Multitarget Potential Research Articles

Herbal Therapeutics as Potential Prophylaxis for SARS-CoV-2 Infection

Introduction: The global pandemic COVID-19 and its uncontrolled spread and lack of effective therapeutics demand to investigate the herbal resources in search of novel, safe and potent therapeutics. Herbal medicines have proven the advantage of multi-target potential and thus can be investigated for virus-host interaction protein and viral protein targets. Objectives: Manuscript aims to provide an outcome-based analysis of studies performed towards evaluation of herbal compounds as anti-COVID agents. The studies focus on the proposed mechanism of viral inhibition by herbal compounds. Methods: The details on modern drug discovery approaches for investigation of potential antiviral agents includes in silico screening, ADMET and molecular docking studies. It helps to establish the probable mechanism of viral inhibition as well as to establish pharmacophore. The reports explaining role of herbal therapeutics/phytochemicals in antiviral drug development have been thoroughly searched. Results: The study summarizes herbal therapeutics and phytochemicals based on their antiviral properties against various pathogenic viruses. Herbal compounds that have an interesting role in the development of therapeutics and herd immunity against SARS-CoV-2 are included and discussed. Conclusion: The manuscript provides a summarized description of herbal resources and phytochemicals which are under investigation or have been investigated as potential therapeutic option for SARS-COV-2 inhibition. It will be a useful resource for researchers interested in the development of herbal therapeutics for the prevention and/or treatment of COVID-19.

Therapeutic Importance and Pharmacological Activities of Norisoboldine in Medicine for the Treatment of Human Disorders.

Natural products constitute a unique source of chemical compounds with multi-target potential for the treatment of complex human disorders. Phytochemicals are pure phytoconstituents of plants, mainly responsible for their therapeutic potential and pharmacological activities. Natural products isolated from medicinal plants have been used as a lead source of drug. Norisoboldine is an important isoquinoline alkaloid found to be present in the dry root of Lindera aggregate. In the present paper, scientific data of norisoboldine have been collected from Google, Google Scholar, PubMed, Science Direct and Scopus and analyzed in order to know the biological potential and therapeutic effectiveness of norisoboldine in medicine. Scientific data of medicinal importance and therapeutic potential of norisoboldine has been collected and analyzed in the present work. Moreover, all the collected scientific data have been separated into different sub-section i.e. Medicinal importance, pharmacological activities and analytical aspects. Detailed pharmacological activity data of norisoboldine have been analyzed in the present work to know the therapeutic effectiveness of norisoboldine in medicine. Analytical data of norisoboldine have also been collected and analyzed in the present work. Scientific data analysis revealed the biological importance of isoquinoline alkaloids in medicine. Isoquinoline alkaloids are pure, active phytochemical present in several natural edible products including vegetables, plants, and fruits. Norisoboldine has a biological effect on arthritis, colitis, apoptosis, osteoclast differentiation, inflammatory pain, renal ischemia-reperfusion injury, acute lung injury, pro-inflammatory cytokines, tumor, regulatory T cells, and endothelial cell migration. However nanoemulsifying drug delivery system of norisoboldine has also been prepared in order to get better therapeutic value. Further analytical parameters of norisoboldine were also discussed in the present work in order to get the scientific information of separation, isolation and identification parameter of norisoboldine. Present work revealed the therapeutic potential of norisoboldine in medicine.

Plant-based Isoquinoline Alkaloids: A Chemical and Pharmacological Profile of Some Important Leads

Plant-based products are a one-of-a-kind source of favoured molecules with a wide scaffold variety and broad multi-target potential for the treatment of complicated disorders. Among multi-target NPs, alkaloids have showed anti-inflammatory, anticancer, cardioprotective, and neuroprotective effects, supporting their promise in the treatment of chronic multifactorial disorders. Several recent investigations have revealed that isoquinoline alkaloids (IAs) have multimodal potential, sparking growing interest in the polypharmacological research of these small molecules, particularly in the field of neurological illnesses and cancer. IAs are a broad and diversified category of nitrogenous compounds that are extensively dispersed in living organisms, mostly in plants family. Isoquinolines are known as highly conserved metabolites in early vascular plants at the chemotaxonomic level; moreover, biochemical and molecular phylogenetic investigations have revealed that these alkaloids play an evolutionarily monophyletic role in basal angiosperms.As a result, medicinal chemistry has been experimenting with various ways in order to overcome the constraints of existing paradigms and increase the effectiveness of novel therapeutic molecules. In this context, the search or design of multi-target medications has shown an accelerated breakthrough; in fact, this strategy has sparked the interest of both the scientific community and the pharmaceutical business, allowing several multimodal agents already on the market to be positioned.

Novel benzothiazole derivatives as multitargeted-directed ligands for the treatment of Alzheimer’s disease

Neurodegenerative diseases such as Alzheimer’s disease (AD) are multifactorial with several different pathologic mechanisms. Therefore, it is assumed that multitargeted-directed ligands (MTDLs) which interact with different biological targets relevant to the diseases, might offer an improved therapeutic alternative than using the traditional “one-target, one-molecule” approach. Herein, we describe new benzothiazole-based derivatives as a privileged scaffold for histamine H3 receptor ligands (H3R). The most affine compound, the 3-(azepan-1-yl)propyloxy-linked benzothiazole derivative 4b, displayed a Ki value of 0.012 μM. The multitargeting potential of these H3R ligands towards AChE, BuChE and MAO-B enzymes was evaluated to yield compound 3s (pyrrolidin-1-yl-(6-((5-(pyrrolidin-1-yl)pentyl)oxy)benzo[d]thiazol-2-yl)methanone) as the most promising MTDL with a Ki value of 0.036 μM at H3R and IC50 values of 6.7 µM, 2.35 µM, and 1.6 µM towards AChE, BuChE, and MAO-B, respectively. These findings suggest that compound 3s can be a lead structure for developing new multi-targeting anti-AD agents.

Exploring the Multitarget Potential of Iridoids: Advances and Applications.

Iridoids are secondary plant metabolites that are multitarget compounds active against various diseases. Iridoids are structurally classified into iridoid glycosides and non-glycosidic iridoids according to the presence or absence of intramolecular glycosidic bonds; additionally, iridoid glycosides can be further subdivided into carbocyclic iridoids and secoiridoids. These monoterpenoids belong to the cyclopentan[c]-pyran system, which has a wide range of biological activities, including antiviral, anticancer, antiplasmodial, neuroprotective, anti-thrombolytic, antitrypanosomal, antidiabetic, hepatoprotective, anti-oxidant, antihyperlipidemic and anti-inflammatory properties. The basic chemical structure of iridoids in plants (the iridoid ring scaffold) is biosynthesized in plants by the enzyme iridoid synthase using 8-oxogeranial as a substrate. With advances in phytochemical research, many iridoid compounds with novel structure and outstanding activity have been identified in recent years. Biologically active iridoid derivatives have been found in a variety of plant families, including Plantaginaceae, Rubiaceae, Verbenaceae, and Scrophulariaceae. Iridoids have the potential of modulating many biological events in various diseases. This review highlights the multitarget potential of iridoids and includes a compilation of recent publications on the pharmacology of iridoids. Several in vitro and in vivo models used, along with the results, are also included in the paper. This paper's systematic summary was created by searching for relevant iridoid material on websites such as Google Scholar, PubMed, SciFinder Scholar, Science Direct, and others. The compilation will provide the researchers with a thorough understanding of iridoid and its congeners, which will further help in designing a large number of potential compounds with a strong impact on curing various diseases.

A sulphated glycosaminoglycan extract from Placopecten magellanicus inhibits the Alzheimer's disease β-site amyloid precursor protein cleaving enzyme 1 (BACE-1)

The clinically important anticoagulant heparin, a member of the glycosaminoglycan family of carbohydrates that is extracted predominantly from porcine and bovine tissue sources, has previously been shown to inhibit the β-site amyloid precursor protein cleaving enzyme 1 (BACE-1), a key drug target in Alzheimer's Disease. In addition, heparin has been shown to exert favourable bioactivities through a number of pathophysiological pathways involved in the disease processes of Alzheimer's Disease including inflammation, oxidative stress, tau phosphorylation and amyloid peptide generation. Despite the multi-target potential of heparin as a therapeutic option for Alzheimer's disease, the repurposing of this medically important biomolecule has to-date been precluded by its high anticoagulant potential. An alternative source to mammalian-derived glycosaminoglycans are those extracted from marine environments and these have been shown to display an expanded repertoire of sequence-space and heterogeneity compared to their mammalian counterparts. Furthermore, many marine-derived glycosaminoglycans appear to retain favourable bioactivities, whilst lacking the high anticoagulant potential of their mammalian counterparts. Here we describe a sulphated, marine-derived glycosaminoglycan extract from the Atlantic Sea Scallop, Placopecten magellanicus that displays high inhibitory potential against BACE-1 (IC50 = 4.8 μg.mL−1) combined with low anticoagulant activity; 25-fold less than that of heparin. This extract possesses a more favourable therapeutic profile compared to pharmaceutical heparin of mammalian provenance and is composed of a mixture of heparan sulphate (HS), with a high content of 6-sulphated N-acetyl glucosamine (64%), and chondroitin sulphate.

Multitarget Potential of Phytochemicals from Traditional Medicinal Tree, Terminalia arjuna (Roxb. ex DC.) Wight & Arnot as Potential Medicaments for Cardiovascular Disease: An In-Silico Approach.

Cardiovascular diseases (CVDs) are the leading cause of mortality worldwide. Terminalia arjuna (Roxb. ex DC.) Wight & Arnot of the Combretaceae family is one of the most frequently approved and utilized medicinal trees in the traditional medicinal system, which was used for the treatment of a variety of diseases, including cardiovascular disorders. The present study aims to identify phytochemicals from T. arjuna, that do not exhibit any toxicity and have significant cardioprotective activity using an in-silico technique. Four different cardiovascular proteins, namely human angiotensin receptor (PDB ID: 4YAY), P38 mitogen-activated protein kinase (MAPK, PDB ID: 4DLI), 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-Co A) reductase (PDB ID: 1HW9), and human C-reactive protein (PDB ID: 1B09), were used as target proteins to identify potential inhibitors using a virtual screening of the phytochemicals in T. arjuna revealed casuarinin as a potential inhibitor of all selected target proteins with strong binding energy. Furthermore, MD simulations for a 100 ns time scale also revealed that most of the key protein contacts of all target proteins were retained throughout the simulation trajectories. Binding free energy calculations using the MM-GBSA approach also support a strong inhibitory effect of casuarinin on target proteins. Casuarinin's effective binding to these proteins lays the groundwork for the development of broad-spectrum drugs as well as the understanding of the underlying mechanism against cardiovascular diseases through in vivo and clinical studies.

An Exemestane Derivative, Oxymestane-D1, as a New Multi-Target Steroidal Aromatase Inhibitor for Estrogen Receptor-Positive (ER+) Breast Cancer: Effects on Sensitive and Resistant Cell Lines.

Around 70-85% of all breast cancer (BC) cases are estrogen receptor-positive (ER+). The third generation of aromatase inhibitors (AIs) is the first-line treatment option for these tumors. Despite their therapeutic success, they induce several side effects and resistance, which limits their efficacy. Thus, it is crucial to search for novel, safe and more effective anti-cancer molecules. Currently, multi-target drugs are emerging, as they present higher efficacy and lower toxicity in comparison to standard options. Considering this, this work aimed to investigate the anti-cancer properties and the multi-target potential of the compound 1α,2α-epoxy-6-methylenandrost-4-ene-3,17-dione (Oxy), also designated by Oxymestane-D1, a derivative of Exemestane, which we previously synthesized and demonstrated to be a potent AI. For this purpose, it was studied for its effects on the ER+ BC cell line that overexpresses aromatase, MCF-7aro cells, as well as on the AIs-resistant BC cell line, LTEDaro cells. Oxy reduces cell viability, impairs DNA synthesis and induces apoptosis in MCF-7aro cells. Moreover, its growth-inhibitory properties are inhibited in the presence of ERα, ERβ and AR antagonists, suggesting a mechanism of action dependent on these receptors. In fact, Oxy decreased ERα expression and activation and induced AR overexpression with a pro-death effect. Complementary transactivation assays demonstrated that Oxy presents ER antagonist and AR agonist activities. In addition, Oxy also decreased the viability and caused apoptosis of LTEDaro cells. Therefore, this work highlights the discovery of a new and promising multi-target drug that, besides acting as an AI, appears to also act as an ERα antagonist and AR agonist. Thus, the multi-target action of Oxy may be a therapeutic advantage over the three AIs applied in clinic. Furthermore, this new multi-target compound has the ability to sensitize the AI-resistant BC cells, which represents another advantage over the endocrine therapy used in the clinic, since resistance is a major drawback in the clinic.

The Multiple Sclerosis Modulatory Potential of Natural Multi-Targeting Antioxidants

Multiple sclerosis (MS) is a complex neurodegenerative disease. Although its pathogenesis is rather vague in some aspects, it is well known to be an inflammatory process characterized by inflammatory cytokine release and oxidative burden, resulting in demyelination and reduced remyelination and axonal survival together with microglial activation. Antioxidant compounds are gaining interest towards the manipulation of MS, since they offer, in most of the cases, many benefits, due to their pleiotropical activity, that mainly derives from the oxidative stress decrease. This review analyzes research articles, of the last decade, which describe biological in vitro, in vivo and clinical evaluation of various categories of the most therapeutically applied natural antioxidant compounds, and some of their derivatives, with anti-MS activity. It also summarizes some of the main characteristics of MS and the role the reactive oxygen and nitrogen species may have in its progression, as well as their relation with the other mechanistic aspects of the disease, in order for the multi-targeting potential of those antioxidants to be defined and the source of origination of such activity explained. Antioxidant compounds with specific characteristics are expected to affect positively some aspects of the disease, and their potential may render them as effective candidates for neurological impairment reduction in combination with the MS treatment regimen. However, more studies are needed in order such antioxidants to be established as recommended treatment to MS patients.

Pristimerin mediated anticancer effects and sensitization of human skin cancer cells through modulation of MAPK signaling pathways

Squamous cell carcinoma is a frequent skin cancer still demanding to understand the underlying mechanisms for better clinical outcomes. Pristimerin, a natural quinonemethide triterpenoid, has shown promising therapeutic outcome due to its anti-cancer activity and multi-targeting potential. We explored the underlying mechanisms of pristimerin-induced programmed cell death of primary (A431) and metastatic (A388) cutaneous squamous cell carcinoma (cSCC) cells. Our results show that pristimerin inhibits growth and proliferation of cSCC through JNK activation. Moreover, pristimerin causes cell cycle arrest and induces cell death via apoptosis and autophagy. Interestingly, use of apoptosis (z-VAD-FMK) and autophagy (3-methyladenine) inhibitors confirmed vital role of programmed cell death in pristimerin-mediated anti-cancer actions. JNK inhibitor, SP600125, also mitigated pristimerin-induced apoptotic and autophagic actions. Moreover, pristimerin-mediated anti-cancer activity acts by generating reactive oxygen species (ROS) thereby inducing JNK signaling. Use of N-acetyl cystine (NAC), a universal ROS scavenger, significantly reversed pristimerin-induced programmed cell death through downregulation of JNK. Pristimerin sensitized skin cancer cells to conventional anticancer drugs cisplatin, azacytidine and doxorubicin through JNK activation, as confirmed by SP600125. Our results indicate that pristimerin mediates programmed cell death and sensitized skin cancer cells to conventional anti-cancer drugs via ROS-mediated JNK activation.

Multi-Target Potential of Berberine as an Antineoplastic and Antimetastatic Agent: A Special Focus on Lung Cancer Treatment.

Despite therapeutic advancements, lung cancer remains the principal cause of cancer mortality in a global scenario. The increased incidence of tumor reoccurrence and progression and the highly metastatic nature of lung cancer are of great concern and hence require the investigation of novel therapies and/or medications. Naturally occurring compounds from plants serve as important resources for novel drugs for cancer therapy. Amongst these phytochemicals, Berberine, an alkaloid, has been extensively explored as a potential natural anticancer therapeutic agent. Several studies have shown the effectiveness of Berberine in inhibiting cancer growth and progression mediated via several different mechanisms, which include cell cycle arrest, inducing cell death by apoptosis and autophagy, inhibiting cell proliferation and invasion, as well as regulating the expression of microRNA, telomerase activity, and the tumor microenvironment, which usually varies for different cancer types. In this review, we aim to provide a better understanding of molecular insights of Berberine and its various derivative-induced antiproliferative and antimetastatic effects against lung cancer. In conclusion, the Berberine imparts its anticancer efficacy against lung cancers via modulation of several signaling pathways involved in cancer cell viability and proliferation, as well as migration, invasion, and metastasis.

Review on Compounds Isolated from Eriocaulaceae Family and Evaluation of Biological Activities by Machine Learning.

Eriocaulaceae is a pantropical family whose main center of biodiversity is in Brazil. In general, the family has about 1200 species, in which phytochemical and biological studies have shown a variety of structures and activities. The aim of this research is to compile the compounds isolated in the Eriocaulaceae family and carry out a computational study on their biological targets. The bibliographic research was carried out on six databases. Tables were built and organized according to the chemical class. In addition, a summary of the methods of isolating the compounds was also made. In the computational study were used ChEMBL platform, DRAGON 7.0, and the KNIME 4.4.0 software. Two hundred and twenty-two different compounds have been isolated in sixty-eight species, divided mainly into flavonoids and naphthopyranones, and minor compounds. The ligand-based virtual screening found promising molecules and molecules with multitarget potential, such as xanthones 194, 196, 200 and saponin 202, with xanthone 194 as the most promising. Several compounds with biological activities were isolated in the family, but the chemical profiles of many species are still unknown. The selected structures are a starting point for further studies to develop new antiparasitic and antiviral compounds based on natural products.

Unveiling the multitargeted potential of N-(4-Aminobutanoyl)-S-(4-methoxybenzyl)-L-cysteinylglycine (NSL-CG) against SARS CoV-2: a virtual screening and molecular dynamics simulation study

The coronaviridae family has caused the most destruction among all the viral families in modern sciences. It is one of the recently discovered and added members of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which has caused the global pandemic and significant destruction worldwide. However, scientists worldwide have developed vaccines, which are being given to humans. The mutated strain of the virus has caused various uncertainties about whether the discovered drug and vaccines affect it. Even after the World Health Organization's approval for the vaccines, their effectiveness and protection ratio are still a major concern. At the community level, to this date, there is no medicine available to cure the patients. In this study, we have screened the vast library from Drug Bank and identified N-(4-Aminobutanoyl)-S-(4-methoxybenzyl)-L-cysteinylglycine (NSL-CG) that can work against two major targets of SARS CoV-2, replication-transcription and RNA dependent polymerase. Further, we have performed the Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) and molecular dynamics simulation of the compound with both proteins individually, giving us enough evidence that the said drugs can work against the two targets together. Inhibiting the action of any of both proteins may lead to retaining the virus, and having a dual-targeted drug can be an extra precise measure for this process. The NSL-CG is an experimental drug belonging to the peptidomimetics class included in the small group of drugs with a docking score of −9.079 kcal/mol with replication-transcription −7.885 kcal/mol with RNA-dependent polymerase. Hence, through the complete flowed study, the NSL-CG can be further experimentally validated in in-vitro and in-vivo conditions before human utilisation. Communicated by Ramaswamy H. Sarma

Leveraging Bulk and Single-Cell RNA Sequencing Data of NSCLC Tumor Microenvironment and Therapeutic Potential of NLOC-15A, A Novel Multi-Target Small Molecule.

Lung cancer poses a serious threat to human health and has recently been tagged the most common malignant disease with the highest incidence and mortality rate. Although epidermal growth factor (EGFR)-tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis of advanced non-small cell lung cancer (NSCLC) patients with EGFR mutations, patients often develop resistance to these drugs. There is therefore a need to identify new drug candidates with multitarget potential for treating NSCLC. We hereby provide preclinical evidence of the therapeutic efficacy of NLOC-015A a multitarget small-molecule inhibitor of EGFR/mitogen-activated protein (MAP) kinase kinase 1 (MAP2K1)/mammalian target of rapamycin (mTOR)/yes-associated protein 1 (YAP1) for the treatment NSCLC. Our multi-omics analysis of clinical data from cohorts of NSCLC revealed that dysregulation of EGFR/MAP2K1/mTOR/YAP1 signaling pathways was associated with the progression, therapeutic resistance, immune-invasive phenotypes, and worse prognoses of NSCLC patients. Analysis of single-cell RNA sequencing datasets revealed that MAP2K1, mTOR, YAP1 and EGFR were predominantly located on monocytes/macrophages, Treg and exhaustive CD8 T cell, and are involved in M2 polarization within the TME of patients with primary and metastatic NSCLC which further implied gene’s role in remodeling the tumor immune microenvironment. A molecular-docking analysis revealed that NLOC-015A bound to YAP1, EGFR, MAP kinase/extracellular signal-related kinase kinase 1 (MEK1), and mTOR with strong binding efficacies ranging –8.4 to –9.50 kcal/mol. Interestingly, compared to osimertinib, NLOC-015 bound with higher efficacy to the tyrosine kinase (TK) domains of both T790M and T790M/C797S mutant-bearing EGFR. Our in vitro studies and sequencing analysis revealed that NLOC-015A inhibited the proliferation and oncogenic phenotypes of NSCLC cell lines with concomitant downregulation of expression levels of mTOR, EGFR, YAP1, and MEK1 signaling network. We, therefore, suggest that NLOC-015A might represent a new candidate for treating NSCLC via acting as a multitarget inhibitor of EGFR, mTOR/NF-κB, YAP1, MEK1 in NSCLC.

Multi-target potential of Indian phytochemicals against SARS-CoV-2: A docking, molecular dynamics and MM-GBSA approach extended to Omicron B.1.1.529.

BackgroundSARS-CoV-2, an emerged strain of corona virus family became almost serious health concern worldwide. Despite vaccines availability, reports suggest the occurrence of SARS-CoV-2 infection even in a vaccinated population. With frequent evolution and expected multiple COVID-19 waves, improved preventive, diagnostic, and treatment measures are required. In recent times, phytochemicals have gained attention due to their therapeutic characteristics and are suggested as alternative and complementary treatments for infectious diseases. This present study aimed to identify potential inhibitors against reported protein targets of SARS-CoV-2. MethodologyWe computationally investigated potential SARS-CoV-2 protein targets from the literature and collected druggable phytochemicals from Indian Medicinal Plants, Phytochemistry and Therapeutics (IMPPAT) database. Further, we implemented a systematic workflow of molecular docking, dynamic simulations and generalized born surface area free-energy calculations (MM-GBSA). ResultsExtensive literature search and assessment of 1508 articles identifies 13 potential SARS-CoV-2 protein targets. We screened 501 druggable phytochemicals with proven biological activities. Analysis of 6513(501 *13) docked phytochemicals complex, 26 were efficient against SARS-CoV-2. Amongst, 4,8-dihydroxysesamin and arboreal from Gmelina arborea were ranked potential against most of the targets with binding energy ranging between − 10.7 to − 8.2 kcal/mol. Additionally, comparative docking with known drugs such as arbidol (−6.6 to −5.1 kcal/mol), favipiravir (−5.5 to −4.5 kcal/mol), hydroxychloroquine (−6.5 to −5.1 kcal/mol), and remedesivir (−8.0 to −5.3 kcal/mol) revealed equal/less affinity than 4,8-dihydroxysesamin and arboreal. Interestingly, the nucleocapsid target was found commonly inhibited by 4,8-dihydroxysesamin and arboreal. Molecular dynamic simulation and Molecular mechanics generalized born surface area (MM-GBSA)calculations reflect that both the compounds possess high inhibiting potential against SARS-CoV-2 including the recently emerged Omicron variant (B.1.1.529). ConclusionOverall our study imparts the usage of phytochemicals as antiviral agents for SARS-CoV-2 infection. Additional in vitro and in vivo testing of these phytochemicals is required to confirm their potency.

Molecular regulation of neuroinflammation in glaucoma: Current knowledge and the ongoing search for new treatment targets.

Neuroinflammation relying on the inflammatory responses of glial cells has emerged as an impactful component of the multifactorial etiology of neurodegeneration in glaucoma. It has become increasingly evident that despite early adaptive and reparative features of glial responses, prolonged reactivity of the resident glia, along with the peripheral immune cells, create widespread toxicity to retinal ganglion cell (RGC) axons, somas, and synapses. As much as the synchronized responses of astrocytes and microglia to glaucoma-related stress or neuron injury, their bi-directional interactions are critical to build and amplify neuroinflammation and to dictate the neurodegenerative outcome. Although distinct molecular programs regulate somatic and axonal degeneration in glaucoma, inhibition of neurodegenerative inflammation can provide a broadly beneficial treatment strategy to rescue RGC integrity and function. Since inflammatory toxicity and mitochondrial dysfunction are converging etiological paths that can boost each other and feed into a vicious cycle, anti-inflammatory treatments may also offer a multi-target potential. This review presents an overview of the current knowledge on neuroinflammation in glaucoma with particular emphasis on the cell-intrinsic and cell-extrinsic factors involved in the reciprocal regulation of glial responses, the interdependence between inflammatory and mitochondrial routes of neurodegeneration, and the research aspects inspiring for prospective immunomodulatory treatments. With the advent of powerful technologies, ongoing research on molecular and functional characteristics of glial responses is expected to accumulate more comprehensive and complementary information and to rapidly move the field forward to safe and effective modulation of the glial pro-inflammatory activities, while restoring or augmenting the glial immune-regulatory and neurosupport functions.

Molecular docking and dynamic simulation study to explore quercetin as a multi-potent candidate against gliomas


 
 
 
 Purpose: To search for novel gliomas targets and their inhibitors using a molecular docking approach.
 Methods: Quercetin multi-targeting potential was investigated against some of the emerging gliomas targets such as epidermal growth factor receptor (EGFR), ephrin type-A receptor 2 (EphA2), nicotinamide phosphoribosyltransferase (NMRPTase) and plasminogen activator inhibitor-1 (PAI-1). Crucial biochemical interaction of quercetin with these targets were analyzed using molecular docking study.
 Results: Quercetin interacted strongly via hydrogen bonding with important active sites consisting of amino acid residues of EphA2 and PAI-1, and showed binding energy of -7.44 and -7.38 kcal/mol, respectively. Some crucial active site amino acids involved in the interaction of known EphA2 and PAI-1 inhibitors (Alw-II-41-27 and ACT001) were common in quercetin interactions as well, and both inhibitors as well as quercetin did not violate Lipinski rules. Importantly, the quercetin-EphA2 and quercetin-PAI-1 complexes were stable as minimal fluctuations within the permissible limit were observed during a 20 ns trajectory performed on desmond simulation platform.
 Conclusion: Despite the fact that quercetin has been studied extensively against various cancer pathways, its transformation from a long-time bench candidate into bedside medications still needs further exploration. Nevertheless, the present predictive biochemical interaction analysis against emerging glioma targets might pave way for the design of novel therapeutic agents based on quercetin scaffolds.
 
 
 

Progression of the Wei-Qi-Ying-Xue syndrome, microcirculatory disturbances, in infectious diseases and treatment with traditional Chinese medicine

Lipopolysaccharide (LPS)-induced endotoxemia is a critical condition that initiates microcirculatory disturbance and may progress to multiple organ failure that threatens the lives of millions of people around the world each year. The pathology of endotoxemia involves multiple insults mediated by a range of signaling pathways. Multitarget management is required to relieve endotoxemia. Traditional Chinese medicine (TCM) is a type of therapeutic that commonly contains numerous components and, thus, exhibits multitarget potential. More importantly, some TCM formulas have been proposed and used for effective treatment of endotoxemia-like diseases. In the past 20 years, an increasing number of studies have explored the effects and mechanisms of these formulas and their major bioactive components on microcirculatory disturbance and organ injury caused by LPS. The results obtained thus far provide support for the clinical use of TCM and shed light on the underlying mechanisms.

Celastrol in cancer therapy: Recent developments, challenges and prospects.

Cancer is one of the world's biggest healthcare burdens and despite the current advancements made in treatment plans, the outcomes for oncology patients have yet to reach their full potential. Hence, there is a pressing need to develop novel anti-cancer drugs. A popular drug class for research are natural compounds, due to their multi-targeting potential and enhanced safety profile. One such promising natural bioactive compound derived from a vine, Tripterygium wilfordii is celastrol. Pre-clinical studies revolving around the use of celastrol have revealed positive pharmacological activities in various types of cancers, thus suggesting the chemical's potential anti-cancerous effects. However, despite the numerous preclinical studies carried out over the past few decades, celastrol has not reached human trials for cancer. In this review, we summarize the mechanisms and therapeutic potentials of celastrol in treatment for different types of cancer. Subsequently, we also explore the possible reasons hindering its development for human use as cancer therapy, like its narrow therapeutic window and poor pharmacokinetic properties. Additionally, after critically analysing both in vitro and in vivo evidence, we discuss about the key pathways effected by celastrol and the suitable types of cancer that can be targeted by the natural drug, thus giving insight into future directions that can be taken, such as in-depth analysis and research of the druggability of celastrol derivatives, to aid the clinical translation of this promising anti-cancer lead compound.

High-Throughput Screening and Molecular Dynamics Simulation of Natural Product-like Compounds against Alzheimer's Disease through Multitarget Approach.

Alzheimer’s disease (AD) is a progressive neurological disorder that affects 50 million people. Despite this, only two classes of medication have been approved by the FDA. Therefore, we have planned to develop therapeutics by multitarget approach. We have explored the library of 2029 natural product-like compounds for their multi-targeting potential against AD by inhibiting AChE, BChE (cholinergic pathway) MAO-A, and MOA-B (oxidative stress pathway) through in silico high-throughput screening and molecular dynamics simulation. Based on the binding energy of these target enzymes, approximately 189 compounds exhibited a score of less than −10 kcal/mol against all targets. However, none of the control inhibitors exhibited a binding affinity of less than −10 kcal/mol. Among these, the top 10 hits of compounds against all four targets were selected for ADME-T analysis. As a result, only F0850-4777 exhibited an acceptable range of physicochemical properties, drug-likeness, pharmacokinetics, and suitability for BBB permeation with high GI-A and non-toxic effects. The molecular dynamics study confirmed that F0850-4777 remained inside the binding cavity of targets in a stable conformation throughout the simulation and Prime-MM/GBSA study revealed that van der Waals’ energy (ΔGvdW) and non-polar solvation or lipophilic energy (ΔGSol_Lipo) contribute favorably towards the formation of a stable protein–ligand complex. Thus, F0850-4777 could be a potential candidate against multiple targets of two pathophysiological pathways of AD and opens the doors for further confirmation through in vitro and in vivo systems.