Showing papers in "Current Topics in Medicinal Chemistry in 2021"

Bioactive Compounds Effective Against Type 2 Diabetes Mellitus: A Systematic Review

Abstract: BACKGROUND Type 2 diabetes (adult onset diabetes) is the most common type of diabetes, accounting for around 90% of all diabetes cases with insulin resistance and insulin secretion defect. The key goal of anti-diabetic therapy is to increase the development of insulin, immunity and/or decrease the amount of blood glucose. While many synthetic compounds have been produced as antidiabetic agents, due to their side effects and limited effectiveness, their usefulness has been hindered. METHODS This systematic review investigated the bioactive compounds reported to possess activities against type 2 diabetes. Three (3) databases, PubMed, ScienceDirect and Google Scholar were searched for research articles published between January 2010 and October 2020. A total of 6464 articles were identified out of which 84 articles were identified to be elligible for the study. RESULT AND DISCUSSION From the data extracted, it was found that quercetin, Kaempferol, Rosmarinic acid, Cyanidin, Rutin, Catechin, Luteolin and Ellagic acid were the most cited bioactive compounds which all falls within the class of polyphenolic compounds. The major sources of these bioactive compounds includes citrus fruits, grapes, onions, berries, cherries, broccoli, honey, apples, green tea, Ginkgo biloba, St. John's wort, green beans, cucumber, spinach, tea, Rosmarinus officinalis, Aloe vera, Moringa oleifera, tomatoes, potatoes, oregano, lemon balm, thyme, peppermint, Ocimum basilicum, red cabbage, pears, olive oil and walnut.

A Review on Natural Sources Derived Protein Nanoparticles as Anticancer Agents.

Abstract: Cancer notably carcinoma represents a prominent health challenge worldwide. A variety of chemotherapeutic agents are being used to deal with a variety of carcinomas. However, these delivering agents not only enter the targeted site but also affect normal tissues yielding poor therapeutic outcomes. Chemotherapeutic-associated problems are being attributed to drug non-specificity resulting from poor drug delivery systems. These problems are now being solved using nanomedicine, which entails using nanoparticles as drug delivery systems or nanocarriers. This nanoparticle-based drug delivery system enhances clinical outcomes by enabling targeted delivery, improving drug internalization, enhanced permeability, easy biodistribution, prolonged circulation and enhanced permeability rate, thereby improving the therapeutic effectiveness of several anticancer agents. Natural Protein-based Nanoparticles (PNPs) such as ferritin, lipoprotein, and lectins from natural sources have gained extensive importance at a scientific community level as nanovehicle for effective drug delivery and photo acoustic labeling replacing several synthetic nanocarriers that have shown limited therapeutic outcomes. The bioavailability of PNP, the chance of genetic engineering techniques to modify their biological properties made them one of the important raw material sources for drug delivery research. This current review highlighted different chemotherapeutic agents used in the treatment of some carcinomas. It also focused on the wide variety of natural protein sources derived nanoparticles (NPs) as anticancer delivery of agents for cancer therapy.

The effect of recombinant human interferon alpha nasal drops to prevent COVID-19 pneumonia for medical staff in an epidemic area.

Abstract: BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), known as Coronavirus disease-2019 (COVID-19), has caused the sixth world's public health emergency. Healthcare staff, as the frontline population fighting the pandemic, are exposed to a high risk of infection. Therefore, developing a protective intervention for medical staff is of significant importance. OBJECTIVE: The aim of the study was to explore the effectiveness and safety of recombinant human interferon alpha (rhIFN-α) nasal drops for the prevention of coronavirus disease 2019 (COVID-19) through administering it to medical staff. METHODS: This was a prospective open-label clinical trial with parallel intervention assignment conducted on 2944 medical staff including both doctors and nurses from Taihe Hospital, Shiyan City, Hubei Province, China from January 21, 2020 to July 30, 2020. The participants were bifurcated into two groups of low risk and high risk groups according to the level of direct exposure to COVID-19 patients. The individuals of the low-risk group received rhIFN-α nasal drops for one month in addition to first level protection, and the high-risk group received a combination of rhIFN-α nasal drops coupled with thymosin-α1 with either second or third-level protection protocol. Moreover, the new-outset of COVID-19 pneumonia diagnosed by chest computed tomography (CT), after thirty days, was the primary outcome. The adverse reactions were recorded in all participants. RESULTS: 2415 of 2944 individuals belonged to the low-risk group, while 529 to the high-risk group. There was no COVID-19 pneumonia in either of the group after thirty days. The pulmonary CT scans were negative for COVID-19 pneumonia in both the groups with no new clinical symptoms. No serious adverse event was observed during the course of the intervention. CONCLUSION: The rhIFN-α nasal drops along with augmented safeguards based on standard physical isolation could effectively protect medical staff against COVID-19 pneumonia.

An Updated Review on SARS-CoV-2 Main Proteinase (MPro): Protein Structure and Small-Molecule Inhibitors.

Abstract: Coronaviruses (CoVs) are enveloped positive-stranded RNA viruses with spike (S) protein projections that allow the virus to enter and infect host cells. The S protein is a key virulence factor determining viral pathogenesis, host tropism, and disease pathogenesis. There are currently diverse corona viruses that are known to cause disease in humans. The occurrence of Middle East respiratory syndrome coronavirus (MERS-CoV) and Severe Acute Respiratory Syndrome coronavirus (SARS-CoV), as fatal human CoV diseases, has induced significant interest in the medical field. The novel coronavirus disease (COVID-19) is an infectious disease caused by a novel strain of coronavirus (SAR-CoV-2). The SARSCoV2 outbreak has been evolved in Wuhan, China, in December 2019, and identified as a pandemic on March 2020 resulting in 53.24 M cases and 1.20M deaths worldwide. SARS-CoV-2 main proteinase (MPro), a key protease of CoV-2, mediates viral replication and transcription. SARS-CoV-2 MPro has been emerged as an attractive target for SARS-CoV-2 drug design and development. Diverse scaffolds have been released targeting SARS-CoV-2 MPro. In this review, we culminate the latest published information about SARS-CoV-2 main proteinase (MPro) and reported inhibitors.

Cruzain and Rhodesain Inhibitors: Last Decade of Advances in Seeking for New Compounds Against American and African Trypanosomiases.

Abstract: Neglected tropical diseases (NTDs) are a group of approximately 20 diseases that affect part of the population in Sub- and Tropical countries In the past, pharmaceutical industries and governmental agencies have invested in the control, elimination and eradication of such diseases Among these diseases, Chagas disease (CD) and Human African trypanosomiasis (HAT) are a public health problem, mainly in the countries from the American continent and sub-Saharan African In this context, the search for new therapeutic alternatives against such diseases has been growing in recent years, presenting cysteine proteases as the main strategy to discover new anti-trypanosomal drugs Thus, cruzain and rhodesain enzymes are targets widely studied, since the cruzain is present in all stages of the parasite's life, related to the stages of proliferation and differentiation and infection of macrophages; while the rhodesain is related to the immune defense process In addition, knowledge about the amino acid sequences and availability of X-ray complexes have stimulated the drug searching against these targets, mainly through molecular modeling studies Thus, this review manuscript will be addressed to cruzain and rhodesain inhibitors developed in the last 10 years, and which could provide basis for new lead compounds in the discovery of new trypanocidal drugs We found 117 studies involving inhibitors of cruzain and rhodesain, being thiosemicarbazones, semicarbazones, N-acylhydrazones, thiazoles-hydrazone, thiazolidinones-hydrazones, oxadiazoles, triazoles, triazines, imidazoles, peptidomimetic, and others All references were obtained using "cruzain" or "rhodesain" and "inhibitor" as keywords in Science Direct, Bentham Science, PubMed, Espacenet, Springer, ACS Publisher, Wiley, Taylor and Francis, and MDPI (Multidisciplinary Digital Publishing Institute) databases Finally, we highlighted all these chemical classes of molecules to provide valuable information that could be used to design new inhibitors against Chagas disease and sleeping sickness in the future

Coumarin-1,2,3-triazole Hybrid Molecules: An Emerging Scaffold for Combating Drug Resistance.

Abstract: Undoubtedly, antibiotics have saved billions of lives, but lack of novel antibiotics, development of resistance mechanisms in almost all clinical isolates of bacteria, and recurrent infections caused by persistent bacteria hamper the successful treatment of the infections. Due to the widespread emergence of resistance, even the new families of anti-microbial agents have a short life expectancy. Drugs acting on a single target often lead to drug resistance and are associated with various side effects. For overcoming this problem, either multidrug therapy, or a single drug acting on multiple targets may be used. The latter is called 'hybrid molecules,' which are formed by clubbing two biologically active pharmacophores together, with or without an appropriate linker. In this rapidly evolving era, the development of natural product-based hybrid molecules may be a super-alternative to multidrug therapy, for combating drug resistance caused by various bacterial and fungal strains. Coumarins (benzopyran-2-one) are one of the earliest reported plant secondary metabolites having a clinically proven diverse range of pharmacological properties. On the other hand, 1,2,3-triazole is a common pharmacophore in many drugs responsible for polar interactions, improving the solubility and binding affinity to biomolecular targets. In this review, we discuss recent advances in Coumarin-1,2,3-triazole hybrids as potential anti-bacterial agents, aiming to provide a useful platform for the exploration of new leads with a broader spectrum, more effectiveness and less toxicity with multiple modes of action for the development of cost-effective and safer drugs in the future.

Chemical and Biological Evaluation of Thiosemicarbazone-Bearing Heterocyclic Metal Complexes.

Abstract: Thiosemicarbazones (TSCNs) constitute a broad family of compounds (R1R2C=N-NH-C(S)- NR3R4), particularly attractive because many of them display some biological activity against a wide range of microorganisms and cancer cells. Their activity can be related to their electronic and structural properties, which offer a rich set of donor atoms for metal coordination and a high electronic delocalization providing different binding modes for biomolecules. Heterocycles such as pyrrole, imidazole and triazole are present in biological molecules such as Vitamine B12 and amino acids and could potentially target multiple biological processes. Considering this, we have explored the chemistry and biological properties of thiosemicarbazones series and their complexes bearing heterocycles such as pyrrole, imidazole, thiazole and triazole. We focus at the chemistry and cytotoxicity of those derivatives to find out the structure activity relationships, and particularly we analyzed those examples with the TSCN units in which the mechanism of action information has been profoundly studied and pathways determined, to promote future studies for heterocycle derivatives.

Computational and Experimental Approaches to Investigate Lipid Nanoparticles as Drug and Gene Delivery Systems.

Abstract: Lipid nanoparticles (LNPs) have been widely applied in drug and gene delivery. More than twenty years ago, DoxilTM was the first LNPs-based drug approved by the US Food and Drug Administration (FDA). Since then, with decades of research and development, more and more LNP-based therapeutics have been used to treat diverse diseases, which often offer the benefits of reduced toxicity and/or enhanced efficacy compared to the active ingredients alone. Here, we provide a review of recent advances in the development of efficient and robust LNPs for drug/gene delivery. We emphasize the importance of rationally combining experimental and computational approaches, especially those providing multiscale structural and functional information of LNPs, to the design of novel and powerful LNP-based delivery systems.

New Pharmacological Targets for the Treatment of Schizophrenia: A Literature Review.

Abstract: BACKGROUND The pharmacological treatment of schizophrenia is currently based on the employment of antipsychotic medications showing an antagonism of dopaminergic and serotoninergic inhibitors. 20-40% of patients are drug-resistant or residually symptomatic in the long-term antipsychotic treatment, and new strategies are needed for improving their functional and cognitive impairment. METHODS This systematic review has summarized evidences from the literature regarding the newer pharmacological targets proposed for the treatment of psychosis. We included 128 peer-reviewed articles and 5 other relevant sources published from 2002 to 2020 on PubMed EMBASE, The Cochrane Library, and Google Scholar. RESULTS The possible role of glutamate and its receptors as targets of the antipsychotic mechanism of action has been described. Glutamatergic neurotransmission and NMDA receptors hypofunction are involved in the neurobiological explanatory model of psychosis and possibly targeted for the successful treatment of cognitive and residual symptoms. Results show an efficacy of D-cycloserine (antagonist at the Glycine site of the NMDA-R) in the treatment of negative symptoms of schizophrenia as well as Memantine (NMDA- Receptor antagonist) for cognition and psychopathology. The putative antipsychotic effect of cannabidiol on positive symptoms and cognition will also be discussed. The action on serotoninergic and GABAergic receptors will be considered as a new pharmacological target, with a possible efficacy of Vabicaserin on symptoms of psychosis. Mynocicline has shown to induce improvements in cognitive symptoms in schizophrenia, as well as Erythropoietin. Oxytocin has been reported to have an antipsychotic-like effect; moreover, COX-2 inhibitors lead to a reduction in positive symptoms of psychosis, specifically in the first episode of illness. CONCLUSION This narrative report suggests a promising role of new agents in the treatment of Schizophrenia; however, more research is needed to approve their clinical employment.

Docking Paradigm in Drug Design.

Abstract: Docking is demanded in the rational computer aided structural based drug design. A review of docking methods and programs is presented. Different types of docking programs are described. They include docking of non-covalent small ligands, protein-protein docking, supercomputer docking, quantum docking, the new generation of the docking programs and the application of docking for covalent inhibitors discovery. Taking into account the threat of COVID-19 we present here a short review of docking applications to discovery of inhibitors of SARS-CoV and SARS-CoV-2 target proteins including our own original result of the search for inhibitors of SARS-CoV-2 main protease using docking and quantum chemical post-processing. The conclusion is made that docking is extremely demanded in the fighting against COVID-19 at the process of development of antivirus drugs of the direct action on SARS-CoV-2 target proteins.

Bergenin - a biologically active scaffold: Nanotechnological perspectives.

Abstract: Bergenin, 4-O-methyl gallic acid glucoside, is a bioactive compound present in various plants belonging to different families. The present work compiles scattered information on pharmacology, structure activity relationship and nanotechnological aspects of bergenin, collected from various electronic databases such as Sci Finder, PubMed, Google scholar, etc. Bergenin has been reported to exhibit hepatoprotective, anti-inflammatory, anticancer, neuroprotective, antiviral and antimicrobial activities. Molecular docking studies have shown that isocoumarin pharmacophore of bergenin is essential for its bioactivities. Bergenin holds a great potential to be used as lead molecule and also as a therapeutic agent for development of more efficacious and safer semisynthetic derivatives. Nanotechnological concepts can be employed to overcome poor bioavailability of bergenin. Finally, it is concluded that bergenin can be emerged as clinically potential medicine in modern therapeutics.

Indole Alkaloids, Synthetic Dimers and Hybrids with Potential In Vivo Anticancer Activity.

Abstract: Indole, a heterocyclic organic compound, is one of the most promising heterocycles found in natural and synthetic sources since its derivatives possess fascinating structural diversity and various therapeutic properties. Indole alkaloids, synthetic dimers and hybrids could act on diverse targets in cancer cells, and consequently, possess potential antiproliferative effects on various cancers both in vitro and in vivo. Vinblastine, midostaurin, and anlotinib as the representative of indole alkaloids, synthetic dimers and hybrids respectively, have already been clinically applied to treat many types of cancers, demonstrating indole alkaloids, synthetic dimers and hybrids are useful scaffolds for the development of novel anticancer agents. Covering articles published between 2010 and 2020, this review emphasizes the recent development of indole alkaloids, synthetic dimers and hybrids with potential in vivo therapeutic application for cancers.

The Effects on Angiogenesis of Relevant Inorganic Chemotherapeutics.

Abstract: Angiogenesis is a key process allowing the formation of blood vessels. It is crucial for all the tissues and organs, ensuring their function and growth. Angiogenesis is finely controlled by several mechanisms involving complex interactions between pro- or antiangiogenic factors, and an imbalance in this control chain may result in pathological conditions. Metals as copper, zinc and iron cover an essential role in regulating angiogenesis, thus therapies having physiological metals as target have been proposed. In addition, some complexes of heavier metal ions (e.g., Pt, Au, Ru) are currently used as established or experimental anticancer agents targeting genomic or non-genomic targets. These molecules may affect the angiogenic mechanisms determining different effects that have been only poorly and non-systematically investigated so far. Accordingly, in this review article, we aim to recapitulate the impact on the angiogenic process of some reference anticancer drugs, and how it is connected to the overall pharmacological effects. In addition, we highlight how the activity of these drugs can be related to the role of biological essential metal ions. Overall, this may allow a deeper description and understanding of the antineoplastic activity of both approved or experimental metal complexes, providing important insights for the synthesis of new inorganic drugs able to overcome resistance and recurrence phenomena.

Breast Cancer Transcriptional Regulatory Network Reprogramming by using the CRISPR/Cas9 system: An Oncogenetics Perspective.

Abstract: Breast cancer (BC) is the second most commonly diagnosed cancer in the world. BC develops due to dysregulation of transcriptional profiles, substantial interpatient variations, genetic mutations, and dysregulation of signaling pathways in breast cells. These events are regulated by many genes such as BRCA1/2, PTEN, TP53, mTOR, TERT, AKT, PI3K and others genes. Treatment options for BC remain a hurdle, which warrants a comprehensive understanding that establishes an interlinking connection between these genes in BC tumorigenesis. Consequently, there is an increasing demand for alternative treatment approaches and the design of more effective treatments. In this regard, it is crucial to build the corresponding transcriptional regulatory networks governing BC by using advanced genetic tools and techniques. In the past, several molecular editing technologies have been used to edit genes with several limitations. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR Associated Protein 9 (CRISPR/Cas9) recently received a profound attention due to its potential in biomedical and therapeutic applications. Here, we review the role of various molecular signalling pathways dysregulated in BC development such as PTEN/PI3K/AKT/mTOR as well as BRCA1/BRCA2/TP53/TERT and their interplay between the related gene networks in BC initiation, progression and development of resistance against available targeted therapeutic agents. Use of CRISPR/Cas9 gene-editing technology to generate BC gene-specific transgenic cell lines and animal models to decipher their role and interactions with other gene products has been employed successfully. Moreover, the significance of using CRISPR/Cas9 technology to develop early BC diagnostic tools and treatments is discussed here.

Quinoline-based compounds with potential activity against drug-resistant cancers

Abstract: Drug resistance is the major cause of the failure of cancer chemotherapy, so one of the most important features in developing effective cancer therapeutic strategies is to overcome drug resistance Quinoline moiety has become one of the most privileged structural motifs in anticancer agent discovery since its derivatives possess potential activity against various cancers including drug-resistant cancers Several quinoline-based compounds which are represented by Anlotinib, Bosutinib, Lenvatinib, and Neratinib have already been applied in clinical practice to fight against cancers, so quinoline-based compounds are potential anticancer agents The present short review article provides an overview about the recent advances of quinoline-based compounds with potential activity against drug-resistant cancers The structure-activity relationship and mechanisms of action are also discussed

Interaction of Platinum-based Drugs with Proteins: An Overview of Representative Crystallographic Studies

Abstract: Pt-based drugs are widely used in clinics for the treatment of cancer The mechanism of action of these molecules relies on their interaction with DNA However, the recognition of these metal compounds by proteins plays an important role in defining pharmacokinetics, side effects and their overall pharmacological profiles Single crystal X-ray diffraction studies provided important information on the molecular mechanisms at the basis of this process Here, the molecular structures of representative adducts obtained upon reaction with proteins of selected Pt-based drugs, including cisplatin, carboplatin and oxaliplatin, are briefly described and comparatively examined Data indicate that metal ligands play a significant role in driving the reaction of Pt compounds with proteins; non-covalent interactions that occur in the early steps of Pt compound/protein recognition process play a crucial role in defining the structure of the final Pt-protein adduct In the metallated protein structures, Pt centers coordinate few protein side chains, such as His, Met, Cys, Asp, Glu and Lys residues upon releasing labile ligands

Multi-target Drug Discovery via PTML Modeling: Applications to the Design of Virtual Dual Inhibitors of CDK4 and HER2.

Abstract: Background Cyclin-dependent kinase 4 (CDK4) and the human epidermal growth factor receptor 2 (HER2) are two of the most promising targets in oncology research. Thus, a series of computational approaches have been applied to the search for more potent inhibitors of these cancerrelated proteins. However, current approaches have focused on chemical analogs while predicting the inhibitory activity against only one of these targets, but never against both. Aims We report the first perturbation model combined with machine learning (PTML) to enable the design and prediction of dual inhibitors of CDK4 and HER2. Methods Inhibition data for CDK4 and HER2 were extracted from ChEMBL. The PTML model relied on artificial neural networks to allow the classification/prediction of molecules as active or inactive against CDK4 and/or HER2. Results The PTML model displayed sensitivity and specificity higher than 80% in the training set. The same statistical metrics had values above 75% in the test set. We extracted several molecular fragments and estimated their quantitative contributions to the inhibitory activity against CDK4 and HER2. Guided by the physicochemical and structural interpretations of the molecular descriptors in the PTML model, we designed six molecules by assembling several fragments with positive contributions. Three of these molecules were predicted as potent dual inhibitors of CDK4 and HER2, while the other three were predicted as inhibitors of at least one of these proteins. All the molecules complied with Lipinski's rule of five and its variants. Conclusion The present work represents an encouraging alternative for future anticancer chemotherapies.

"Big Three" Infectious Diseases: Tuberculosis, Malaria and HIV/AIDS.

Abstract: Infectious diseases have been evolving and re-evolving over the ages and causing immense misery to humans. Among them, some have been prevented and eradicated, but few are still threatening the modern era since their origin. The majority of these infectious diseases are poverty-driven, hence highly prevalent in the lower-income and mid-income countries of Africa and Asia. The world's deadliest infections, including Tuberculosis, Malaria and HIV/AIDS, have been considered as the "Big Three" infectious diseases (BTIDs). With leading infections and deaths every year, the BTIDs have been recognized as the world's greatest pandemics. In light of these alarming situations, this review has been aimed to provide a comprehensive overview of the current status of chemotherapeutics, associated challenges and future perspectives of BTIDs.

An Overview of Ovarian Cancer: Molecular Processes Involved and Development of Target-based Chemotherapeutics.

Abstract: Ovarian cancer is one of the leading gynecologic diseases with a high mortality rate worldwide. Current statistical studies on cancer reveal that over the past two decades, the fifth most common cause of death related to cancer in females of the western world is ovarian cancer. In spite of significant strides made in genomics, proteomics and radiomics, there has been little progress in transitioning these research advances into effective clinical administration of ovarian cancer. Consequently, researchers have diverted their attention to finding various molecular processes involved in the development of this cancer and how these processes can be exploited to develop potential chemotherapeutics to treat this cancer. The present review gives an overview of these studies which may update the researchers on where we stand and where to go further. The unfortunate situation with ovarian cancer that still exists is that most patients with it do not show any symptoms until the disease has moved to an advanced stage. Undoubtedly, several targets-based drugs have been developed to treat it, but drug-resistance and the recurrence of this disease are still a problem. For the development of potential chemotherapeutics for ovarian cancer, however, some theoretical approaches have also been applied. A description of such methods and their success in this direction is also covered in this review.

The Reification of the Clinical Diagnosis of Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) as an Immune and Oxidative Stress Disorder: Construction of a Data-driven Nomothethic Network and Exposure of ME/CFS Subgroups

Abstract: The approach towards myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) remains in a permanent state of crisis with fierce competition between the psychosocial school, which attributes ME/CFS to the perception of effort, and the medical approach (Maes and Twisk, BMC Med, 2010,8,35). The aim of this paper is to review how to construct a nomothetic model of ME/CFS using Partial Least Squares (PLS) path analysis and ensembling causome (bacterial translocation as assessed with IgM/IgA responses to LPS), protectome (lowered coenzyme Q10), adverse outcome pathways (AOP) including increased lysozyme, CD38+ T cell activation, cell-mediated immune activation (CMI), and IgM responses to oxidative specific epitopes and NO-adducts (IgM OSENO). Using PLS, we trained, tested and validated this knowledge- and data-driven causal ME/CFS model, which showed adequate convergence, construct and replicability validity. This bottom-up explicit data model of ME/CFS objectivates the descriptive narratives of the ME/CFS phenome, using causome-protectome-AOP data, whereby the abstract concept ME/CFS is translated into pathways, thereby securing the reification of the ME/CFS phenome. We found that 31.6% of the variance in the physiosomatic symptom dimension of ME/CFS was explained by the cumulative effects of CMI and CD38+ activation, IgM OSENO, IgA LPS, lysozyme (all positive) and coenzyme Q10 (inversely). Cluster analysis performed on the PLS-generated latent vector scores of all feature sets exposed three distinct immune groups of ME/CFS, namely one with increased lysozyme, one with increased CMI + CD38 activation + depressive symptoms, and another with increased bacterial translocation + autoimmune responses to OSENO.

Tuberculosis: An Update on Pathophysiology, Molecular Mechanisms of Drug Resistance, Newer Anti-TB Drugs, Treatment Regimens and Host- Directed Therapies.

Abstract: Human tuberculosis (TB) is primarily caused by Mycobacterium tuberculosis (Mtb) that inhabits inside and amidst immune cells of the host with adapted physiology to regulate interdependent cellular functions with intact pathogenic potential. The complexity of this disease is attributed to various factors such as the reactivation of latent TB form after prolonged persistence, disease progression specifically in immunocompromised patients, advent of multi- and extensivelydrug resistant (MDR and XDR) Mtb strains, adverse effects of tailor-made regimens, and drug-drug interactions among anti-TB drugs and anti-HIV therapies. Thus, there is a compelling demand for newer anti-TB drugs or regimens to overcome these obstacles. Considerable multifaceted transformations in the current TB methodologies and molecular interventions underpinning hostpathogen interactions and drug resistance mechanisms may assist to overcome the emerging drug resistance. Evidently, recent scientific and clinical advances have revolutionised the diagnosis, prevention, and treatment of all forms of the disease. This review sheds light on the current understanding of the pathogenesis of TB disease, molecular mechanisms of drug-resistance, progress on the development of novel or repurposed anti-TB drugs and regimens, host-directed therapies, with particular emphasis on underlying knowledge gaps and prospective for futuristic TB control programs.

Predicting Metabolic Reaction Networks with Perturbation-Theory Machine Learning (PTML) Models

Abstract: Background Checking the connectivity (structure) of complex Metabolic Reaction Networks (MRNs) models proposed for new microorganisms with promising properties is an important goal for chemical biology. Objective In principle, we can perform a hand-on checking (Manual Curation). However, this is a challenging task due to the high number of combinations of pairs of nodes (possible metabolic reactions). Results The CPTML linear model obtained using the LDA algorithm is able to discriminate nodes (metabolites) with the correct assignation of reactions from incorrect nodes with values of accuracy, specificity, and sensitivity in the range of 85-100% in both training and external validation data series. Methods In this work, we used Combinatorial Perturbation Theory and Machine Learning techniques to seek a CPTML model for MRNs g40 organisms compiled by Barabasis' group. First, we quantified the local structure of a very large set of nodes in each MRN using a new class of node index called Markov linear indices fk. Next, we calculated CPT operators for 150000 combinations of query and reference nodes of MRNs. Last, we used these CPT operators as inputs of different ML algorithms. Conclusion Meanwhile, PTML models based on Bayesian network, J48-Decision Tree and Random Forest algorithms were identified as the three best non-linear models with accuracy greater than 97.5%. The present work opens the door to the study of MRNs of multiple organisms using PTML models.

An Updated Review on Betacoronavirus Viral Entry Inhibitors: Learning from Past Discoveries to Advance COVID-19 Drug Discovery.

Abstract: Even after one year of its first outbreak reported in China, the coronavirus disease 2019 (COVID-19) pandemic is still sweeping the World, causing serious infections and claiming more fatalities. COVID-19 is caused by the novel coronavirus SARS-CoV-2, which belongs to the genus Betacoronavirus (β-CoVs), which is of greatest clinical importance since it contains many other viruses that cause respiratory disease in humans, including OC43, HKU1, SARS-CoV, and MERS. The spike (S) glycoprotein of β-CoVs is a key virulence factor in determining disease pathogenesis and host tropism, and it also mediates virus binding to the host's receptors to allow viral entry into host cells, i.e., the first step in virus lifecycle. Viral entry inhibitors are considered promising putative drugs for COVID-19. Herein, we mined the biomedical literature for viral entry inhibitors of other coronaviruses, with special emphasis on β-CoVs entry inhibitors. We also outlined the structural features of SARS-CoV-2 S protein and how it differs from other β-CoVs to better understand the structural determinants of S protein binding to its human receptor (ACE2). This review highlighted several promising viral entry inhibitors as potential treatments for COVID-19.

The Role of Peroxisome Proliferator-Activated Receptor in Addiction: A Novel Drug Target.

Abstract: The peroxisome proliferator activated receptors (PPARs) are a superfamily of well-recognized ligand-binding nuclear receptors comprising three isoforms: PPARα, PPARγ, and PPARβ/δ. In response to endogenous lipid messengers, PPARs trigger the transcription of genes related to a wider spectrum of physiological phenomena, including fatty acid oxidation, inflammation, adipogenesis, among many others. Thus, the importance of PPARs as putative protective therapy in health issues has increased the interest of studying these nuclear receptors, including the management of neurodegenerative disorders, multiple sclerosis, and likely addiction. In recent years, several pieces of evidence from animal models have demonstrated the promising role of PPARs as a critical element for interventions in addictive behaviors by reducing the reinforcing properties of addictive substances such as alcohol. However, there is a lack of data in the scope and has so far been unexplored the function of PPARs in additional drugs such as cannabis, opioids, methamphetamine, or cocaine. A similar scenario has been found for the management of binge-type eating disorders. Thus, here we review recent advances in understanding the relevance of the PPAR controlling addiction.

Nanoscale Drug Delivery Systems for Glaucoma: Experimental and In Silico Advances.

Abstract: In this review, nanoscale-based drug delivery systems, particularly in relevance to the antiglaucoma drugs, have been discussed. In addition to that, the latest computational/in silico advances in this field are examined in brief. Using nanoscale materials for drug delivery is an ideal option to target tumours, and the drug can be released in areas of the body where traditional drugs may fail to act. Nanoparticles, polymeric nanomaterials, single-wall carbon nanotubes (SWCNTs), quantum dots (QDs), liposomes and graphene are the most important nanomaterials used for drug delivery. Ocular drug delivery is one of the most common and difficult tasks faced by pharmaceutical scientists because of many challenges like circumventing the blood-retinal barrier, corneal epithelium and the blood-aqueous barrier. Authors found compelling empirical evidence of scientists relying on in-silico approaches to develop novel drugs and drug delivery systems for treating glaucoma. This review in nanoscale drug delivery systems will help us understand the existing queries and evidence gaps and will pave the way for the effective design of novel ocular drug delivery systems.

Role of Phytomolecules in the Treatment of Obesity: Targets, Mechanisms and Limitations.

Abstract: Obesity has become a worldwide health problem. It triggers additional co-morbidities like cardiovascular diseases, cancer, depression, sleep disorders, gastrointestinal problems and many more. Excess accumulation of fat in obesity could be caused by many factors like sedentary lifestyle, consumption of high-fat diet, genetic predisposition, etc. Imbalanced energy metabolism i.e., greater energy consumption than utilisation, invariably underlies obesity. Considering the high prevalence and continuous, uncontrolled increase of this major public health issue, there is an urgent need to find appropriate therapeutic agents with minimal or no side effects. The high prevalence of obesity in recent years has led to a surge in the number of drugs available in the market that claim to control obesity. Although there is a long list of medicines and management strategies that are available, selecting the right therapeutic intervention and feasible management of obesity is a challenge. Several phytochemicals like hydroxycitric acid, flavonoids, tannins, anthocyanins, phytohaemagglutinin, thymoquinone and epigallocatechin gallate have been shown to possess promising anti-obesity properties. However, studies providing information on how various phytochemicals exert their anti-obesity effects are inadequate. This calls for more experimentation in this less explored area of research. Additionally, the complication of obesity arises when it is a result of multiple factors and associated with a number of co-morbidities. In order to handle such complexities, combinatorial therapeutic interventions become effective. In this review, we have described the medicinal chemistry of different highly effective phytochemicals which can be used in the effective treatment and management of obesity.

Role of Extracellular Vesicles in Glioma Progression: Deciphering Cellular Biological Processes to Clinical Applications.

Abstract: Glioma predominantly targets glial cells in the brain and spinal cord. There are grade I, II, III, and IV gliomas with anaplastic astrocytoma and glioblastoma multiforme as the most severe forms of the disease. Current diagnostic methods are limited in their data acquisition and interpretation, markedly affecting treatment modalities and patient outcomes. Circulating extracellular vesicles (EVs) or "magic bullets" contain bioactive signature molecules such as DNA, RNA, proteins, lipids, and metabolites. These secretory "smart probes" participate in myriad cellular activities, including glioma progression. EVs are released by all cell populations and may serve as novel diagnostic biomarkers and efficient nanovehicles in the targeted delivery of encapsulated therapeutics. The present review describes the potential of EVbased biomarkers for glioma management.

Detection of Natural Inhibitors against Human Liver Cancer Cell Lines through QSAR, Molecular Docking and ADMET Studies.

Abstract: BACKGROUND Liver cancer is ranked as the fifth most prevalent and third most lethal cancer worldwide. The incidence rates of this cancer are on the rise, and only limited treatment options are available. METHODS To identify and optimize the inhibitors of liver cancer cell-lines, a QSAR model was developed by using multiple linear regression methods. The robustness of the model was validated through statistical methods and wet-lab experiments. RESULTS The developed QSAR models yielded high activity descriptor relationship accuracy of 91%, referred to by regression coefficient (r2= 0.91), and a high activity prediction accuracy of 89%. The external predicted (pred_r2) ability of the model was found to be 90%. CONCLUSION The QSAR study indicates that chemical descriptors such as to measure of electronegative atom count (Epsilon3), atom type count descriptors (MMFF_10), number of a carbon atom connected with four single bonds (SssssCE- index), molecular weight and, number of oxygen atom connected with two aromatic bonds (SaaOE-index) are significantly correlated with anticancer activity. The model, which was validated statistically and through wet-lab experiments, was further used in the virtual screening of potential inhibitors against the liver cancer cell line WRL68. ADMET risk screening, synthetic accessibility, and Lipinski's rule of five are used to filter false positive hits. AfterwardS, to achieve a set of aligned ligand poses and rank the predicted active compounds, docking studies were carried out. The studied compounds and their metabolites were also analyzed for different pharmacokinetics parameters. Finally, a series of compounds was proposed as anticancer agents.

Hyaluronan-based Multifunctional Nano-carriers for Combination Cancer Therapy.

Abstract: Hyaluronan (HA) is a natural linear polysaccharide that has excellent hydrophilicity, biocompatibility, biodegradability, and low immunogenicity, making it one of the most attractive biopolymers used for biomedical researches and applications. Due to the multiple functional sites on HA and its intrinsic affinity for CD44, a receptor highly expressed on various cancer cells, HA has been widely engineered to construct different drug-loading nanoparticles (NPs) for CD44-targeted anti-tumor therapy. When a cocktail of drugs is co-loaded in HA NP, a multifunctional nano-carriers could be obtained, which features as a highly effective and self-targeting strategy to combat cancers with CD44 overexpression. The HA-based multidrug nano-carriers can be a combination of different drugs, various therapeutic modalities, or the integration of therapy and diagnostics (theranostics). Up to now, there are many types of HA-based multidrug nano-carriers constructed by different formulation strategies, including drug co-conjugates, micelles, nano-gels and hybrid NP of HA and so on. This multidrug nano-carrier takes the full advantages of HA as an NP matrix, drug carriers and targeting ligand, representing a simplified and biocompatible platform to realize the targeted and synergistic combination therapy against the cancers. In this review, recent progress of HA-based multidrug nano-carriers for combination cancer therapy is summarized and the potential challenges for translational applications have been discussed.