Showing papers in "Current Drug Discovery Technologies in 2022"

Cancer Chemotherapy via Natural Bioactive Compounds.

Abstract: BACKGROUND Cancer-induced mortality is increasingly prevalent globally which skyrocketed the necessity to discover new/novel safe and effective anticancer drugs. Cancer is characterized by the continuous multiplication of cells in the human which is unable to control. Scientific research is drawing its attention towards naturally-derived bioactive compounds as they have fewer side effects compared to the current synthetic drugs used for chemotherapy. OBJECTIVE Drugs isolated from natural sources and their role in the manipulation of epigenetic markers in cancer are discussed briefly in this review article. METHODS With advancing medicinal plant biotechnology and microbiology in the past century, several anticancer phytomedicines were developed. Modern pharmacopeia contains at least 25% herbal-based remedy including clinically used anticancer drugs. These drugs mainly include the podophyllotoxin derivatives vinca alkaloids, curcumin, mistletoe plant extracts, taxanes, camptothecin, combretastatin, and others including colchicine, artesunate, homoharringtonine, ellipticine, roscovitine, maytanasin, tapsigargin,andbruceantin. RESULTS Compounds (psammaplin, didemnin, dolastin, ecteinascidin,and halichondrin) isolated from marine sources and animals such as microalgae, cyanobacteria, heterotrophic bacteria, invertebrates. They have been evaluated for their anticancer activity on cells and experimental animal models and used chemotherapy.Drug induced manipulation of epigenetic markers plays an important role in the treatment of cancer. CONCLUSION The development of a new drug from isolated bioactive compounds of plant sources has been a feasible way to lower the toxicity and increase their effectiveness against cancer. Potential anticancer therapeutic leads obtained from various ethnomedicinal plants, foods, marine, and microorganisms are showing effective yet realistically safe pharmacological activity. This review will highlight important plant-based bioactive compounds like curcumin, stilbenes, terpenes, other polyphenolic phyto-compounds, and structurally related families that are used to prevent/ ameliorate cancer. However, a contribution from all possible fields of science is still a prerequisite for discovering safe and effective anticancer drugs.

Targeting G-Quadruplex Dna For Cancer Chemotherapy.

Abstract: The self-association of DNA formed by Hoogsteen hydrogen bonding comprises several layers of four guanine or G-tetrads or G4s. The distinct feature of G4s, such as the G-tetrads and loops, qualify structure-selective recognition by small molecules and various ligands and can act as potential anticancer therapeutic molecules. The G4 selective-ligands, can influence gene expression by targeting a nucleic acid structure rather than sequence. Telomere G4 can be targeted for cancer treatment by small molecules inhibiting the telomerase activity whereas c-MYC is capable of controlling transcription, can be targeted to influence transcription. The k-RAS is one of the most frequently encountered oncogenic driver mutations in pancreatic, colorectal, and lung cancers. The k-RAS oncogene plays important role in acquiring and increasing the drug resistance and can also be directly targeted by small molecules to combat k-RAS mutant tumors. Modular G4 ligands with different functional groups, side chains and rotatable bonds as well as conformation affect the binding affinity/selectivity in cancer chemotherapeutic interventions. These modular G4 ligands act by targeting the diversity of G4 loops and groves and assists to develop more drug-like compounds with selectivity. In this review, we present the recent research on synthetic G4 DNA-interacting ligands as an approach toward the discovery of target specific anticancer chemotherapeutic agents.

A Review on Herbal Drugs Used in the Treatment of Peptic Ulcer.

Abstract: BACKGROUND An ulcer is a condition characterized by inflammation, irritation, or erosion in the mucosal lining of the stomach or duodenum. Hence, peptic ulcer is the ulcer of both the stomach and the duodenum. 10% of the world's population is affected by chronic peptic ulcers. The formation of peptic ulcers depends on gastric juice pH and the decrease in mucosal defenses. Nonsteroidal anti-inflammatory drugs (NSAIDs) and Helicobacter pylori (H. pylori) infection are the two significant factors disrupting mucosal resistance to injury. Indian herbal plants are exceptional for their ethnic, ethnobotanical, and ethno-pharmaceutical use. In this review, attempts have been made to gain information regarding some plants that may be used to treat or prevent peptic ulcers. The ultimate goal of peptic ulcer disease treatment is to reduce pain, cure ulcers, and prevent recurrence. OBJECTIVE The aim of the study was to gain knowledge about several common medicinal plants employed in Ayurveda or contemporary science for the treatment or prevention of peptic ulcers and some natural and simple approaches to cure ulcers using readily available herbs. METHOD The literature search was carried out using search engines, like Google Scholar, Scopus, PubMed, Medline, Springer, etc. Results: The extensive literature search showed natural herbs to have potential anti-ulcer activity, including cabbage, bananas, liquorice, fenugreek, garlic, Terminalia chebula, Acacia arabica, Aegle marmelos, Aloe vera, Allium sativum, Plantago ispagula, Mimosa pudica, Annona squamosa, Azadirachta indica, and Galega purpurea. CONCLUSION This study concluded several medicinal plants to effectively prevent or cure peptic ulcers caused by a variety of factors, including H. pylori, aspirin, indomethacin, alcohol, and others.

Small Molecule Allosteric Activators of Human Glucokinase for the Treatment of Type 2 Diabetes: Current Status and Challenges.

Abstract:

Evaluating the antifungal activity of Rumex acetosella, Teucrium polium, and Glycyrrihize globra var. violacca on pathogenic dermatophytes and determining phenolic compounds.

Abstract: INTRODUCTION Dermatophytes are a group of fungi that can invade the keratinized tissues of humans and other animals, thereby causing dermatophytosis. The high cost of treatment, side effects of drugs, and sometimes resistance of pathogens to synthetic drugs are some of the factors that have led to search attempts for new drugs. This study aimed to investigate the anti-dermatophytic effects of ethanolic and methanolic extracts of Romex acetosella, Teucrium polium, and Glycyrrhiza glabra against dermatophytes of Microsporum canis, Microsporum gypseum, and Trichophyton mentagrophytes and to determine the amount of phenol in these plants. METHODS In this descriptive comparative study, after collecting and identifying Rumex acetosella, Teucrium polium, and Glycyrrhiza glabra, they were washed and dried in the shade. Then, methanolic and ethanolic extracts of these plants were prepared using the Soxhlet apparatus. The antifungal activity of these extracts was investigated in vitro against Microsporum canis, Microsporum gypseum, and Trichophyton mentagrophytes through diffusion and agar dilution method according to CLSI instructions. Further, the minimum inhibitory concentration [MIC] and the minimum fungicidal concentration [MFC] of the extracts were determined in comparison with griseofulvin. In addition, the amount of phenol in these extracts was determined by an optical spectrophotometer. RESULTS Methanolic and ethanolic extracts of Tocrium polium, Rumex acetosella, and Glabra glycyrrhizae revealed that the highest inhibition zones of Trichophyton mentagrophytes PTCC 5054, Microsporum canis PTCC 5069, and Microsporum gypseum PTCC 5070 were related to the methanolic extract of Teucrium polium at 200 mg/ml at 23.41, 23.45, and 25.30 mm, respectively. The highest growth rates of Trichophyton mentagrophytes, Microsporum canis, and Microsporum gypseum at 2.5 mg/ml in Glabra glycyrrhizae ethanolic extract by agar dilution method were 19.07, 18.32, and 17.81 mm, respectively. The minimum growths of Trichophyton mentagrophytes, Microsporum canis, and Microsporum gypseum were observed in the plate containing 40 mg/ml of the methanolic extract of Teucrium polium with 5.62, 3.72, and 5.41 mm diameters, respectively. Their MIC was less than 6.25 mg/ml. The ethanolic and methanolic extracts of Teucrium polium had 227.33 and 482.89 μg of tannic acid/ml of the extract, respectively. The ethanolic and methanolic extracts of Rumex acetosella had 94 and 475.48 μg of tannic acid/ml of the extract, respectively. Finally, the ethanolic and methanolic extracts of Glabra glycerol had 27.33 and 60.67 μg of tannic acid/ml of the extract, respectively. CONCLUSION Based on the results, methanolic extracts of the studied plants had a greater inhibitory effect than ethanolic extracts. Methanolic extracts of these plants after extensive testing for toxicity and in vivo studies can be a suitable treatment option as adjunctive drugs or alternatives to chemical drugs.

Herbal medicines for idiopathic male infertility: A Systematic Review.

Abstract: BACKGROUND Various medications, surgeries, and assisted reproductive techniques are used to treat male infertility, but the high cost and low effectiveness have made these methods unpopular. the use of herbal medicines such as Withania somnifera, Ceratonia siliqua, Nigella sativa and Alpinia officinarum for the treatment of male infertility has become highly popular in recent years. OBJECTIVE We conducted this systematic review to evaluate the recent scientific evidence regarding herbal medicines used to treat idiopathic male infertility [IMI]. METHOD Online literature resources were checked using different search engines, including ISI, Web of Knowledge, Medline, PubMed, Scopus, and Google Scholar. Date restrictions were applied to 2020, and the publication language was restricted to English and Persian. The risk of bias was evaluated using the Cochrane method. RESULT Out of 851 articles, 14 trials with 1218 participants were included. Of the 15 plants and medicinal products introduced in the selected studies, 12 cases were effective in treating male infertility. Each of these plants or products affects specific components of male fertility for which various mechanisms were mentioned, but most of them had antioxidant effects. No serious side effects were reported. CONCLUSION Whitania somnifera roots, Alpinia officinarum, Nigella sativa seeds, Tomato, and Ceratonia siliqua and the formulation of Xperm, PHF, Churna Ratnam, Svaguptadi Churna, Y virilin capsule, manix capsule, and Tradafertil tablet revealed successful outcomes in treatment of idiopathic male infertility.

Hesperidin: A Potential Therapeutic agent against COVID-19.

Abstract: COVID-19, aka Coronavirus Disease 2019, triggered by new severe acute respiratory syndrome coronavirus-2 or SARS-CoV-2, is now a public health emergency due to its rapid spread, high transmission efficiency, and severe viral pandemic that is significantly increasing the number of patients and associated deaths. At present, no specific treatment is available that can this highly contagious virus. The unavailability of effective and specific treatments and the severity of this epidemic situation potentiate medicinal chemists' in supporting new prophylactic or therapeutic interventions against COVID-19. This study discusses the therapeutic potential of hesperidin, a traditionally used herbal medicine with an exceptional safety profile. Recent studies on hesperidin advocate its promising potential in the prevention and management of COVID 19. This paper also discussess the recent clinical studies based on the previously documented antiviral activity of hesperidin. Herein, we propose the detailed preclinical and clinical manifestations of hesperidin based on its multifaceted bioactivities to develop a novel anti-COVID-19 lead.

Hydrophobically Modified Abelmoschus Esculentus Polysaccharide Based Nanoparticles and Applications: A Review.

Abstract: Nanomaterials are indeed a nanoscale technology that deals with the creation, evaluation, fabrication, and utilization of systems at the nanometre scale by manipulating their size and shape. We consider natural polysaccharides such as promising polysaccharides, which are biodegradable, nontoxic, abundant, and inexpensive bio-polymeric precursors for preparing the materials of choice in various industries. The aim is to review different methods to produce hydrophobically modified Abelmoschus esculentus nanoparticles and study the evaluation processes of these nanoparticles as given in the literature. It proved the benefits of derivatives of gum by introducing different chemical groups. The chemical functionalization of gum mainly includes the esterification, etherification, and cross-linking reactions of the hydroxyl groups and contains a special fibre which takes sugar levels in the blood under control, providing a sugar quantity acceptable for the bowels. Okra contains mucilage that helps remove poisonous chemicals and bad cholesterol, often overloads the liver. Recovering from psychological conditions, like depression, general weakness, and joint healthiness, can be done with Okra. Someone additionally applied it for pulmonary inflammation, bowel irritation, and sore throat. Purgative properties okra possesses are beneficial for bowel purification. It is used to counteract the acids. Fibre okra contains is a valuable nutrient for intestinal microorganisms and ensures proper intestine functionality. It also protects the mucosa of the digestive tract by covering them with an extra layer because of its alkaline nature. Nanotechnology has emerged as a critical component of pharmaceutics, with many applications in drug carriers of interest aimed at improving drug clinical outcomes such as cancer, diabetes mellitus, wound care management, atopic dermatitis, cosmeceutical, etc and discussed briefly the beneficial outcomes of this review.

Physical Instabilities of Therapeutic Monoclonal Antibodies: A Critical Review.

Abstract: The proteinaceous nature of monoclonal antibodies (mAbs) makes them highly sensitive towards various physical and chemical conditions, thus leading to instabilities which are classified as physical and chemical instabilities. In this review, we are discussing in detail about the physical instability of mAbs because a large number of articles previously published are solely focusing on the chemical aspect of the instability with little coverage on the physical side. The physical instabilities of mAbs are classified into denaturation and aggregation (precipitation, visible and subvisible particles). The mechanism involved in their formation is discussed in the article along with the pathways correlating the denaturation of mAb or formation of aggregates to immunogenicity. Further equations like Gibbs-Helmholtz involved in the detection and quantification of denaturation are discussed along with various factors causing the denaturation. Moreover, questions related to aggregation like the types of aggregates and the pathway involved in their formation are answered in this article. Factors influencing the physical stability of the mAbs by causing denaturation or formation of aggregates involving the structure of protein, concentration of mAbs, pH of the protein and the formulations, excipients involved in the formulations, salts added to the formulations, storage temperature, light and UV radiation exposure and processing factors are mentioned in this article. Finally, the analytical approaches used for detecting and quantifying the physical instability of mAbs at all levels of structural conformation like far and near UV, infrared spectroscopy, capillary electrophoresis, LC-MS, micro flow imagining, circular dichroism and peptide mapping are discussed.

A Systematic Review on Curcumin and Anti-Plasmodium berghei Effects.

Abstract: BACKGROUND Turmeric (Curcuma longa L.) is a popular spice, containing curcumin that is responsible for its therapeutic effects. Curcumin with anti-inflammatory, antioxidant, anti-cancer, and antimicrobial activities has led to a lot of research focusing on it over the years. This systematic review aimed to evaluate researches on anti-Plasmodium berghei activity of curcumin and its derivatives. METHODS Our study was performed according to PRISMA guidelines and was recorded in the database of systematic review and preclinical meta-analysis of CAMARADESNC3Rs (SyRF). The search was performed in five databases, namely Scopus, PubMed, Web of Science, EMBASE, and Google Scholar from 2010 to 2020. The following keywords were searched: "Plasmodium berghei", "Medicinal Plants", "Curcumin", "Concentration", Animals kind", "Treatment Durations", "Routes of Administration" and "in vivo". RESULTS Of the 3,500 papers initially obtained, 14 articles were reliable and were thus scrutinized. Animal models were included in all studies. The most commonly used animal strain were Albino (43%) followed by C57BL/6 (22%). The other studies used various murine strains, including BALB/c (14%) and ICR (7%). Two (14%) studies did not mention the strain of animal model used. Curcumin alone or in combination with other compounds depending on the dose used, route of administration, and animal model showed a moderate to strong anti-Plasmodium berghei effect. CONCLUSION According to the studies, curcumin has anti-malarial effects on Plasmodium berghei and, however, its effect on human Plasmodium is unclear. Due to the side effects and drug resistance of current drugs in the treatment of human malaria, the use of new compounds with few or no side effects such as curcumin is recommended as an alternative or complementary treatment.

Synthesis and Biological Evaluation of Some New Chalcone Derivatives as Anti-inflammatory Agents.

Abstract: Aim-The present research work aims to prepare a series of 1-(4-(2-(1H-indol-1-yl)-2-oxoethoxy)phenyl)-3-phenylprop-2-en-1-one derivatives. Method- The major compound was achieved by the reaction of indole with chloroacetylchloride in benzene afforded 2-chloro-1-(indoline-1-yl) ethanone which reacts o- hydroxy acetophenone in presence of acetonitrile to form 2-(4-acetylphenoxy)-1-(1H-indol-1-yl)ethan-1-one then is goes through aldol condensation to give various final derivatives. Results and conclusion- After synthesis of compounds, the synthesized compounds were characterized by checking their solubility, melting point, thin layer chromatography, IR, 1HNMR spectral data and elemental analysis. All of prepared derivatives were evaluated for their anti-inflammatory activity on wistar albino rats by following carrageenan induced Rat Hind Paw Edema model.

In vivo and in vitro anti-schistosomiasis effect of garlic (Allium sativum): a systematic review.

Abstract: BACKGROUND Garlic (Allium sativum) is currently used as a natural supplement for the treatment of various diseases and disorders, because it has antibacterial, antiviral, antifungal, antiparasitic, antioxidant, and anti-inflammatory properties. This systematic review aimed to summarize the in vitro and in vivo effects of garlic against Schistosoma spp. METHOD The current study was carried out according to the PRISMA guideline and registered in the CAMARADES-NC3Rs Preclinical Systematic Review and Meta-analysis Facility (SyRF) database. Literature search was conducted using five databases; namely Scopus, PubMed, Web of Science, EMBASE, and Google Scholar from January 2008 to January 2021. The search was restricted to articles published in English language. The search was performed using appropriate syntax and specific tags for each database. RESULTS Of 2,600 studies, 10 met the eligibility criteria for review. All studies used Schistosoma mansoni and garlic. Ten studies (90%) were performed in vivo and one study in vitro. The results of studies showed that garlic can remove the parasite through a direct effect on the parasite itself, such as changes in the parasite's coat or destruction of its spines, or indirectly by strengthening the immune response against the parasite. CONCLUSION Effective anti-schistosomal responses of garlic in studies show that the active compounds of garlic can be used as a complement with chemical drugs or as an alternative for them, and this is needed to optimize the consumption of these active compounds for medicinal uses.

Genus Zanthoxylum as Sources of Drugs for Treatment of Tropical Parasitic Diseases.

Abstract: The tropical parasitic infections account to more than 2 billion infections and cause substantial morbidity and mortality, and accounts to several million deaths every year. Majorly parasitic infections in humans and animals are caused by protozoa and helminths. Chronic infections in host can cause retardation, impairment of cognitive skills, development in young children and weaken the immune system. The burden is felt to a greater extent in developing countries due to poverty, inaccessibility to medicines and resistance observed to drugs. Thus, human health continues to be severely harmed by parasitic infections. Medicinal plants have received much attention as alternative sources of drugs. Zanthoxylum genus has been used ethnobotanically as an antiparasitic agent and the phytoconstituents in Zanthoxylum, show wide variety of chemical substances with proven pharmacological actions such as alkaloids (isoquinolines and quinolines responsible for antitumor activity, antimalarial, antioxidant and antimicrobial actions), lignans, coumarins (antibacterial, antitumour, vasodilatory and anticoagulant activities), alkamide (strong insecticidal properties, anthelminthic, antitussive and analgesic anti antimalarial property). Therefore, this article is an attempt to review the existing literature that emphasizes on potential of genus Zanthoxylum as source of lead compounds for treatment of parasitic diseases.

PROTAC: A Novel drug delivery technology for targeting proteins in cancer cells.

Abstract: The treatment measures of malignant carcinomas are most important for the progress of human health. In recent years the use of targeted therapy based on small molecules compounds and identical immunoglobulin are the most frequently used tools to combat cancerous cells. But there are still several limitations in their clinical development and applications of these technologies comprising their ability to bind multiple molecular target sites including both cell surface receptors and intracellular proteins and therefore promoting greater risk of toxicity. PROTAC a novel technology that work on maintaining balance between protein synthesis and degradation and make use of molecules instead of conventional enzyme inhibitor, containing two active domains and a linker to destroy unwanted selective protein (like kinase, skeleton protein and regulatory protein). PROTACs are the heterobifunctional nano molecules with size range of about 10 nanometres find application to eliminate the protein complexes formed by protein-protein interaction through large and flat surface generally defined as "undruggable" in conventional drug delivery system, which include around 85 % of proteins present in humans, suggesting their wide application in the field of drug development. Such peptide-based PROTACs have shown the destruction of targets in cultured cells successfully (e.g., MetAP-2, and FKBP12F36V, receptors for estrogens and androgen). However, some obstacles prevent this technology from transferring from the laboratory to its actual clinical utility, such as delivery system and bioavailability. The scope of the presented review is to gives an overview of novel PROTAC technology with its limitations, advantages , mechanism of action, development of photo-controlled PROTACs and to summarize its futuristic approach in targeting proteins in cancer cells.

Computational Approach to Combat COVID-19 Infection: Emerging Tool for Accelerating Drug Research.

Abstract: BACKGROUND Drug discovery and development process is an expensive, complex, time-consuming and risky. There are different techniques involved in the drug development process which include random screening, computational approach, molecular manipulation and serendipitous research. Among these methods, the computational approach is considered as an efficient strategy to accelerate and economize the drug discovery process. OBJECTIVE This approach is mainly applied in various phases of drug discovery process including target identification, target validation, lead identification and lead optimization. Due to increase in the availability of information regarding various biological targets of different disease states, computational approaches such as molecular docking, de novo design, molecular similarity calculation, virtual screening, pharmacophore-based modeling and pharmacophore mapping have been applied extensively. METHODS Various drug molecules can be designed by applying computational tools to explore the drug candidates for treatment of Coronavirus infection. The world health organization has announced the novel corona virus disease as COVID-19 and declared it as pandemic globally on 11 February 2020. So, it is thought of interest to scientific community to apply computational methods to design and optimize the pharmacological properties of various clinically available and FDA approved drugs such as remdesivir, ribavirin, favipiravir, oseltamivir, ritonavir, arbidol, chloroquine, hydroxychloroquine, carfilzomib, baraticinib, prulifloxacin, etc for effective treatment of COVID-19 infection. RESULTS Further, various survey reports suggest that the extensive studies are carried out by various research communities to find out the safety and efficacy profile of these drug candidates. CONCLUSION This review is focused on the study of various aspects of these drugs related to their target sites on virus, binding interactions, physicochemical properties etc.

In silico analysis of the antidepressant fluoxetine and related drugs at SARS-CoV-2 main protease (Mpro) and papain-like protease (PLpro).

Abstract: BACKGROUND SARS-CoV-2 main protease (Mpro or 3CLpro) and papain-like protease (PLpro) are common viral targets for repurposed drugs to combat COVID-19 disease. Recently, several anti-depressants (such as fluoxetine, venlafaxine and citalopram) belonging to the Selective Serotonin Reuptake Inhibitors (SSRIs) and the Serotonin-Norepinephrine Reuptake Inhibitors (SNRI) classes have been shown to in vitro inhibit viral replication. AIM Investigate a possible action of fluoxetine and derivatives on SARS-CoV-2 protease sites. METHODS molecular docking was performed using AutoDock Vina. Both proteases structures and different drugs conformations were used to explore the possibility of SARS-CoV-2 inhibition on a Mpro or PLpro related pathway. Drug structures were obtained by optimization with the Avogadro software and MOPAC using PM6 method. Results were analysed on Discovery Studio Visualizer. RESULTS The results indicated that Mpro interacted in a thermodynamically favorable way with fluoxetine, venlafaxine, citalopram, atomoxetine, nisoxetine and norfluoxetine in the region of the active site, whether PLpro conformers did not come close to active site. CONCLUSION In an in silico perspective, it is likely that the SSRIs and other anti-depressants could interact with Mpro and cause the enzyme to malfunction. Unfortunately, the same drugs did not present similar results on PLpro crystal, therefore no inhibition is expected on an in vitro trial. Anyway, in vitro test are necessary for the better understanding the links between SARS-CoV-2 proteases and anti-depressants.

In Vitro and In Vivo Approaches for Screening the Potential of Anticancer Agents: A Review

Abstract: Anticancer drug development is a tedious process, requiring several in vitro, in vivo, and clinical studies. To avoid chemical toxicity in animals during an experiment, it is necessary to envisage toxic doses of screened drugs in vivo at different concentrations. Several in vitro and in vivo studies have been reported to discover the management of cancer.This study has focused on bringing together a wide range of in vivo and in vitro assay methods, developed to evaluate each hallmark feature of cancer.This review provides elaborated information about target-based and cell-based screening of new anticancer drugs in the molecular targeting period. This would help to incite an alteration from the preclinical screening of pragmatic compound-orientated to target-orientated drug selection.Selection methodologies for finding anticancer activity have importance for tumor-specific agents. In this study, advanced rationalization of the cell-based assay is explored along with broad applications of the cell-based methodologies considering other opportunities also.

Insilico prediction and pharmacokinetic studies on glucosinolates as potential drug and key inhibitor molecule for lanosterol-14α-demethylase, fungal membrane biosynthesis.

Abstract: BACKGROUND Glucosinolates (b-thioglucoside-N-hydroxysulfates) are a water-soluble organic anion with sulfur- and nitrogen-containing glycosides which are found in abundance in Cruciferous plants. Ergosterol (ERG13) lanosterol-14α-demethylase protein has been targeted for inihibition studies as a key regulator enzyme of fungal membrane biosynthesis. OBJECTIVES To understand the molecular mechanism of inhibition of Ergosterol (ERG13) lanosterol-14α-demethylase by various phytochemicals from brassicals i.e. glucosinolates and their potential role as putative drug molecules Methodology: In this study, insilico analysis were performed to predict the molecular basis of various glucosinolates as a potential inhibitor of lanosterol-14α-demethylase protein which is a key regulator of fungal membrane biosynthesis and their pharmacodynamics and toxicity profile. 3d Structures of various glucosinolates were retrieved from Pubchem and the target protein, lanosterol-14α-demethylase (Pdb ID- 4lxj) was retrieved from the RCSB protein data bank. Molecular docking and interactions were carried out using the PyRx software using AutoDOCK tool bar with default parameters. DruLiTo, ORISIS web servers were used to predict various drug likeliness predictions and Lipinski's Rule of 5 whereas admetSAR was used for prediction of toxicity and PASS Program was used to study the antifungal and antimicrobial properties of these compounds. RESULTS This study shows that among the different compounds screened, gluconasturtiin, Glucotropaeolin), Indolylmethyl-Glucosinolate showed highest binding energies of -8.7 kcal/mol, -8.5 kcal/mol, -8.3 kcal/mol with the lanosterol-14α-demethylase respectively. Further all the compounds follow the Lipinski rule as well as they are found to be non-carcinogenic and non-cytotoxic in nature. These compounds also show the antifungal properties. CONCLUSION This study thus reveals that various glucosinolates interact with the ERG13 enzyme at various aminoacid positions which behaves a catalytic site thus indicates the probable mechanism of inactivation and subsequently these can be used as potential drug molecules. Invitro studies can be taken to further examine the utility of these compounds as antifungal agents.

Modulatory potential of Citrus sinensis and Moringa oleifera extracts and epiphytes on rat liver mitochondrial permeability transition pore.

Abstract: BACKGROUND Bioactive agents from medicinal and dietary plants have been reported to modulate the mitochondrial membrane permeability transition pores. OBJECTIVE This study investigated the in vitro effects of C. sinensis (CSE) and M. oleifera (MOE) methanol leaf extracts and their epiphytes (CEP and MEP) on mitochondria permeability transition pores. METHODS In vitro antioxidant activities of the extracts were determined using standard procedures and quantification of polyphenolic compounds in the extracts was done using HPLC-DAD. Opening of the mitochondrial permeability transition pores was assessed as mitochondrial swelling and observed spectrophotometrically as changes in absorbance under succinate-energized conditions. Cytochrome c release was also assessed spectrophotometrically. RESULTS From the results, CSE, MOE, CEP, and MEP inhibited lipid peroxidation and scavenged nitric oxide and DPPH radicals in a concentration-dependent manner. All extracts exhibited greater ferric reducing antioxidant potential. More so, the results showed that CSE, MOE, CEP, and MEP possess the substantive amount of total flavonoids and total phenolics. CSE and MOE had higher total flavonoids and total phenolic content when compared with the epiphytes. HPLC-DAD results revealed Tangeretin as the most abundant in CSE; Eriocitrin in citrus epiphytes; Moringine in MOE and Flavones in moringa epiphytes. All extracts inhibited calcium-induced opening of the pores in a concentration-dependent manner with C. sinensis leaf extract (CSE) and moringa epiphyte (MEP) being the most potent in this regard with no significant release of cytochrome c at all concentrations. CONCLUSION The results suggest that CSE and MEP have bioactive agents which could be useful in the management of diseases where too much apoptosis occurs characterized by excessive tissue wastage such as neurodegenerative conditions.

Inhibitory effect of standardized extract and fractions of Nigella sativa L. on nystatin susceptible and clinically nystatin resistant Candida albicans.

Abstract: INTRODUCTION Candidiasis infection is caused by different species of Candida, which are characterized by host immunologic weakness. Black cumin seeds (Nigella sativa) have shown inhibitory effect against Candida albicans. In this work, the inhibitory effect of standardized extract and different fractions of Nigella sativa seeds has been evaluated on nystatin susceptible. MATERIALS AND METHOD Canadida albicans (NSCA) with ATCC 76645 and nystatin resistant Candida albicans (NRCA) was prepared from oral samples of HIV individuals. Total extract and different fractions of N. sativa were prepared using maceration and sonication methods. Thymoquinone (TQ) content of the plant was determined by spectrophotometry. Total extract (TTE) and the fractions along with TQ were evaluated on NSCA and NRCA by microdilution method. TQ content of the plant was 0.92±0.37g/100g dried extract. The least MIC and MFC (62.5 and 125 µg/ml respectively) was due to petroleum ether fraction (PEF) against both NSCA and NRCA followed by chloroform fraction (CHF) with MIC and MFC of 125 and 250 µg/ml. TQ exhibited MIC of 0.78 and 3.12 µg/ml against NSCA and NRCA which was stronger than nystatin (MIC of 2 and 16 µg/ml). Results Thymoquinone was detected in the PEF and CHF. CONCLUSION Considering more inhibitory effects of PEF and CHF than TTE, can conclude that active components of the plant belong to non-polar compounds. PEF showed identical inhibitory effect on NRCA and NSCA that is valuable result for finding novel medicaments against NRCA infections.

Extracting Atomic Contributions to Binding Free Energy Using Molecular Dynamics Simulations with Mixed Solvents (MDmix)

Abstract: Mixed solvents MD (MDmix) simulations have proved to be a useful and increasingly accepted technique with several applications in structure-based drug discovery. One of the assumptions behind the methodology is the transferability of free energy values from the simulated cosolvent molecules to larger drug-like molecules. However, the binding free energy maps (ΔGbind) calculated for the different moieties of the cosolvent molecules (e.g. a hydroxyl map for the ethanol) are largely influenced by the rest of the solvent molecule and do not reflect the intrinsic affinity of the moiety in question. As such, they are hardly transferable to different molecules.To achieve transferable energies, we present here a method for decomposing the molecular binding free energy into accurate atomic contributions.We demonstrate with two qualitative visual examples how the corrected energy maps better match known binding hotspots and how they can reveal hidden hotspots with actual drug design potential.Atomic decomposition of binding free energies derived from MDmix simulations provides transferable and quantitative binding free energy maps.

Comparing the effects of a herbal drug based on Echium Amoenum with fluvoxamine in the treatment of adolescents with obsessive-compulsive disorder.

Abstract: BACKGROUND Obsessive-compulsive disorder (OCD) is a severe and debilitating neuropsychiatric condition. Although selective serotonin reuptake inhibitors, tricyclic antidepressants, and cognitive-behavioral therapy are the first-line medication and treatment for OCD, an estimated 30% of patients are treatment-resistant, and complete functional recovery is rare. Natural products as adjuvant or alternative therapies should be examined to find safer and more effective ways to manage OCD. OBJECTIVE To investigate the potential benefits of a combined herbal drug based on Echium amoenum in the treatment of OCD. METHODS Design and Setting: In the psychiatric clinics of Mashhad University of Medical Sciences, 40 patients who met the criteria for obsessive-compulsive disorder based on DSM-5 were studied in a parallel double-blind randomized clinical trial. INTERVENTION Subjects were randomly assigned to receive Echium amoenum-Melissa officinalis syrup and fluvoxamine or placebo syrup and fluvoxamine for 8 weeks. OUTCOME MEASURES The efficacy of treatment and recurrence of disease were surveyed and compared according to Yale-Brown Obsessive Compulsive Scale at weeks 0, 4, and 8. RESULTS Evaluation at the 4th and 8th week showed no significant differences between the two groups (p-value = 0.11, p-value = 0.445, respectively). At the 8th week of treatment, patients in the intervention group showed a remarkable reduction in scores on the Yale-Brown Obsessive-Compulsive Scale questionnaire (p- value= 0.003), and patients in the control group didn't ((p- value= 0.180).This study showed that the E.amoneum-M.officinalis syrup was not significantly more efficacious than fluvoxamine tablet, but the intervention group showed a significant improving trend (p-value= 0.001). CONCLUSION While monotherapy is usually the gold standard methodology, combination or augmentation therapy may also be of merit. Consequently, studies with larger sample sizes and the inclusion of para-clinical assessments such as serologic tests can further shed light on the mechanism of action of the E.amoneum- M.officinalis syrup and deepen our understanding of its effects.

Molecular Docking and simulation studies of Flavanone and its Derived compounds on PI3K-AKT Pathway Targeting against Cancer.

Abstract: BACKGROUND Flavanone compounds and its related derivatives are reported to participating in controlling cell cycle, Angiogenesis, and metastasis. Phosphoinositide 3-kinases is major drug target. METHODS Crystalize structure of Phosphoinositide 3-kinases-Akt complex obtained from Protein Data Bank (PDBID: 3CQW) was selected as receptor protein and binding site has been identified with PDBSum Database. Flavanone and its derivatives were retrieved using freely available existing drug database like Drug Bank, Zinc and PubChem. Modifications of new derivatives was performed by altering the flavanone at Beta ring position this modification would help in maintaining stable structural conformation and retaining better anticancer activity. Retrieved Flavanone derivatives from the drug database were docked against 3CQW Protein with advance docking tool FlexX. MD simulations of best molecule were performed with Desmond package by calculating nonbonding interactions such as electrostatic interaction and hydrogen bond stable and favorable conformations were calculated. RESULTS These interaction studies would help in identifying new potential drug candidate with the help of computer aided drug designing techniques. CONCLUSION Natural chemicals have received a lot of attention because of their vast range of applications in human health and disease prevention without creating any negative side effects. Molecular docking is an essential approach for drug development since it allows for effective screening of potential therapeutics in a short amount of time. We hypothesized in this paper that natural Flavanone and its derivatives may be effective as Akt-1 inhibitors.

Preparation of zinc oxide nanoparticles assisted by okra mucilage and evaluation of its biological activities.

Abstract: BACKGROUND In this study, zinc oxide nanoparticles (ZnO-NPs) were biologically synthesized from Abelmoschus esculentus L. (Okra) mucilage fraction (OM). METHODS Analytical techniques were employed to study the formation and properties of OM-ZnO NPs, including their morphology, shape, size distribution, and surface charges. Additionally, OM-ZnO NPs were assessed for their antimicrobial, antioxidant, and cytotoxic properties. RESULTS UV-visible spectroscopy confirmed the formation of OM-ZnO NPs, evident by the appearance of an SPR peak at 368.8 nm. The FTIR spectroscopy demonstrated that OM functional groups contribute to the formation and stability of the NPs. Micrographs from TEM and SEM showed that OM-ZnO NPs ranged from 15-40 nm in diameter, whereas hydrodynamic diameter and surface charge values obtained from Zeta and DLS were 72.8 nm and 14.6 mv, respectively. XRD analysis indicated the OM-ZnO NPs were crystalline with a wurtzite structure and a crystallite size of 27.3 nm, while EDX revealed a zinc: oxygen ratio of 67.5:34. Further, the OM-ZnO NPs demonstrated significant antimicrobial activity in response to different types of bacteria. In the antioxidant assay, the OM-ZnO NPs scavenged DPPH with 68.6 % of the efficiency of ascorbic acid (100 %). CONCLUSION The present study demonstrated the cytotoxic efficacy of MO-ZnO NPs against MCF7 cells with an IC50 of 43.99 µg/ml. Overall, the green synthesis of ZnO NPs by OM was successful for many biological applications, such as antimicrobial, antioxidant, and anticancer. Moreover, OM-ZnO NPs can be applied as a biologically-derived nanotherapeutic agent.

Structure-based <i>De Novo</i> Design and Docking Studies of 5(S)-Methyl-L-Proline Containing Peptidomimetic Compounds as Dipeptidyl Peptidase-4 Inhibitors

Abstract: Diabetes affects millions of people worldwide, with predicted numbers of about 700 million adults affected by 2045. Among the several anti-diabetic drug therapies available in the market, Dipeptidyl Peptidase-4 (DPP-4) inhibitors have emerged as a promising therapeutic approach with scope for exploration in the segment of peptidomimetics.Series of proline-containing peptidomimetic compounds were designed and investigated for their drug-likeness through Lipinski's rule of five, lead-likeness through the rule of three, predictive pharmacokinetic studies (absorption, distribution, metabolism, and excretion), and toxicity properties through in-silico approaches. The designed compounds were evaluated for their interactions with binding sites of the enzyme DPP-4 using an extra precision docking approach.Proline-containing peptidomimetic compounds were designed rationally. Drug-likeness and lead-likeness properties were calculated using Schrödinger Maestro v11.2 software. ADME and toxicity properties were predicted using PreADMET version 2.0. Docking study was performed using Schrödinger Maestro v11.2 software, and ligands for the study were designed using MarvinSketch software.5(S)-methyl-L-proline containing 17 ligands were designed. All of them were found to obey Lipinski's rule of five. Compounds were found to have good ADME profile and low toxicity predictions.Four compounds were found to have good interactions with DPP-4 binding sites and hence created the scope to develop DPP-4 inhibitors containing 5(S)-methyl-L-proline moiety.

Cytotoxic effects of Garcinia mangostana pericarp extract in cancer cell lines.

Abstract: BACKGROUND Garcinia mangostana, commonly also called mangosteen, is an evergreen tropical tree, and its pericarps have been used in traditional herbal medicine for different diseases. The anticancer efficacy of the ethanolic extract from pericarps of Garcinia mangostana was investigated in human prostate cancer cells (PC3), melanoma cells (B16F10), breast cancer cells (MCF7) and glioblastoma (U87) cell lines. METHODS 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay was used to measure cell viability. propidium iodide (PI) staining and analysis on a flow cytometer was used to identify apoptosis. Action on cell migration was evaluated by scratch assay and gelatin zymography. Furthermore, the level of intracellular reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) activity was measured. Moreover, we investigated the synergistic efficacy with several combinations of Garcinia mangostana extract (GME) with doxorubicin. RESULTS GME reduced cell viability in malignant cell dose and time-dependently. GME-induced sub-G1 peak in flow cytometry histogram of treated cells control representing apoptotic cell death is involved in GME toxicity. Furthermore, GME exhibited inhibitory effects on the migration ability of U87 cells, which was accompanied by inhibition in the activity and expression of MMP2 (matrix metalloproteinase-2). Besides, GSH level and SOD activity was significantly reduced while there was an increase in ROS and MDA concentration following 24 hr GME treatment. Moreover, combination of GME (1.5-25μg/mL) with Dox (6 µg/mL) displayed synergistic efficacy and cell growth inhibition. CONCLUSION In conclusion, GME could cause cell death in PC3, MCF7, U87, and B16F10 cell lines, in which apoptosis plays an imperative role. Plant extract decreased the migration ability of the cells by inhibiting the activity and expression of Matrix metalloproteinases (MMPs). G. mangostana could be a promising therapeutic strategy to treat cancer in the future.

A New Bacteriocin From Latilactobacillus Sakei: In Vitro And In Situ Application.

Abstract: AIMS AND BACKGROUND Natural preservatives are a viable alternative to replace chemical preservatives that have potential toxicity and carcinogenic effects. OBJECTIVE To prove the effectiveness in increasing the microbiological stability of Minas Frescal cheese with the addition of a bacteriocin obtained from Latilactobacillus sakei as a natural preservative Method: A new broad-spectrum bacteriocin was evaluated for its functional activity in vitro and in situ when applied in the formulation of Minas Frescal cheese. A commercial bacteriocin was used as a positive control. RESULTS The inhibitory action of the bacteriocin studied was confirmed, with a reduction of 42.86% in the count of coagulase-positive Staphylococcus in relation to the negative control, at the end of the 30 days of study. For the group of thermotolerant coliforms, the bacteriocin studied showed greater efficiency than the commercial preservative. In vitro analyzes showed the inhibitory action of bacteriocin, above 87% inhibition against S. aureus, E. coli and Salmonela enteritidis, and approximately 90% against Listeria monocytogenes. CONCLUSION It was concluded that the bacteriocin produced by the Latilactobacillus sakei strain has great potential for application in foods such as Minas Frescal cheese.

Synthesis and biological activity evaluation of pyrazole-1,2,4-triazole hybrids: A computer-aided docking studies.

Abstract: AIMS/BACKGROUND In the present study, a new series of 1,2,4-triazole linked to pyrazole derivatives (8a-j) of 4-(((7-amino-7H-[1,2,4]triazolo[4,3-b][1,2,4]triazol-6-yl)methyl)amino)-1,5-dimethyl-2-phenyl-1H-pyrazol-3(2H)-one were synthesized and assessed for their antibacterial and anticancer activity. OBJECTIVE Encouraged by these results, these analogues 4-(((7-amino-7H-[1,2,4]triazolo[4,3-b][1,2,4]triazol-6-yl)methyl)amino)-1,5-dimethyl-2-phenyl-1H-pyrazol-3(2H)-ones 8 have been synthesized and their inhibitory potential activity against different bacterial microorganisms and cancer cell lines was discussed. METHODS All the synthesized final scaffolds were characterized by 1H NMR, 13C NMR, IR, mass and elemental analysis. All the synthesized 1,2,4-triazole linked to pyrazole compounds were evaluated for their antimicrobial sensitivity by using the agar dilution technique. The anticancer activity of these compounds has been assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide colorimetric assay and docking results are described by Autodock 4.2. RESULTS In vitro analysis suggests that compounds 8h, 8f, and 8b demonstrated excellent antibacterial activity against S. auras, P. aeruginosa, S. epidermidis with MICs of 8, 8, 11 µg/mL respectively, while the remaining compounds showed moderate to good inhibitory potential. Some of them exhibited potent cytotoxicity against MCF-7 and P388 cancer cell lines and compounds 8c, 8f, and 8d reveal the highest potency against MCF-7 with IC50 values 2.8 ± 0.4, 3.1 ± 0.4, 3.5 ± 0.2 µM, respectively. Especially 8c, 8i and 8f showed better interaction patterns with amino acids Ala197 (N-N), Lys168 (N-N), Asn163 (O-N) at 3.13, 3.09, 3.00 A˚ as reported in DNA (Topo II) complex (1ZXM). CONCLUSION New findings have established the fact that fused 1,2,4-triazoles linked to pyrazole contributed great significance in the field of medicinal chemistry due to their various biological properties.

Structure-Based Drug Design and Development of Novel Synthetic Compounds with Anti-Viral Property against SARS-COV-2.

Abstract: • Background : The world is suffering from health and economic devastation due to the Corona Virus Disease-2019 (COVID-19) pandemic. Given the number of people affected and also the death rate, the virus is definitely a serious threat to humanity. By analogy with previous reports on the Severe Acute Respiratory Syndrome (SARS-CoV-2) virus, the novel replication mechanism of the coronavirus is likely well understood. • Objective : The antiviral activity of various compounds of the flavonoid class was checked against SARS-COVID-19 using diverse tools and software. • Method : From the flavonoid compound class, 100 synthetic compounds with potential antiviral activity were selected and improved for screening and induced fit docking, which was reduced to 25 compounds with good docking score and docking energy. In addition to the apparent match of the molecule with the shape of the binding pocket, a full analysis of the non-covalent interactions in the active site was assessed. • Results : Compounds (nol26), (fla37-fl40), (an32), (an39) showed a maximum docking score, which shows essential interactions for a tight bond. Now, all compounds are synthetic with beneficial drug-like properties. • Conclusion : During the docking study, an increased lipophilic interaction of compounds due to the presence of chlorine in (nol26), (fla37-fl40), (an32), (an39) was discovered. (fla37-fla40) can be investigated as lead molecules against SARS-COV-2 in futuristic drug development.