the IC50 value of 34.43 ± 0.25 compared to its effect against tyrosinase (IC50 12.449 ± 0.68). The in silico approach was used to highlight the mechanisms underlying the enzyme inhibitory effect of the plant volatile oil. The stigmastene and γ-santonin demonstrate stronger binding affinity towards AChE and tyrosinase compared to the co-crystalized controls, donepezil and tropolone. The study provides significant information for the environmental changes effect on the volatile constituents of C. maritimum and highlights the plant’s importance within the scope of its antioxidant and enzyme inhibition activities.

Evaluation of Antimicrobial, Antitumor, Antioxidant Activities, and Molecular Docking Studies of Some Co(II), Cu(II), Mn(II), Ni(II), Pd(II), and Pt(II) Complexes With a Schiff Base Derived From 2‐Chloro‐5‐(trifluoromethyl)aniline

ABSTRACTThe antimicrobial, antitumor and antioxidant potential of Co(II), Cu(II), Mn(II), Ni(II), Pd(II), and Pt(II) complexes with 2‐(((2‐chloro‐5‐(trifluoromethyl)phenyl)imino)methyl)phenol HL ligand was investigated. A molecular docking study was carried out to estimate the predicted binding affinity of the compounds to protein targets involved in proliferative and bacterial activities. Fluorescence quenching studies and synchronous spectra were used to examine the metal complexes interactions with CT‐DNA and BSA protein. The DNA binding study have revealed that the complexes are capable of binding with DNA via intercalative mode. The antimicrobial activity of the ligand and metal complexes was studied against three Gram‐positive bacteria, two Gram‐negative bacteria, and three strains of fungi. The best antibacterial effect was demonstrated by the Pt(II) complex on the Staphylococcus aureus strain, and as for the inhibitory effect on fungi, it was stronger on the Candida albicans strain after treatment with the Co(II) complex. The in vitro antiproliferative activity of ligand and complexes was analyzed using MTT, Annexin V/PI, and cell cycle assays. The in vitro results showed that, except for Pd(II) complex, where slight effects were observed, the MCF‐7 line was resistant to the activity of the complexes. In the case of A549 cells, Cu(II) and Pd(II) complexes showed a dose‐dependent antitumor activity, confirmed by both the Alamar blue and the Annexin V/PI analysis. Finally, the antioxidant activity of the compounds was examined by ABTS and DPPH methods. Antioxidant investigation showed that the Ni(II) complex possesses a remarkable ability to trap the cation of the ABTS+ radical (IC50 value 9.35 μM).

Design, Synthesis, Molecular Docking, Pharmacokinetic Properties, and Molecular Dynamics Simulation of Sulfonyl Derivatives of Benzimidazole against Parkinson's Disease.

The disability and mortality related to Parkinson's disease (PD), a neurodegenerative disease, are increasing globally at a faster rate than other neurological disorders. With no permanent cure for PD, there is an urgent need to develop novel and effective anti-PD drugs. Targeting monoamine oxidases (MAO), which catalyze the breakdown of neurotransmitters, is one way to treat neurodegenerative diseases. In this context, an initial molecular docking of twenty designed sulfonyl derivatives of benzimidazole against monoamine oxidase B (MAO-B) associated with PD was conducted using AutoDock Vina. The results were compared with those of the conventional inhibitors, selegiline and rasagiline. Based on the docking score, the in-silico pharmacokinetic properties (ADME), drug-likeness, and toxicity profiles of the newly synthesized molecules were examined using SwissADME, PreADMET, ProTox-3.0, vNN, and ADMETlab web tools. Then, twelve potential derivatives were synthesized and characterized by IR, 1H-NMR, 13C-NMR, 19F-NMR (for some compounds), and mass spectrometry. Derivatives 2cj and 1bj were the two molecules having the best binding affinity of -11.9 and -11.8 kcal/mol, respectively, against MAOB, exhibiting a higher binding affinity compared to that of some commercially available drugs. A 50 ns MD simulation run was performed to observe the stability of the top two docked complexes, MAO-B-2cj and MAO-B-1bj, in order to further validate the efficacy of those two substances. Moreover, the MM-PBSA method was used to calculate the final, binding free energy of the simulated (MAO-B-2cj) complex. This study indicates that the binding affinity of most of the hits was superior to that of known MAO inhibitors; therefore, these newly synthesized benzimidazole derivatives may be developed into essential drug candidates for the treatment of PD.

In silico Study of Novel Tryptanthrin-Based Topoisomerase Inhibitors

Background: Over the past ten years, a remarkable number of changes have occurred in the field of cancer drug research. Most anticancer drugs from the first generation work by breaking down DNA, preventing its production, interfering with cell division processes, or attaching to microtubules. The potential use of tryptanthrin as well as its analogues is well documented for anticancer properties. Objective: To design a novel hybrid of tryptanthrin analogs with expected anticancer activity. Method: By changing the C-6 carbonyl position of the tryptanthrin molecule, a set of 72 derivatives of substituted-6-benzylidine-6H-indolo[2,1-b] quinazoline-12-one was developed. These ligands were screened in silico using Schrodinger Glide extra precision docking against DNA topoisomerase using doxorubicin and teniposide as references to identify their potential anticancer properties. Further, these ligands were subjected to an in silico ADMET study to identify their drug likeliness. Results: Combined results of molecular docking and in silico ADMET study suggest that out of the total 72 ligands, 6 ligands RC 51, RC 29, RC 42, RC 3, RC 54, and RC 63 were showing very better binding affinity than the natural ligand adenylyl-imidodiphosphate and the two standard reference drugs- doxorubicin and teniposide. Conclusion: Our computational approach was successful in identifying ligands that are potentially potent topoisomerase inhibitors. These can be tested further using in vitro and in vivo analysis.

Chaperone-Derived Copper(I)-Binding Peptide Nanofibers Disrupt Copper Homeostasis in Cancer Cells.

Copper (Cu) is a transition metal that plays crucial roles in cellular metabolism. Cu+ homeostasis is upregulated in many cancers and contributes to tumorigenesis. However, therapeutic strategies to target Cu+ homeostasis in cancer cells are rarely explored because small molecule Cu+ chelators have poor binding affinity in comparison to the intracellular Cu+ chaperones, enzymes, or ligands. To address this challenge, we introduce a Cu+ chaperone-inspired supramolecular approach to disrupt Cu+ homeostasis in cancer cells that induces programmed cell death. The Nap-FFMTCGGCR peptide self-assembles into nanofibers inside cancer cells with high binding affinity and selectivity for Cu+ due to the presence of the unique MT/CGGC motif, which is conserved in intracellular Cu+ chaperones. Nap-FFMTCGGCR exhibits cytotoxicity towards triple negative breast cancer cells (MDA-MB-231), impairs the activity of Cu+ dependent co-chaperone super oxide dismutase1 (SOD1), and induces oxidative stress. In contrast, Nap-FFMTCGGCR has minimal impact on normal HEK 293T cells. Control peptides show that the self-assembly and Cu+ binding must work in synergy to successfully disrupt Cu+ homeostasis. We show that assembly-enhanced affinity for metal ions opens new therapeutic strategies to address disease-relevant metal ion homeostasis.

The leaf essential oils of Meiogyne virgata (Blume) Miq., M. vietnamica Jaikhamseub, T.A.Le & Chaowasku, and Orophea polycarpa A.DC.: Chemical composition, antimicrobial activity, molecular docking, and toxicity profiling

The present study aims to describe the chemical composition of essential oils from three Vietnamese Annonaceae species, Meiogyne virgata, M. vietnamica, and Orophea polycarpa, and their antimicrobial activity. Essential oils were extracted by hydro-distillation. From the GC-FID/MS (gas chromatography-flame ionization detection and mass spectrometry) analysis, the leaf essential oil of M. virgata was reported to contain the major compound germacrene D (42.48%). Spathulenol (24.51%), bicyclogermacrene (18.58%), β-selinene (11.14%), and germacrene D (8.20%) can be seen as the main compound in M. vietnamica leaf essential oil. α-Phellandrene (39.35%), bicyclogermacrene (13.07%), β-phellandrene (10.87%), and limonene (8.27%) represented O. polycarpa leaf essential oil. Essential oil of M. virgata leaves exhibited strong antimicrobial activity against the Gram (+) bacterium Bacillus subtilis ATCC 5230, the Gram (-) bacterium Escherichia coli ATCC 8739, and the fungus Aspergillus niger ATCC 9587 with the same MIC value of 16 μg/mL. The docking method showed that germacrene D has the ΔGbinding (binding affinity) values of –6.68, –5.265, and –5.602 kcal/mol with the proteins E. coli DNA gyrase, B. subtilis TasA, and A. niger PhyA, respectively. Alkyl and pi-alkyl interactions are the main contributors to the binding affinity between the studied proteins and ligands. Furthermore, germacrene D is predicted to have low toxicity and is not active against any of the considered organ targets.

Identification of Phytoconstituents from Natural Product Database as SIRT2 Inhibitors for Potential Role in Alzheimer's Disease: An In-Silico Screening.

We aimed to conduct in silico screening of the potential phytoconstituent from a natural product database to find SIRT2 inhibitors. Alzheimer's disease (AD) is the most prevalent type of dementia, characterized by behavioral and mental symptoms as well as a progressive loss of cognitive ability. Since SIRT2 may be detrimental to neurological illnesses, it is a prime target for research into SIRT2 inhibitors. To identify the SIRT2 inhibitors and their role in AD. We have utilized NPAtlas database and screened using pharmacophore-based virtual screening, molecular docking, and simulation. The Natural Products Atlas provides unrestricted access to various natural products derived from bacteria and fungi, allowing researchers to investigate and visualize the extensive chemical diversity in the natural world. From in silico screening data, we have found phytoconstituents that could function as SIRT2 inhibitors. Six phytoconstituents were identified using pharmacophore-based virtual screening. According to molecular docking, Kurasoin B outperformed the reference molecule regarding binding energy. Kurasoin B exhibited a binding affinity of -12.543 kcal/mol, whereas the binding affinity of the reference molecule was -12.089 kcal/mol. The Kurasoin B complex with SIRT2 was determined to be stable throughout the simulation by performing MD simulation, with an RMSD of 2.88 (Å), whereas the reference and free protein displayed RMSDs of 3.74 and 4.70 (Å), respectively. In silico studies and data analysis, suggest that Kurasoin B may be able to suppress the SIRT2 protein for managing AD.

Abietic acid antagonizes the anti-inflammatory effects of celecoxib and ketoprofen: Preclinical assessment and molecular dynamic simulations

The present work is designed to explore the anti-inflammatory properties of AA and its modulatory effects on celecoxib (CEL) and ketoprofen (KET) through in vitro, ex vivo, in vivo, and in silico approaches. Different concentrations of AA were utilized to evaluate the membrane-stabilizing potential via egg albumin and the Human Red Blood Cell (HRBC) denaturation model. In the animal model, formalin (50 μL) was injected into the right hind paw of young chicks to induce inflammation. AA was administered at 20 and 40 mg/kg (p.o.) to the experimental animals. We used CEL and KET as positive controls. The vehicle was provided as a control group. Two combinations of AA with CEL and KET were also investigated in all tests to assess the modulatory activity of AA. In addition, in silico investigation was used for predictions about drug-likeness, pharmacokinetics, and toxicity of the selected chemical compounds, and the study also evaluated the binding affinity, visualization, and stability of ligand-receptor interactions through molecular dynamic (MD) simulation. Results manifested that AA concentration-dependently significantly inhibited the egg albumin denaturation (IC50: 27.53 ± 0.88 μg/ml) and breakdown of HRBC (IC50: 15.69 ± 0.75 μg/ml), indicating the membrane stabilizing potential compared to the control group. AA also significantly (p < 0.05) lessened the frequency of licking and alleviated the paw edema in a dose-dependent manner in an in vivo test. However, AA reduced the activity of CEL and KET in combination treatment. AA showed good pharmacokinetic characteristics to be considered as a therapeutic candidate. Additionally, the in silico study displayed that AA demonstrated a relatively higher docking score of −9.1 kcal/mol with the cyclooxygenase-2 (COX-2) enzyme and stable binding in MD simulation. Whereas the standard ligand (CEL) expressed the highest binding value of −9.2 kcal/mol to the COX-2.