Development Of Potential Drug Candidates Research Articles

Cladoic Acid, an Anti-Trypanosoma cruzi Polyketide from Cladosporium sp. TP-F2020.

A new polyketide, cladoic acid, was isolated from a fungus of the genus Cladosporium. The structure of the highly oxygenated trans-decalin ring with an all-E triene side chain was elucidated by extensive spectroscopic analysis. The unique chair/twist-boat conformation of the trans-decalin core and the flexibility of the B-ring were demonstrated by computer-aided conformational analysis. Cladoic acid was active against Trypanosoma cruzi and inhibited the proliferation of amastigotes and epimastigotes with IC50 values of 27 and 46 μM, respectively, but it did not show any appreciable activity against P388 murine leukemia cells, bacteria, or fungi, indicating it is a potential candidate for drug development against Chagas disease.

Exploring allocryptopine as a neuroprotective agent against oxidative stress-induced neural apoptosis via Akt/GSK-3β/tau pathway modulation

Alzheimer’s disease (AD) is characterized by neuronal loss due to hyperphosphorylated proteins induced by oxidative stress. AD remains a formidable challenge in the medical field, as current treatments focusing on single biomarkers have yielded limited success. Hence, there’s a burgeoning interest in investigating novel compounds that can target mechanisms, offering alternative therapeutic approaches. The aim of this study is to investigate the effects of allocryptopine, an isoquinoline alkaloid, on mechanisms related to AD in order to develop alternative treatment strategies. In this study, the in vitro AD cell model was obtained by inducing nerve growth factor (NGF)-differentiated PC12 (dPC12) cells to oxidative stress with H2O2, and also the effect mechanism of different allocryptopine concentrations on the in vitro AD cell model was studied. The treatments’ antioxidative effects at the ROS level and their regulation of the cell cycle were assessed through flow cytometry, while their anti-apoptotic effects were evaluated using both flow cytometry and qRT-PCR. Additionally, the phosphorylation levels of Akt, GSK-3β, and tau proteins were analyzed via western blot, and the interactions between Akt, GSK-3β, CDK5 proteins, and allocryptopine were demonstrated through molecular docking. Our study’s conclusive results revealed that allocryptopine effectively suppressed intracellular ROS levels, while simultaneously enhancing the Akt/GSK-3β signaling pathway by increasing p-Akt and p-GSK-3β proteins. This mechanism played a critical role in inhibiting neural cell apoptosis and preventing tau hyperphosphorylation. Moreover, allocryptopine demonstrated its ability to regulate the G1/S cell cycle progression, leading to cell cycle arrest in the G1 phase, and facilitating cellular repair mechanisms, potentially contributing to the suppression of neural apoptosis. The in silico results of allocryptopine were shown to docking with the cyclin-dependent kinase 5 (CDK 5) playing a role in tau phosphorylation Akt and GSK-3β from target proteins. Therefore, the in silico study results supported the in vitro results. The results showed that allocryptopine can protect dPC12 cells from oxidative stress-induced apoptosis and hyperphosphorylation of the tau protein by regulating the Akt/GSK-3β signaling pathway. Based on these findings, it can be suggested that allocryptopine, with its ability to target biomarkers and its significant effects on AD-associated mechanisms, holds promise as a potential candidate for drug development in the treatment of AD. Further research and clinical trials are recommended in the future.

Biosynthesis and Assembly Logic of Fungal Hybrid Terpenoid Natural Products.

In recent decades, fungi have emerged as significant sources of diverse hybrid terpenoid natural products,andtheir biosynthetic pathways are increasingly unveiled. This review mainly focuses on elucidating the various strategies underlying the biosynthesis and assembly logic of these compounds. These pathways combine terpenoid moieties with diverse building blocks including polyketides, nonribosomal peptides, amino acids, p-hydroxybenzoic acid, saccharides, and adenine, resulting in the formation of plenty of hybrid terpenoid natural products via C-O, C-C, or C-N bond linkages. Subsequent tailoring steps, such as oxidation, cyclization, and rearrangement, further enhance the biological diversity and structural complexity of these hybrid terpenoid natural products. Understanding these biosynthetic mechanisms holds promise for the discovery of novel hybrid terpenoid natural products from fungi, which will promote the development of potential drug candidates in the future.

Abstract 2760: Novel GPCR recombinant monoclonal antibodies for cancer biology research

Abstract Recombinant technology is becoming the preferred production mechanism for creation of antibody reagents used in academic and clinical cancer biology research. Recombinant antibodies (rAbs) are superior to standard polyclonal and hybridoma-generated monoclonal reagents as they offer reproducible performance and consistent, scalable supply. A major focus of antibody manufacturers is to leverage rAb production strategies to generate antibodies against challenging targets for which there are few, if any, reliable antibodies. G-protein coupled receptors (GPCRs) are encoded by more than 820 human genes and represent the largest membrane protein superfamily in the genome. These seven-pass transmembrane domain receptors are involved in a multitude of physiological and pathophysiological processes related to various chronic diseases, including an array of malignancies. Perhaps 30-40% of all therapeutics are directed against GPCR activity, and ~350 of the non-olfactory GPCRs are thought to be potential candidates for drug development. However, for a slew of technical reasons, the development and validation of high-quality antibodies against GPCRs has proven difficult. In an effort to facilitate further research into GPCRs, GeneTex is combining its recombinant antibody production platform with enhanced validation techniques to make specific monoclonal antibodies against GPCRs with direct relevance to cancer and other diseases. GeneTex’s rAb production protocol employs a multi-parameter fluorescence-activated single cell sorting (FACS)-based methodology to identify and select antigen-specific IgG+ memory B cells from an immunized rabbit (Starkie et al., 2016). The heavy and light chain variable region genes from single cells are amplified, cloned, and co-expressed in mammalian cells to generate a monoclonal IgG. Application-specific testing is performed in conjunction with knockout/knockdown (KO/KD), differential expression comparison in cells and tissues, cell fraction enrichment (i.e., membrane extracts versus whole cell extracts), and other methodologies. Antibodies directed against extracellular GPCR domains are validated for specificity using GPCR arrays (CDI Labs, Baltimore, MD). This workflow has resulted in the production of specific antibodies for a number of GPCRs studied by cancer biologists. These include novel recombinant monoclonal antibodies to the dopamine D2 receptor (DRD2), retinoic acid-induced protein 3 (RAI3), CXC motif chemokine receptor 2 (CXCR2), CXCR4, and CXCR7. All of these antibodies were validated for at least two applications, while the specificity of three (i.e., RAI3, CXCR4, and CXCR7) is supported by KO/KD data. GPCR array data argues for the specificity of the other two antibodies (i.e., DRD2 and CXCR2). This same production/validation approach will be applied as GeneTex targets the remaining GPCRs. Citation Format: Alexander Ball, Yung Lin Hsieh, Chun Kai Huang, Sega Huang, Shang Ru Wu, Yue Yun Chang, Jiming Liu, Po Shin Peng, Chia Yi Lin. Novel GPCR recombinant monoclonal antibodies for cancer biology research [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2760.

A Brain-Protective Sterol from Soft Coral Inhibits Lipopolysaccharide-Induced Matrix Metalloproteinase-9-Mediated Astrocytic Migration.

Matrix metalloproteinases (MMPs), which are proteolytic enzymes, promote blood-brain barrier (BBB) disruption, leading to neuronal damage and neuroinflammation. Among them, MMP-9 upregulation serves as an inflammatory biomarker in the central nervous system (CNS). Currently, the development of marine organism-derived bioactive compounds or metabolites as anti-inflammatory drugs has received considerable attention. The 9,11-secosteroid, 3β,11-dihydroxy-9,11-secogorgost-5-en-9-one (4p3f), is a novel sterol compound extracted from the soft coral Sinularia leptoclado with potential anti-inflammatory activity. However, the effect of and potential for brain protection of 4p3f on brain astrocytes remain unclear. Herein, we used rat brain astrocytes (RBAs) to investigate the effects and signaling mechanisms of 4p3f on lipopolysaccharide (LPS)-induced MMP-9 expression via zymographic, quantitative reverse transcription-polymerase chain reaction (qRT-PCR), Western blot, immunofluorescence staining, promoter-reporter, and cell migration analyses. We first found that 4p3f blocked LPS-induced MMP-9 expression in RBAs. Next, we demonstrated that LPS induced MMP-9 expression via the activation of ERK1/2, p38 MAPK, and JNK1/2, which is linked to the STAT3-mediated NF-κB signaling pathway. Finally, 4p3f effectively inhibited LPS-induced upregulation of MMP-9-triggered RBA cell migration. These data suggest that a novel sterol from soft coral, 4p3f, may have anti-inflammatory and brain-protective effects by attenuating these signaling pathways of MMP-9-mediated events in brain astrocytes. Accordingly, the soft coral-derived sterol 4p3f may emerge as a potential candidate for drug development or as a natural compound with neuroprotective properties.

Advancements in Drug Delivery Systems for Natural Compounds Targeting Metabolic Disorders Associated with Inflammation

The global incidence of metabolic disorders is on the rise, posing a significant challenge to public health. With remarkable advancements in diagnostic tools and clinical procedures, our understanding of the etiology and underlying pathophysiology of these disorders has expanded considerably. Furthermore, the utilization of in vitro and in vivo experimental models, preceding clinical investigations, has catalyzed numerous breakthroughs in biomedicine, particularly in the identification and development of potential drug candidates for the management of metabolic disorders. Natural compounds isolated from various sources have garnered extensive attention as prospective drug candidates for the treatment of conditions such as diabetes, obesity, heart-related diseases, and cancer. This interest is partly attributed to their inherent antioxidant and anti-inflammatory properties. Concurrently, intensive research efforts have been directed towards enhancing the bioactivity and bioavailability of these compounds through selected drug delivery strategies. In this article, we provide valuable insights into recent advancements that shed light on the role of inflammatory-mediated responses in the initiation of metabolic disorders, with a specific focus on conditions like diabetes mellitus, obesity, heart-related diseases, cancer, and related drug delivery systems. Additionally, we explore the promising potential of natural products in managing these metabolic disorders. Furthermore, we present lists of potential biological targets suitable for high throughput screening in the drug discovery and development process. Finally, we delve into the findings gleaned from preclinical and clinical studies, setting the stage for the identification of suitable approaches in the realm of phytochemical drug delivery systems that hold promise for the treatment of metabolic disorders.

Discovery of 2-Aminothiazole-4-carboxylic Acids as Broad-Spectrum Metallo-β-lactamase Inhibitors by Mimicking Carbapenem Hydrolysate Binding.

Metallo-β-lactamases (MBLs) are zinc-dependent enzymes capable of hydrolyzing all bicyclic β-lactam antibiotics, posing a great threat to public health. However, there are currently no clinically approved MBL inhibitors. Despite variations in their active sites, MBLs share a common catalytic mechanism with carbapenems, forming similar reaction species and hydrolysates. We here report the development of 2-aminothiazole-4-carboxylic acids (AtCs) as broad-spectrum MBL inhibitors by mimicking the anchor pharmacophore features of carbapenem hydrolysate binding. Several AtCs manifested potent activity against B1, B2, and B3 MBLs. Crystallographic analyses revealed a common binding mode of AtCs with B1, B2, and B3 MBLs, resembling binding observed in the MBL-carbapenem product complexes. AtCs restored Meropenem activity against MBL-producing isolates. In the murine sepsis model, AtCs exhibited favorable synergistic efficacy with Meropenem, along with acceptable pharmacokinetics and safety profiles. This work offers promising lead compounds and a structural basis for the development of potential drug candidates to combat MBL-mediated antimicrobial resistance.

Computational Discovery of Marine Molecules of the Cyclopeptide Family with Therapeutic Potential.

Stellatolides are natural compounds that have shown promising biological activities, including antitumor, antimicrobial, and anti-inflammatory properties, making them potential candidates for drug development. Chemical Reactivity Theory (CRT) is a branch of chemistry that explains and predicts the behavior of chemical reactions based on the electronic structure of molecules. Conceptual Density Functional Theory (CDFT) and Computational Peptidology (CP) are computational approaches used to study the behavior of atoms, molecules, and peptides. In this study, we present the results of our investigation of the chemical reactivity and ADMET properties of Stellatolides A-H using a novel computational approach called Conceptual DFT-based Computational Peptidology (CDFT-CP). Our study uses CDFT and CP to predict the reactivity and stability of molecules and to understand the behavior of peptides at the molecular level. We also predict the ADMET properties of the Stellatolides A-H to provide insight into their effectiveness, potential side effects, and optimal dosage and route of administration, as well as their biological targets. This study sheds light on the potential of Stellatolides A-H as promising candidates for drug development and highlights the potential of CDFT-CP for the study of other natural compounds and peptides.

Review on the protective activity of osthole against the pathogenesis of osteoporosis.

Osteoporosis (OP), characterized by continuous bone loss and increased fracture risk, has posed a challenge to patients and society. Long-term administration of current pharmacological agents may cause severe side effects. Traditional medicines, acting as alternative agents, show promise in treating OP. Osthole, a natural coumarin derivative separated from Cnidium monnieri (L.) Cusson and Angelica pubescens Maxim. f., exhibits protective effects against the pathological development of OP. Osthole increases osteoblast-related bone formation and decreases osteoclast-related bone resorption, suppressing OP-related fragility fracture. In addition, the metabolites of osthole may exhibit pharmacological effectiveness against OP development. Mechanically, osthole promotes osteogenic differentiation by activating the Wnt/β-catenin and BMP-2/Smad1/5/8 signaling pathways and suppresses RANKL-induced osteoclastogenesis and osteoclast activity. Thus, osthole may become a promising agent to protect against OP development. However, more studies should be performed due to, at least in part, the uncertainty of drug targets. Further pharmacological investigation of osthole in OP treatment might lead to the development of potential drug candidates.

MicroRNA-484 / Akt axis in the regulation of breast cancer cells sensitivity to antitumor drugs

The development of acquired resistance of malignant tumors to specific drugs, such as target and hormonal drugs, is usually associated with a rearrangement of the intracellular signaling network and activation of unblocked growth pathways. Epigenetic regulators, in particular, non-coding miRNAs that control the level of expression of specific signaling proteins, are directly involved in the development and maintenance of such changes. We have previously shown that the development of resistance of breast cancer cells to mTOR (mammalian target of rapamycin) inhibitors and hormonal drugs is accompanied by constitutive activation of protein kinase Akt, the key anti-apoptotic protein.Aim. To study the role of microRNAs in the regulation of Akt expression and the formation of a resistant phenotype of breast cancer cells.We have shown that Akt activation in the tamoxifen- or rapamycin-resistant MCF-7 sublines is associated with a decrease in the level of miRNA-484, one of the Akt suppressors. Transfection of microRNA-484 into MCF-7 cells does not affect the activity of estrogen signaling, but leads to a marked decrease in Akt expression and is accompanied by an increase in cell sensitivity to tamoxifen and rapamycin. The obtained data demonstrate the involvement of the miRNA-484 / Akt axis in the breast cancer cells’ sensitization to target and hormonal drugs, which allows us to consider miRNA-484 as a potential candidate for drug development to cure resistant cancers.

An automatic hypothesis generation for plausible linkage between xanthium and diabetes

There has been a significant increase in text mining implementation for biomedical literature in recent years. Previous studies introduced the implementation of text mining and literature-based discovery to generate hypotheses of potential candidates for drug development. By conducting a hypothesis-generation step and using evidence from published journal articles or proceedings, previous studies have managed to reduce experimental time and costs. First, we applied the closed discovery approach from Swanson’s ABC model to collect publications related to 36 Xanthium compounds or diabetes. Second, we extracted biomedical entities and relations using a knowledge extraction engine, the Public Knowledge Discovery Engine for Java or PKDE4J. Third, we built a knowledge graph using the obtained bio entities and relations and then generated paths with Xanthium compounds as source nodes and diabetes as the target node. Lastly, we employed graph embeddings to rank each path and evaluated the results based on domain experts’ opinions and literature. Among 36 Xanthium compounds, 35 had direct paths to five diabetes-related nodes. We ranked 2,740,314 paths in total between 35 Xanthium compounds and three diabetes-related phrases: type 1 diabetes, type 2 diabetes, and diabetes mellitus. Based on the top five percentile paths, we concluded that adenosine, choline, beta-sitosterol, rhamnose, and scopoletin were potential candidates for diabetes drug development using natural products. Our framework for hypothesis generation employs a closed discovery from Swanson’s ABC model that has proven very helpful in discovering biological linkages between bio entities. The PKDE4J tools we used to capture bio entities from our document collection could label entities into five categories: genes, compounds, phenotypes, biological processes, and molecular functions. Using the BioPREP model, we managed to interpret the semantic relatedness between two nodes and provided paths containing valuable hypotheses. Lastly, using a graph-embedding algorithm in our path-ranking analysis, we exploited the semantic relatedness while preserving the graph structure properties.

Elucidation of Binding Features and Dissociation Pathways of Inhibitors and Modulators in SARS-CoV-2 Main Protease by Multiple Molecular Dynamics Simulations.

COVID-19 can cause different neurological symptoms in some people, including smell, inability to taste, dizziness, confusion, delirium, seizures, stroke, etc. Owing to the issue of vaccine effectiveness, update and coverage, we still need one or more diversified strategies as the backstop to manage illness. Characterizing the structural basis of ligand recognition in the main protease (Mpro) of SARS-CoV-2 will facilitate its rational design and development of potential drug candidates with high affinity and selectivity against COVID-19. Up to date, covalent-, non-covalent inhibitors and allosteric modulators have been reported to bind to different active sites of Mpro. In the present work, we applied the molecular dynamics (MD) simulations to systematically characterize the potential binding features of catalytic active site and allosteric binding sites in Mpro using a dataset of 163 3D structures of Mpro-inhibitor complexes, in which our results are consistent with the current studies. In addition, umbrella sampling (US) simulations were used to explore the dissociation processes of substrate pathway and allosteric pathway. All the information provided new insights into the protein features of Mpro and will facilitate its rational drug design for COVID-19.

Phytochemical Screening, Anti-Inflammatory, and Antidiabetic Activities of Different Extracts from Caralluma edulis Plant.

The plant Caralluma edulis is traditionally used against diabetes and inflammatory conditions in Pakistan. This study was designed to provide scientific validation of the traditional use of Caralluma edulis. Phytochemicals were extracted from the plant by different solvents (distilled water, methanol, ethanol, and acetone) using the Soxhlet’s extraction method. Bioactive compounds were detected by gas chromatography–mass spectrometry (GC-MS). The in vitro anti-inflammatory activities (albumin denaturation, membrane stabilization, and proteinase inhibition) and antioxidant capacity (DPPH scavenging activity, FRAP reducing activity) of different extracts from Caralluma edulis were assessed. The antidiabetic potential of Caralluma edulis plant extracts was determined in acute and subacute diabetic rabbit models. Oxidative stress and enzymatic antioxidant status were also estimated in MDA, CAT, and SOD levels. Results showed that the methanol extract yielded the highest contents of phenolics, flavonoids, alkaloids, and terpenoids. The in vitro anti-inflammatory activity and antioxidant potential of the methanol extract were the highest among the tested solvents. The tested extracts did not show any remarkable antidiabetic activity in the acute diabetic model. However, all tested extracts demonstrated antidiabetic potential in the subacute diabetic model. No adverse effect was observed at the tested dose (200 mg/kg) of Caralluma edulis extracts in experimental animals. It is concluded that methanol is the key solvent for extracting bioactive compounds from Caralluma edulis. The plant can be used against inflammatory disorders and may prove a potential candidate for drug development. Long-term use of Caralluma edulis at the tested dose (200 mg/kg) showed antidiabetic properties in the animal model.

P. edulis Extract Protects Against Amyloid-β Toxicity in Alzheimer's Disease Models Through Maintenance of Mitochondrial Homeostasis via the FOXO3/DAF-16 Pathway.

Alzheimer's disease (AD) is a common and devastating disease characterized by pathological aggregations of beta-amyloid (Aβ) plaques extracellularly, and Tau tangles intracellularly. While our understandings of the aetiologies of AD have greatly expanded over the decades, there is no drug available to stop disease progression. Here, we demonstrate the potential of Passiflora edulis (P. edulis) pericarp extract in protecting against Aβ-mediated neurotoxicity in mammalian cells and Caenorhabditis elegans (C. elegans) models of AD. We show P. edulis pericarp protects against memory deficit and neuronal loss, and promotes longevity in the Aβ model of AD via stimulation of mitophagy, a selective cellular clearance of damaged and dysfunctional mitochondria. P. edulis pericarp also restores memory and increases neuronal resilience in a C. elegans Tau model of AD. While defective mitophagy-induced accumulation of damaged mitochondria contributes to AD progression, P. edulis pericarp improves mitochondrial quality and homeostasis through BNIP3/DCT1-dependent mitophagy and SOD-3-dependent mitochondrial resilience, both via increased nuclear translocation of the upstream transcriptional regulator FOXO3/DAF-16. Further studies to identify active molecules in P. edulis pericarp that could maintain neuronal mitochondrial homeostasis may enable the development of potential drug candidates for AD.

In silico targeting of red complex bacteria virulence factors of periodontitis with β-defensin 1

BackgroundPeriodontitis is a multi-factorial infection with red complex bacteria playing a crucial role in the pathogenesis. As bacteria are tending to develop resistance against conventional antibiotics, new treatment modalities need to be developed. Antimicrobial peptides (AMPs) are potential tools for drug development and are gaining widespread interest. β-defensin 1 is an important AMP and forms the first-line host defense mechanism. The present study analyzed the structure and molecular docking of β-defensin 1 with the virulence factors of red complex bacteria of periodontitis. The physico-chemical properties of β-defensin 1 were determined by various online tools such as ProtParam, ProteinPredict, ToxinPred, and BioPep web servers. The structure of β-defensin 1was predicted by the SWISS-MODEL web server and the structure was evaluated by different web tools. The structure of lipopolysaccharide of Porphyromonas gingivalis was drawn using Chem3D ultra 11.0 software. The structure of important protein virulence factors of red complex bacteria of periodontitis was determined by the SWISS-MODEL web server. The interaction study between β-defensin 1 and virulence factors was carried out by molecular docking using Auto dock version 4.0 software and pyDock WEB server. ResultsUsing online tools, β-defensin 1 was predicted to be stable and non-toxic. SWISS-MODEL web server predicted Ramachandran score as 94.12% and clash score 0.0 for β-defensin 1. Auto dock version 4.0 software and pyDock WEB server analyzed the interaction to have low binding energies and hydrogen bonds were formed between the peptide and virulence factors. Conclusionβ-defensin 1 was found to have good binding interaction with the disease-causing factors of red complex bacteria of periodontitis and in turn could play a role in reducing the severity of infection. β-defensin 1 could be a potential candidate for drug development for periodontitis.

Triazole-containing Heterocycles: Privileged Scaffolds in Anti-Trypanosoma Cruzi Drug Development.

Chagas disease is a potentially life-threatening illness caused by the protozoan parasite Trypanosoma cruzi and is transmitted to humans through the excreta of infected blood-sucking triatomine bugs. According to the World Health Organization, 6 to 7 million people are infected with T. cruzi worldwide, mainly in Latin America, with more than 10000 deaths annually. The present study aims to provide comprehensive literature information on the importance of triazole-containing heterocycles in developing anti-Chagas disease agents. The embodied information was acquired without date limitation by December 2020 using various electronic databases including, SciFinder, PubMed (National Library of Medicine), Science Direct, Wiley, ACS (American Chemical Society), SciELO (Scientific Electronic Library Online), Google Scholar, Springer, Scopus, and Web of Science. Upon in vitro studies, more than 100 triazole-containing heterocycles have been predicted as active compounds against the pathogen responsible for the American trypanosomiasis. However, less is known about their in vivo activity in animal models and their clinical studies in humans. Moreover, the pharmacokinetic studies of these bioactive compounds are still pending. Despite the variety of mechanisms of action attributed to most of these molecules, the exact mechanism involved is still controversial. Thus, in vivo experiments, followed by pharmacokinetics, and the mechanism of action of the most active compounds, should be the subject of future investigation. All in all, recent studies have demonstrated the importance of triazole-containing heterocycles in search of potential candidates for drug development against Chagas disease. Nonetheless, the use of new catalysts and chemical transformations is expected to provide avenues for the synthesis of unexplored triazole derivatives, leading to the development of triazole-containing compounds with new properties and trypanocidal activity.

Antioxidant and anti-inflammatory activities of methanol and aqueous extracts of Sargassum wightii

Introduction: Antioxidants of natural sources for the treatment of many ailments have taken priority since the last decades. Recently, researches have been focused on marine algae as they are the largest reservoir of bioactive compounds. Hence, the objective of this study was to explore the in-vitro antioxidant and anti-inflammatory activities of methanolic and aqueous extracts of Sargassum wightii. Methods: The total phenolics, flavonoids, and ascorbic acid (AA) contents were evaluated informs of gallic acid equivalent (GAE), rutin equivalent (RUE), and AA equivalent, respectively. The aqueous and methanolic extracts were isolated. The antioxidant activities were explored using2,2-diphenyl-1-picrylhydrazil (DPPH), superoxide dismutase (SOD), hydroxyl radical scavenging, and ferric reducing power assays. The in vitro anti-inflammatory activity was assayed using nitric oxide radical scavenging, inhibition of protein denaturation, and antiproteinase activities. Results: We observed significant changes in DPPH scavenging activity with both methanolicSargassum extract (MSE) and aqueous Sargassum extract (ASE) [IC50: 511.15 µg/mL and 927.05µg/mL, respectively]. Methanolic extract showed a greater SOD scavenging activity [IC50: 369.56µg/mL] and hydroxyl radical scavenging potential [IC50: 668.93 µg/mL] than that of ASE [SOD,IC50: 923.94 µg/mL; hydroxyl ion, IC50: 953.57 µg/mL]. In the Ferric reducing antioxidant power assay, MSE and ASE exhibited absorbance of 0.93±0.12 and 0.59±0.08, respectively, at 1200 µg/mL each. Both methanol and ASEs showed NO– scavenging activity having IC50 in order, AA(96.46 µg/mL) <MSE (963.50 µg/mL) <ASE (1974.88 µg/mL). However, the protein denaturation inhibition and antiproteinase activity of both these extracts at 1000 µg/mL were similar. Conclusion: Sargassum wightii has promising antioxidant and anti-inflammatory activities and could be a potential candidate for drug development targeting oxidative stress-mediated inflammatory diseases.

Plant-Based Phytochemical Screening by Targeting Main Protease of SARS-CoV-2 to Design Effective Potent Inhibitors.

Simple SummaryVirtual screening schemes, including molecular docking in conjunction with molecular dynamics simulation, were accomplished, as they extend an ample opportunity to screen plausible inhibitors of the main protease from an extensive phytochemical library. The preferential phytochemicals were retrieved from Asian plants through the data mining procedure and comprehensive literature study. The three preeminent reliable phytochemical exhibited toxicity by no means during the scrutinization of ADMET prominences. Moreover, pharmacologically distinguishing characteristics and the biological activity of the lead phytochemicals were satisfying as a repurposing antiviral drug contender. Additionally, the molecular dynamics simulation exhibited thermal stability and a stable binding affinity of the protein-compound complex that refers to the appreciable efficacy of the lead optimization. Therefore, the preferable phytochemicals are worth substantial evaluation in the biological laboratory to recommend plausible antiviral drug contenders.Currently, a worldwide pandemic has been declared in response to the spread of coronavirus disease 2019 (COVID-19), a fatal and fast-spreading viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The low availability of efficient vaccines and treatment options has resulted in a high mortality rate, bringing the world economy to its knees. Thus, mechanistic investigations of drugs capable of counteracting this disease are in high demand. The main protease (Mpro) expressed by SARS-CoV-2 has been targeted for the development of potential drug candidates due to the crucial role played by Mpro in viral replication and transcription. We generated a phytochemical library containing 1672 phytochemicals derived from 56 plants, which have been reported as having antiviral, antibacterial, and antifungal activity. A molecular docking program was used to screen the top three candidate compounds: epicatechin-3-O-gallate, psi-taraxasterol, and catechin gallate, which had respective binding affinities of −8.4, −8.5, and −8.8 kcal/mol. Several active sites in the targeted protein, including Cys145, His41, Met49, Glu66, and Met165, were found to interact with the top three candidate compounds. The multiple simulation profile, root-mean-square deviation, root-mean-square fluctuation, radius of gyration, and solvent-accessible surface area values supported the inflexible nature of the docked protein–compound complexes. The toxicity and carcinogenicity profiles were assessed, which showed that epicatechin-3-O-gallate, psi-taraxasterol, and catechin gallate had favorable pharmacological properties with no adverse effects. These findings suggest that these compounds could be developed as part of an effective drug development pathway to treat COVID-19.

Integrated docking and enhanced sampling-based selection of repurposing drugs for SARS-CoV-2 by targeting host dependent factors

Since the onset of global pandemic, the most focused research currently in progress is the development of potential drug candidates and clinical trials of existing FDA approved drugs for other relevant diseases, in order to repurpose them for the COVID-19. At the same time, several high throughput screenings of drugs have been reported to inhibit the viral components during the early course of infection but with little proven efficacies. Here, we investigate the drug repurposing strategies to counteract the coronavirus infection which involves several potential targetable host proteins involved in viral replication and disease progression. We report the high throughput analysis of literature-derived repurposing drug candidates that can be used to target the genetic regulators known to interact with viral proteins based on experimental and interactome studies. In this work we have performed integrated molecular docking followed by molecular dynamics (MD) simulations and free energy calculations through an expedite in silico process where the number of screened candidates reduces sequentially at every step based on physicochemical interactions. We elucidate that in addition to the pre-clinical and FDA approved drugs that targets specific regulatory proteins, a range of chemical compounds (Nafamostat, Chloramphenicol, Ponatinib) binds to the other gene transcription and translation regulatory proteins with higher affinity and may harbour potential for therapeutic uses. There is a rapid growing interest in the development of combination therapy for COVID-19 to target multiple enzymes/pathways. Our in silico approach would be useful in generating leads for experimental screening for rapid drug repurposing against SARS-CoV-2 interacting host proteins. Communicated by Ramaswamy H. Sarma

Total Synthesis of Stelletins through an Unconventional Annulation Strategy.

Marine ecosystems present the largest source of biodiversity on the planet and an immense reservoir of novel chemical entities. Sessile marine organisms such as sponges produce a wide range of complex secondary metabolites, many of these with potent biological activity engineered for chemical defense. That such compounds exert dynamic effects outside of their native context is perhaps not surprising, and the realm of marine natural products has attracted considerable attention as a largely untapped repository of potential candidates for drug development. Only a handful of the more than 15 000 marine natural products that have been isolated to date have advanced to the clinic, and more are to be expected. The rich chemical information encoded in the intricate three-dimensional structures of many marine natural products facilitates highly discriminating interactions with cell signaling pathways, and especially within cancer cells such nuanced effects offer an exciting opportunity for the development of targeted therapies that lack the side effects and general toxicity of conventional chemotherapeutics. The isomalabaricanes are a rare class of marine triterpenoids that have been hailed as promising cytotoxic lead compounds for the treatment of cancer, and they have attracted a flurry of excitement from researchers because of their potent cytotoxicity in certain human cancer cell lines along with a range of other antineoplastic effects. Most notably, their inhibitory activity is highly cell-selective, characterized by large deviations from their mean GI50 concentrations across 3 orders of magnitude in the NCI-60 Human Tumor Cell Lines screen, suggesting mechanistic specificity rather than general and unbridled toxicity. Despite these auspicious preliminary reports, the isomalabaricane scaffold remains largely unexplored as a potential anticancer lead because of lack of material. This Account describes our recent efforts to develop a general, modular synthesis of the isomalabaricanes, as exemplified by the successful total syntheses of rhabdastrellic acid A, stelletin E, and stelletin A. The unorthodox trans-syn-trans configuration of their perhydrobenz[e]indene core severely circumscribes the synthetic methods available for its construction and required several generations of strategy to assemble. Ultimately, a series of unconventional transformations were identified that were capable of building this highly strained motif, and the syntheses of rhabdastrellic acid A and stelletin E were completed in racemic fashion. Subsequently, a second-generation approach to these natural products was developed, rendering the synthesis enantioselective as well as providing access to stelletin A. These synthetic efforts were greatly assisted by computational techniques such as 13C NMR prediction, which enabled structural assignments of hydrocarbon diastereomers, as well as relaxed surface scan conformational analysis, which informed a campaign for directed hydrogenation of an alkene. High-throughput experimentation methods were brought to bear during optimization of a late-stage Suzuki coupling on stelletin A. Finally, preliminary structure-activity relationship studies in glioblastoma and nonsmall cell lung cancer cell lines were conducted on stelletin A, revealing that the singular trans-syn-trans perhydrobenz[e]indene core is essential for the cytotoxic activity of the isomalabaricane triterpenoids.