Search

Introduction: Despite numerous scientific advances, cancer continues to be one of the main causes of death in the world. This situation has driven the search for promising molecules. Lichen substances have been widely described for their pharmacological potential. Objective: The present study evaluated the antitumour potential of a depsidone isolated from Parmotrema concurrens– salazinic acid (SAL) – through in vitro, in vivo and in silico studies. Methods: The molecule was isolated from the acetonic extract of the lichen and recrystallized in acetone. The macrophage J774, sarcoma-180 and MDA-MB-231 cell lines were used for the MTT cytotoxicity assay. The antitumor assay used a murine model (Swiss albino mice) with sarcoma-180. The animals were treated for seven consecutive days with doses of SAL (25 and 50 mg/kg) and 5-fluorouracil (20 mg/kg). Results: Its purity was determined using high-performance liquid chromatography (94%), and its structure was confirmed by H1 and C13 nuclear magnetic resonance. SAL was not considered toxic to cancer cell lines, showing cell viability rates of 79.49 ± 4.15% and 86.88 ± 1.02% for sarcoma-180 and MDA-MB-231, respectively. The tumour inhibition rate was greater than 80% in the animals treated with SAL and 65% for those that received 5-fluorouracil. Simulations of molecular dynamics to estimate the flexibility of the interactions between human thymidylate synthase and derivatives of SAL and 5-fluorouracil revealed that SAL exhibited greater enzymatic interaction capacity, with highly favourable energy, compared to 5-fluorouracil. Conclusion: The present results demonstrate the potential of salazinic acid as a tumour inhibition agent.

Abstract: Alzheimer's is a chronic neurodegenerative disease where amyloid-beta (Aβ) plaques and neurofibrillary tangles are formed inside the brain. It is also characterized by progressive memory loss, depression, neuroinflammation, and derangement of other neurotransmitters. Due to its complex etiopathology, current drugs have failed to completely cure the disease. Natural compounds have been investigated as an alternative therapy for their ability to treat Alzheimer's disease (AD). Traditional herbs and formulations which are used in the Indian ayurvedic system are rich sources of antioxidant, anti-amyloidogenic, neuroprotective, and anti-inflammatory compounds. They promote quality of life by improving cognitive memory and rejuvenating brain functioning through neurogenesis. A rich knowledge base of traditional herbal plants (Turmeric, Gingko, Ashwagandha, Shankhpushpi, Giloy, Gotu kola, Garlic, Tulsi, Ginger, and Cinnamon) combined with modern science could suggest new functional leads for Alzheimer's drug discovery. In this article Ayurveda, the ancient Indian herbal medicine system based on multiple clinical and experimental, evidence have been reviewed for treating AD and improving brain functioning. This article presents a modern perspective on the herbs available in the ancient Indian medicine system as well as their possible mechanisms of action for AD treatment. The main objective of this research is to provide a systematic review of herbal drugs that are easily accessible and effective for the treatment of AD.

Abstract: Alzheimer's and Parkinson's are neurodegenerative disorders that affect a great number of people around the world, seriously compromising the quality of life of individuals, due to motor and cognitive damage. In these diseases, pharmacological treatment is used only to alleviate symptoms. This emphasizes the need to discover alternative molecules for use in prevention. Using Molecular Docking, this review aimed to evaluate the anti-Alzheimer’s and anti-Parkinson’s activity of linalool and citronellal, as well as their derivatives. Before performing Molecular Docking simulations, the compounds’ pharmacokinetic characteristics were evaluated. For Molecular Docking, 7 chemical compounds derived from citronellal, and 10 compounds derived from linalool, and molecular targets involved in Alzheimer's and Parkinson's pathophysiology were selected. According to the Lipinski rules, the compounds under study presented good oral absorption and bioavailability. For toxicity, some tissue irritability was observed. For Parkinson-related targets, the citronellal and linalool derived compounds revealed excellent energetic affinity for α-Synuclein, Adenosine Receptors, Monoamine Oxidase (MAO), and Dopamine D1 receptor proteins. For Alzheimer disease targets, only linalool and its derivatives presented promise against BACE enzyme activity. The compounds studied presented high probability of modulatory activity against the disease targets under study, and are potential candidates for future drugs. Methodology: Before performing Molecular Docking simulations, the compounds’ pharmacokinetic characteristics were evaluated. For Molecular Docking, 7 chemical compounds derived from citron- ellal, and 10 compounds derived from linalool, and molecular targets involved in Alzheimer's and Parkinson's pathophysiology were selected. Results: According to the Lipinski rules, the compounds under study presented good oral absorption and bioavailability. For toxicity, some tissue irritability was observed. For Parkinson-related targets, the citronellal and linalool derived compounds revealed excellent energetic affinity for α-Synuclein, Adenosine Receptors, Monoamine Oxidase (MAO), and Dopamine D1 receptor proteins. For Alzheimer disease targets, only linalool and its derivatives presented promise against BACE enzyme activity. Conclusion: The compounds studied presented high probability of modulatory activity against the dis- ease targets under study, and are potential candidates for future drugs.

Objectives Considering that γ-terpinene (γ-TPN) is a monoterpene found in Cannabis oil, with high lipophilicity and limited pharmacokinetics, our objective was to evaluate whether its complexation in β-cyclodextrin (γ-TPN/β-CD) could improve its physicochemical properties and action on cancer pain, as well as verify the mechanisms of action involved. Methods The γ-TPN/β-CD was prepared and submitted to physicochemical characterization. Animals with sarcoma 180 were treated (vehicle, γ-TPN 50 mg/kg, γ-TPN/β-CD 5 mg/kg or morphine) and assessed for hyperalgesia, TNF-α and IL-1β levels, iNOS and c-Fos activity. The effects of γ-TPN on calcium channels were studied by patch-clamp and molecular docking. Results β-CD improved the physicochemical properties and prolonged the anti-hyperalgesic effect of γ-TPN. This compound also reduced the levels of IL-1β, TNF-α and iNOS in the tumour, and c-Fos protein in the spinal cord. In addition, it reduced Ca2+ current, presenting favourable chemical interactions with different voltage-dependent calcium channels. Conclusion These results indicate that the complexation of γ-TPN into β-CD increases its stability and time effect, reducing spinal neuroactivity and inflammation by blocking calcium channels.

Natural products are compounds isolated from plants that provide a variety of lead structures for the development of new drugs by the pharmaceutical industry. The interest in these substances increases because of their beneficial effects on human health. Alzheimer's disease (AD ) affects occur in about 80% of individuals aged 65 years. AD is the most common cause of dementia in elderly people, is characterized by progressive neurodegenerative alterations, as decrease of cholinergic impulse, increased toxic effects caused by reactive oxygen species and the inflammatory process that the amyloid plaque participates. In silico studies is relevant in the process of drug discovery; through technological advances in the areas of structural characterization of molecules, computational science and molecular biology have contributed to the planning of new drugs used against neurodegenerative diseases. Considering the social impairment caused by increased incidence of disease and that there is no chemotherapy treatment effective against the AD; several compounds are studied. In the researches for effective neuroprotectants as potential treatments for Alzheimer's disease, natural products that have been extensively studied in various AD models. This study aims to carry out a literature review with articles that address the In silico studies of natural products aimed at potential drugs against alzheimer's disease (AD) in the period from 2015 to 2021.

Background: COVID-19 is still causing long-term health consequences, mass deaths, and collapsing healthcare systems around the world. There are no efficient drugs for its treatment. However, previous studies revealed that SARS-CoV-2 and SARS-CoV have 96% and 86.5% similarities in cysteine proteases (3CLpro) and papain-like protease (PLpro) sequences, respectively. This resemblance could be important in the search for drug candidates with antiviral effects against SARS-CoV-2. Objective: This paper is a compilation of natural products that inhibit SARS-CoV 3CLpro and PLpro and, concomitantly, reduce inflammation and/or modulate the immune system as a perspective strategy for COVID-19 drug discovery. It also presents in silico studies performed on these selected natural products using SARS-CoV-2 3CLpro and PLpro as targets to propose a list of hit compounds. Method: The plant metabolites were selected in the literature based on their biological activities on SARS-CoV proteins, inflammatory mediators, and immune response. The consensus docking analysis was performed using four different packages. Results: Seventy-nine compounds reported in the literature with inhibitory effects on SARS-CoV proteins were reported as anti-inflammatory agents. Fourteen of them showed immunomodulatory effects in previous studies. Five and six of these compounds showed significant in silico consensus as drug candidates that can inhibit PLpro and 3CLpro, respectively. Our findings corroborated recent results reported on anti-SARS-CoV-2 in the literature. Conclusion: This study revealed that amentoflavone, rubranoside B, savinin, psoralidin, hirsutenone, and papyriflavonol A are good drug candidates for the search of antibiotics against COVID-19.

Background: Alzheimer's disease (AD) is a very common neurodegenerative disorder in individuals over 65 years of age; however, younger individuals can also be affected due to brain damage. Introduction: The general symptoms of this disease include progressive loss of memory, changes in behavior, deterioration of thinking, and gradual loss of ability to perform daily activities. According to the World Health Organization, dementia has affected more than 50 million people worldwide, and it is estimated that there are 10 million new cases per year, of which 70% are due to AD. Methods: This paper reported a review of scientific articles available on the internet which discuss in silico analyzes such as molecular docking, molecular dynamics, and quantitative structure-activity relationship (QSAR) of different classes of natural products and their derivatives published from 2016 onwards. In addition, this work reports the potential of fermented papaya preparation against oxidative stress in AD. Results: This research reviews the most recent studies on AD, computational analysis methods used in proposing new bioactive compounds and their possible molecular targets, and finally, the molecules or classes of natural products involved in each study. Conclusion: Thus, studies like this can orientate new research works on neurodegenerative diseases, especially AD.

Constant research on natural products has generated, over time, a large number of compounds with the potential to be evaluated in several biological tests and subsequently have been cataloged in databases that allow other researchers to perform virtual screenings of activity in various biological systems. This considerably reduces the time for the development of new drugs. This review describes the main databases of natural products available for searching bioactive compounds. It also describes the main features of virtual screening strategies for the identification of molecules with the potential to be used as new drugs. In addition, a search was made in the Web of Science database, using the search term "Virtual screening of natural products databases" from 2003 to 2018. The search criterion resulted in 230 articles, which had their abstracts evaluated with pertinence to the criteria required for this work, which are: a) be a research article; b) performing a virtual screening on databases of natural products or containing natural products; and c) works that identified drug candidate molecules. Based on these criteria, the bibliographic review on the topic was excluded. After this analysis, 104 works were selected for this review. We selected relevant papers describing the potential drug candidates that were distributed in 15 classes, of which the anticancer, antibacterial and anti-inflammatory hits were the most abundant. The works showing efforts to search for new molecules against various other diseases in distinct biological systems were also described. In this way, this work shows an overview of several methodologies and we hope they can help and inspire the development of new research to improve people's quality of life.

Chagas disease, a neglected tropical disease, is endemic in 21 Latin American countries and particularly prevalent in Brazil. Chagas disease has drawn more attention in recent years due to its expansion into non-endemic areas. The aim of this work was to computationally identify and experimentally validate the natural products from an Annonaceae family as antichagasic agents. Through the ligand-based virtual screening, we identified 57 molecules with potential activity against the epimastigote form of T. cruzi. Then, 16 molecules were analyzed in the in vitro study, of which, six molecules displayed previously unknown antiepimastigote activity. We also evaluated these six molecules for trypanocidal activity. We observed that all six molecules have potential activity against the amastigote form, but no molecules were active against the trypomastigote form. 13-Epicupressic acid seems to be the most promising, as it was predicted as an active compound in the in silico study against the amastigote form of T. cruzi, in addition to having in vitro activity against the epimastigote form.

Background: Natural products, such as phenylpropanoids, which are found in essential oils derived from aromatic plants, have been explored during non-clinical psychopharmacology studies, to discover new molecules with relevant pharmacological activities in the central nervous system, especially antidepressant and anxiolytic activities. Major depressive disorder is a highly debilitating psychiatric disorder and is considered to be a disabling public health problem, worldwide, as a primary factor associated with suicide. Current clinically administered antidepressants have late-onset therapeutic actions, are associated with several side effects, and clinical studies have reported that some patients do not respond well to treatment or reach complete remission. Objective: To review important new targets for antidepressant activity and to select phenylpropanoids with antidepressant activity, using Molegro Virtual Docker and Ossis Data Warris, and to verify substances with more promising antidepressant activity. Results and Conclusion: An in silico molecular modeling study, based on homology, was conducted to determine the three-dimensional structure of the 5-hydroxytryptamine 2A receptor (5- HT2AR), then molecular docking studies were performed and the predisposition for cytotoxicity risk among identified molecules was examined. A model for 5-HT2AR homology, with satisfactory results, was obtained indicating the good stereochemical quality of the model. The phenylpropanoid 4-allyl-2,6-dimethoxyphenol showed the lowest binding energy for 5-HT2AR, with results relevant to the L-arginine/nitric oxide (NO)/cGMP pathway, and showed no toxicity within the parameters of mutagenicity, carcinogenicity, reproductive system toxicity, and skin-tissue irritability, when evaluated in silico; therefore, this molecule can be considered promising for the investigation of antidepressant activity.

Leishmaniasis is a neglected disease that affects 15 million people worldwide. Existing treatments are associated with limitations, including high costs and toxicity. Several classes of natural substances have been reported to display leishmanicidal activity in the literature. Isoquinoline alkaloids, which are commonly found in the Annonaceae family, represent an important skeleton for the development of anti-leishmaniasis products. This study presents an overview of the potential use of Annonaceae alkaloids to treat leishmaniasis and describes a molecular docking study examining 215 isoquinoline alkaloids. All selected compounds contain a bisbenzyltetrahydroisoquinoline, suggesting the affinity of this skeleton for the target.

Background: Epilepsy is a neurological disease affected by an imbalance of inhibitory and excitatory signaling in the brain. Introduction: In this disease, the targets are active in pathophysiology and thus can be used as a focus for pharmacological treatment. Methods: Several studies demonstrated the antiepileptic effect of drugs acting on the following tar-gets: N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, voltage-gated calcium channel (Cav), Gamma aminobutyric acid transporter type 1 (GAT1), voltage-gated sodium channels (Nav), voltage-gated potassium channel of the Q subfam-ily (KCNQ) and Gamma aminobutyric acid type A (GABAA) receiver. Results: These studies highlight the importance of molecular docking. Conclusion: Quantitative Structure-Activity Relationship (QSAR) and computer aided drug design (CADD) in predicting of possible pharmacological activities of these targets.

Background: Tuberculosis is a disease with high incidence and high mortality rate, especially in Brazil. Although there are several medications available for treatment, in cases of resistance, there is a need to use more than one medication. Objective: Therefore, cases of toxicity increase and reports of resistance have been worrying the population. In addition, some medications have a short period of effectiveness. To achieve the goal, ligand-based and structure-based approaches were used. Methods: Thus, in an attempt to discover potent inhibitors against Mycobacterium tuberculosis enzymes, we sought to identify natural products with high therapeutic potential for the treatment of Tuberculosis through QSAR, Molecular Modeling and ADMET studies. Results: The results showed that the models generated from two sets of molecules with known activity against M. tuberculosis enzymes InhA and PS were able to select 11 and 8 compounds, respectively, between Lignans and Neolignans with 50 to 60% activity probability. In addition, molecular docking contributed to confirm the mechanism of action of compounds and increase the accuracy of methodologies. All molecules showed higher binding energy values for the drug Isoniazid. We conclude that compounds 33, 34, 110, 114 and 133 are promising for InhA target and compounds 07, 08, 19, 21, 42, 48, 75 and 141 for target PS. In addition, most molecules did not show any toxicity according to the evaluated parameters. Conclusions: Therefore, Lignans and Neolignans may be an alternative for the treatment of Tuberculosis.

The increasing number of computational studies in medicinal chemistry involving molecular docking has put the technique forward as promising in Computer-Aided Drug Design. Considering the main method in the virtual screening based on the structure, consensus analysis of docking has been applied in several studies to overcome limitations of algorithms of different programs and mainly to increase the reliability of the results and reduce the number of false positives. However, some consensus scoring strategies are difficult to apply and, in some cases, are not reliable due to the small number of datasets tested. Thus, for such a methodology to be successful, it is necessary to understand why, when and how to use consensus docking. Therefore, the present study aims to present different approaches to docking consensus, applications, and several scoring strategies that have been successful and can be applied in future studies.

Background: Nanotechnology has contributed a great deal to the field of medical science. Smart drugdelivery vectors, combined with stimuli-based characteristics, are becoming increasingly important. The use of external and internal stimulating factors can have enormous benefits and increase the targeting efficiency of nanotechnology platforms. The pH values of tumor vascular tissues are acidic in nature, allowing the improved targeting of anticancer drug payloads using drug-delivery vectors. Nanopolymers are smart drug-delivery vectors that have recently been developed and recommended for use by scientists because of their potential targeting capabilities, non-toxicity and biocompatibility, and make them ideal nanocarriers for personalized drug delivery. Method: The present review article provides an overview of current advances in the use of nanoparticles (NPs) as anticancer drug-delivery vectors. Results: This article reviews the molecular basis for the use of NPs in medicine, including personalized medicine, personalized therapy, emerging vistas in anticancer therapy, nanopolymer targeting, passive and active targeting transports, pH-responsive drug carriers, biological barriers, computer-aided drug design, future challenges and perspectives, biodegradability and safety. Conclusions: This article will benefit academia, researchers, clinicians, and government authorities by providing a basis for further research advancements.

Diet is an essential factor affecting the development of and risk for diabetes mellitus. In search of preventative and therapeutic strategies, the potential role of certain foods and their bioactive compounds to prevent the pathogenesis associated with metabolic diseases is to be considered. Human consumption of anthocyanins is among the highest of all flavonoids. Epidemiological studies have suggested that the consumption of anthocyanins lowers the risk of diabetes and diabetic complications. Anthocyanins are important natural bioactive pigments responsible for red to blue colour of fruits, leaves, seeds, stems and flowers, which are present in a variety of plant species particularly in berries and cherries. A large number of bioactive anthocyanins, such as cyanidin, malvidin, delphinidin, pelargonidin, peonidin, petunidin and their metabolites have shown multiple biological activities with apparent effects on glucose absorption, glucose uptake, insulin secretion and sensitivity, on the enzymes involved in glucose metabolism, gene expressions, inflammatory mediators, glucose transporters in progression of diabetes and associated complications, such as diabetic retinopathy, nephropathy, neuropathy and diabetic vascular diseases. The versatility of the anthocyanins provides a promising approach for diabetes management than synthetic drugs. Here we summarize the effect of several anthocyanins on many in vitro, in vivo and clinical studies and also reveal the mechanisms which could prevent or reverse the underlying mechanisms of diabetic pathologies including promotion of antioxidant, antihyperlipidemic, anti-inflammatory and anti-apoptotic activities.

Leishmaniasis is a complex disease caused by over 20 Leishmania species that primarily affects populations with poor socioeconomic conditions. Currently available drugs for treating leishmaniasis include amphotericin B, paromomycin, and pentavalent antimonials, which have been associated with several limitations, such as low efficacy, the development of drug resistance, and high toxicity. Natural products are an interesting source of new drug candidates. The Asteraceae family includes more than 23 000 species worldwide. Secondary metabolites that can be found in species from this family have been widely explored as potential new treatments for leishmaniasis. Recently, computational tools have become more popular in medicinal chemistry to establish experimental designs, identify new drugs, and compare the molecular structures and activities of novel compounds. Herein, we review various studies that have used computational tools to examine various compounds identified in the Asteraceae family in the search for potential drug candidates against Leishmania.

Gastrointestinal stromal tumors (GISTs) are unusual cancers which begin in specialized cells in the gastrointestinal tract wall. Various strategies involving single-agents, combinations, and rapid complementary inhibitor cycling are now being used to control such tumors. Based on promising early clinical trial experience, certain novel KIT, and PDGFRA tyrosine kinase inhibitors have begun advanced clinical development. Resistance to tyrosine kinase inhibitors has brought immense difficulties, with patients now requiring additional therapeutic options. This review describes and discusses the last five years (2016-2020) in developing novel c-KIT kinase inhibitors using virtual screening and docking approaches. Computational techniques can be used to complement experimental studies to identify new candidate molecules for therapeutic use. Molecular modeling strategies allow analysis of the required characteristics that compounds must have to effectively bind c-KIT. Through such analyses, it is possible to both discover and design novel inhibitors against cancer-related proteins that play a critical role in tumor development (including of mutant strains). Docking showed potential in the detection of the key residues responsible for ligand recognition and are very helpful to understand the interactions in the active site that can be used to develop new compounds/classes of anticancer drugs and help millions of cancer patients.

Aim: Selenium-based compounds have antitumor potential. We used a ligand-based virtual screening analysis to identify selenoglycolicamides with potential antitumor activity. Results & Conclusion: Compounds 3, 6, 7 and 8 were selected for in vitro cytotoxicity tests against various cell lines, according to spectrophotometry results. Compound 3 presented the best cytotoxicity results against a promyelocytic leukemia line (HL-60) and was able to induce cell death at a frequency similar to that observed for doxorubicin. The docking study showed that compound 3 has good interaction energies with the targets caspase-3, 7 and 8, which are components of the apoptotic pathway. These results suggested that selenium has significant pharmacological potential for the selective targeting of tumor cells, inducing molecular and cellular events that culminate in tumor cell death.

Chronic orofacial pain is a serious public health problem with a prevalence of 7-11% in the population. This disorder has different etiologies and characteristics that make pharmacological treatment difficult. Natural products have been shown to be a promising source of treatments for the management of chronic pain, as an example the terpenes.The aim of this study was to evaluate the anti-nociceptive and anti-inflammatory effects of one of these terpenes, d-limonene (LIM - a common monoterpene found in citrus fruits) alone and complexed with hydroxypropyl-β-cyclodextrin (LIM/HPβCD) in preclinical animal models.Orofacial pain was induced by the administration of hypertonic saline on the corneal surface, the injection of formalin into the temporomandibular joint (TMJ), or chronic constriction injury of the infraorbital nerve (CCI-IoN). The study used male Wistar rats and Swiss mice treated with LIM (50 mg/kg), LIM/HPβCD (50 mg/kg), vehicle (control), gabapentin or morphine, and eyes wiping (induced by hypertonic saline), face rubbing (formalin-induced in TMJ) or mechanical hyperalgesia (provoked by CCI-IoN) were assessed. Additionally, ELISA was used to measure TNF-α, and western blot analysis to assess levels of PKAcα, NFκB, p38MAPK and phosphorylated PKC substrates. Serum levels of aspartate aminotransferase (AST) and alanine transferase (ALT) were also evaluated.LIM and LIM/HPβCD significantly reduced (p 0.001) corneal nociception and formalin-induced TMJ nociception. In addition, both substances attenuated (p 0.001) mechanical hyperalgesia in the CCI-IoN model. The antinociceptive effect induced by LIM and HPβCD/LIM was associated with decreased TNF-α levels, downregulation of the NFκB and p38MAPK signalling pathways and reduced PKC substrate phosphorylation and PKA immunocontent. Moreover, the results demonstrated that complexation with HPβCD was able to decrease the therapeutic dose of LIM.LIM was found to be a promising molecule for the treatment of orofacial pain due to its capacity to modulate some important mediators essential to the establishment of pain, and HPβCD can be a key tool to improve the profile of LIM.

Background: Natural products are useful agents for the discovery of new lead- compounds and effective drugs to combat coronaviruses (CoV). Objective: The present work provides an overview of natural substances, plant extracts, and essential oils as potential antiSARS-CoV agents. In addition, this work evaluates their drug-like properties which are essential in the selection of compounds in order to accelerate the drug development process. Methods: The search was carried out using PubMed, ScienceDirect and SciFinder. Articles addressing plant-based natural products as potential SARS-CoV or SARS-CoV-2 agents within the last seventeen years were analyzed and selected. The descriptors for Chemometrics analysis were obtained in alvaDesc and the principal component analysis (PCA) was carried out in SIMCA version 13.0. Results: Based on in vitro assays and computational analyses, this review covers twentynine medicinal plant species and more than 300 isolated substances as potential anti-coronavirus agents. Among them, flavonoids and terpenes are the most promising compound classes. In silico analyses of drug-like properties corroborate these findings and indicate promising candidates for in vitro and in vivo studies to validate their activity. Conclusion: This paper highlights the role of ethnopharmacology in drug discovery and simulates the use of integrative (in silico/ in vitro) and chemocentric approaches to strengthen current studies and guide future research in the field of antivirals agents.

Background: Organocalcogens are a class of organic compounds obtained by the synthesis experiments to include S, Se, or Te. Among the elements that comprise this class, Se is characterized as an essential mineral and nutrient for humans. Se has been widely studied in many aspects. Organic synthesis of organoselenides is used for obtaining new potential drug candidates and may be highly beneficial from the use of computational approaches to reduce time and cost of the experiments. Thus, the goal of our study is to evaluate the computational approaches used in the organoselenides research from 1999 to 2019. Methods: A literature review was performed by searching the database “Web of Sciences”. Results: Most of the theoretical studies included structural elucidation or structure-property analysis. We also found research regarding molecular docking approaches and Quantitative Structure-Activity Relationship (QSAR) studies. Conclusion: Computational studies have been widely applied to organoselenides. They demonstrated promising results and resulted in reduced the cost of research, increased efficacy, and, ultimately, novel organoselenides with desired properties.

Due to their versatile biological activity, Azoles are widely studied in pharmacochemistry. It is possible to use them in many applications and in studies aimed at discovering antiparasitic, antineoplastic, antiviral, antimicrobial compounds; and in the production of materials for treatment of varied pathologies. Based on their biological activity, our review presents several studies that involve this class of organic compounds. A bibliographic survey of this type can effectively contribute to pharmaceutical sciences, stimulating the discovery of new compounds, and structural improvements to biological profiles of interest. In this review, articles are discussed involving the synthesis of new compounds and chemoinformatic contributions. Current applications of azoles in both the pharmaceutical and agri-business sectors are well known, yet as this research highlights, azole compounds can also bring important contributions to the fight against many diseases. Among the heterocyclics, azoles are increasingly studied by research groups around the world for application against tuberculosis, HIV, fungal and bacterial infections; and against parasites such as leishmaniasis and trypanosomiasis. Our hope is that this work will help arouse the interest of research groups planning to develop new bioactives to fight against these and other diseases.

Leishmaniasis is endemic in at least 98 countries. Due to the high toxicity and resistance associated with the drugs, we chose lignans as an alternative, due to their favorable properties of absorption, distribution, metabolism, excretion, and toxicity (ADMET). To investigate their leishmanicidal potential, the biological activities of a set of 160 lignans were predicted using predictive models that were built using data for Leishmania major and L. (Viannia) braziliensis. A combined analysis, based on ligand and structure, and several other computational approaches were used. The results showed that the combined analysis was able to select 11 lignans with potential activity against L. major and 21 lignans against L. braziliensis, with multitargeting effects and low or no toxicity. Of these compounds, four were isolated from the species Justicia aequilabris (Nees) Lindau. All of the identified compounds were able to inhibit the growth of L. braziliensis promastigotes, with the most active compound, (159) epipinoresinol-4-O-&beta, d-glucopyranoside, presenting an IC50 value of 5.39 &micro, M and IC50 value of 36.51 &micro, M for L. major. Our findings indicated the potential of computer-aided drug design and development and demonstrated that lignans represent promising prototype compounds for the development of multitarget drugs against leishmaniasis.

Introduction Pain is considered an unpleasant sensory and emotional experience, being considered as one of the most important causes of human suffering. Computational chemistry associated with bioinformatics has stood out in the process of developing new drugs, through natural products, to manage this condition. Objective To analyze, through literature data, recent molecular coupling studies on the antinociceptive activity of essential oils and monoterpenes. Data source Systematic search of the literature considering the years of publications between 2005 and December 2019, in the electronic databases PubMed and Science Direct. Eligibility criteria Were considered as criteria of 1) Biological activity: non-clinical effects of an OE and/or monoterpenes on antinociceptive activity based on animal models and in silico analysis, 2) studies with plant material: chemically characterized essential oils and/or their constituents isolated, 3) clinical and non-clinical studies with in silico analysis to assess antinociceptive activity, 4) articles published in English. Exclusion criteria were literature review, report or case series, meta-analysis, theses, dissertations, and book chapter. Results Of 16,006 articles, 16 articles fulfilled all the criteria. All selected studies were non-clinical. The most prominent plant families used were Asteraceae, Euphorbiaceae, Verbenaceae, Lamiaceae, and Lauraceae. Among the phytochemicals studied were α-Terpineol, 3-(5-substituted-1,3,4-oxadiazol-2-yl)-N'-[2-oxo-1,2-dihydro-3H-indol-3-ylidene] propane hydrazide, β-cyclodextrin complexed with citronellal, (-)-α-bisabolol, β-cyclodextrin complexed with farnesol, and p-Cymene. The softwares used for docking studies were Molegro Virtual Docker, Sybyl®X, Vlife MDS, AutoDock Vina, Hex Protein Docking, and AutoDock 4.2 in PyRx 0.9. The molecular targets/complexes used were Nitric Oxide Synthase, COX-2, GluR2-S1S2, TRPV1, β-CD complex, CaV1, CaV2.1, CaV2.2, and CaV2.3, 5-HT receptor, delta receptor, kappa receptor, and MU (μ) receptor, alpha adrenergic, opioid, and serotonergic receptors, muscarinic receptors and GABAA opioid and serotonin receptors, 5-HT3 and M2 receptors. Many of the covered studies used molecular coupling to investigate the mechanism of action of various compounds, as well as molecular dynamics to investigate the stability of protein-ligand complexes. Conclusions The studies revealed that through the advancement of more robust computational techniques that complement the experimental studies, they may allow some notes on the identification of a new candidate molecule for therapeutic use.

Myrtenol has gained wide interest because of its pharmacological profiles, mainly for treatment of chronic diseases. To improve the solubility of myrtenol, the formation of inclusion complexes with β-cyclodextrin was performed by physical mixture, kneading process or slurry complexation (SC) methods and characterized using thermal analysis, XRD, SEM and NMR. From these results, myrtenol complexed by SC was successfully complexed into β-cyclodextrin cavity. The interaction between myrtenol and β-cyclodextrin was confirmed by molecular docking. Hence, the SC β-cyclodextrin-myrtenol complex was evaluate for its anti-hyperalgesic, anxiolytic and antioxidant activity in a fibromyalgia model. Results show that myrtenol and β-cyclodextrin form a stable complex and have anti-hyperalgesic effect, improve the cognitive impairment caused and have an anxiolytic-like effect. Furthermore, the β-cyclodextrin/myrtenol complex decrease lipoperoxidation, increased catalase activity and a reduce SOD/CAT ratio. Therefore, β-cyclodextrin/myrtenol complex reduce painful behavior, improves motor skills and emotional behavior and decreases oxidative stress in a fibromyalgia model.

Alzheimer’s disease (AD) is characterized by the progressive disturbance in cognition and affects approximately 36 million people, worldwide. However, the drugs used to treat this disease are only moderately effective and do not alter the course of the neurodegenerative process. This is because the pathogenesis of AD is mainly associated with oxidative stress, and current drugs only target two enzymes involved in neurotransmission. Therefore, the present study sought to identify potential multitarget compounds for enzymes that are directly or indirectly involved in the oxidative pathway, with minimal side effects, for AD treatment. A set of 159 lignans were submitted to studies of QSAR and molecular docking. A combined analysis was performed, based on ligand and structure, followed by the prediction of absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. The results showed that the combined analysis was able to select 139 potentially active and multitarget lignans targeting two or more enzymes, among them are c-Jun N-terminal kinase 3 (JNK-3), protein tyrosine phosphatase 1B (PTP1B), nicotinamide adenine dinucleotide phosphate oxidase 1 (NOX1), NADPH quinone oxidoreductase 1 (NQO1), phosphodiesterase 5 (PDE5), nuclear factor erythroid 2-related factor 2 (Nrf2), cycloxygenase 2 (COX-2), and inducible nitric oxide synthase (iNOS). The authors conclude that compounds (06) austrobailignan 6, (11) anolignan c, (19) 7-epi-virolin, (64) 6-[(2R,3R,4R,5R)-3,4-dimethyl-5-(3,4,5-trimethoxyphenyl)oxolan-2-yl]-4-methoxy-1,3-benzodioxole, (116) ococymosin, and (135) mappiodoinin b have probabilities that confer neuroprotection and antioxidant activity and represent potential alternative AD treatment drugs or prototypes for the development of new drugs with anti-AD properties.

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder that is characterized by progressive loss of the upper and lower motor neurons at the spinal or bulbar level. Oxidative stress (OS) associated with mitochondrial dysfunction and the deterioration of the electron transport chain are factors that contribute to neurodegeneration and perform a potential role in the pathogenesis of ALS. Natural antioxidant molecules have been proposed as an alternative form of treatment for the prevention of age-related neurological diseases, in which ALS is included. Researches support that regulations in cellular reduction/oxidation (redox) processes are being increasingly implicated in this disease, and antioxidant drugs are aimed at a promising pathway to treatment. Among the strategies used for obtaining new drugs, we can highlight the isolation of secondary metabolite compounds from natural sources that, along with semisynthetic derivatives, correspond to approximately 40% of the drugs found on the market. Among these compounds, we emphasize oxygenated and nitrogenous compounds, such as flavonoids, coumarins, and alkaloids, in addition to the fatty acids, that already stand out in the literature for their antioxidant properties, consisting in a part of the diets of millions of people worldwide. Therefore, this review is aimed at presenting and summarizing the main articles published within the last years, which represent the therapeutic potential of antioxidant compounds of natural origin for the treatment of ALS.

Inflammation has been very evident in infectious diseases, but in recent times research has increasingly shown that a range of non-infectious diseases may present with inflammatory conditions. This fact becomes important as new anti-inflammatory drugs emerge with different targets for treatment of diseases. Virtual screening (VS) involves applying computational methods to discover new ligands for biological structures from the formation of large libraries composed of a large number of compounds. This review aims to report several studies employing a variety of VS: ligand-based and structure-based VS are being used more frequently in combination to decrease the probability of choosing false positive candidates. There are also studies that use only one approach. Docking is widely employed as structure-based VS methodology, however pharmacophore models based on the structure are becoming more prevalent. Molecular dynamics simulations, despite their computational cost, are still utilized to validate docking scores and analyze the stability of the complex ligand-structure. It is important to note that several studies employed several drug-like rules to screen structures, as well, decoys and PAINS to validate the models. Natural product databases, despite the lower number of the compounds compared to other databases that are available, are commonly referred to as a source of drug-like molecules. There is a literal explosion of software being released for a variety of purposes and several of them are free tools and/or web tools. Overall, VS studies are nowadays a normal part of medicinal chemistry to determine novel potential inhibitors for targets of inflammatory diseases.

Background Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by debilitating motor deficits, as well as autonomic problems, cognitive declines, changes in affect and sleep disturbances. Although the scientific community has performed great efforts in the study of PD, and from the most diverse points of view, the disease remains incurable. The exact mechanism underlying its progression is unclear, but oxidative stress, mitochondrial dysfunction and inflammation are thought to play major roles in the etiology. Objective Current pharmacological therapies for the treatment of Parkinson's disease are mostly inadequate, and new therapeutic agents are much needed. Methods In this review, recent advances in computer-aided drug design for the rational design of new compounds against Parkinson disease; using methods such as Quantitative Structure-Activity Relationships (QSAR), molecular docking, molecular dynamics and pharmacophore modeling are discussed. Results In this review, four targets were selected: the enzyme monoamine oxidase, dopamine agonists, acetylcholine receptors, and adenosine receptors. Conclusion Computer aided-drug design enables the creation of theoretical models that can be used in a large database to virtually screen for and identify novel candidate molecules.

Anthocyanins, a flavonoid class of polyphenols, are water soluble dark colored natural pigments found in fruits and vegetables. Owing to their wide distribution in plant materials, dietary consumption of anthocyanins is high compared to other flavonoids. Anthocyanins, due to their multifaceted medicinal properties are the active components in many herbal folk medicines. As in vitro and in vivo results, animal models, and clinical trials in various cell lines suggest, anthocyanins possess antioxidant, antidiabetic, antihyperlipidemic, anti-inflammatory, anticarcinogenic, antiulcer, and preventive activities against cardiovascular diseases. Additionally, anthocyanins exhibit chemotherapeutic, cardioprotective, hepatoprotective, and neuroprotective activities. In the diet, anthocyanins are absorbed in the stomach and intestinal cells and rapidly detected in the plasma. These promising properties of anthocyanins may well provide health benefits against chronic diseases.

Chagas disease is an endemic disease caused by Trypanosoma cruzi, which affects more than eight million people, mostly in the Americas. A search for new treatments is necessary to control and eliminate this disease. Sesquiterpene lactones (SLs) are an interesting group of secondary metabolites characteristic of the Asteraceae family that have presented a wide range of biological activities. From the ChEMBL database, we selected a diverse set of 4452, 1635, and 1322 structures with tested activity against the three T. cruzi parasitic forms: amastigote, trypomastigote, and epimastigote, respectively, to create random forest (RF) models with an accuracy of greater than 74 % for cross-validation and test sets. Afterward, a ligand-based virtual screen of the entire SLs of the Asteraceae database stored in SistematX (1306 structures) was performed. In addition, a structure-based virtual screen was also performed for the same set of SLs using molecular docking. Finally, using an approach combining ligand-based and structure-based virtual screening along with the equations proposed in this study to normalize the probability scores, we verified potentially active compounds and established a possible mechanism of action.

The hepatoprotective effect of P. leschenaultii. (DC) leaves was investigated in rats under paracetamol induced oxidative stress. Leaf acetone extract (200 and 400mg/kg) were administered daily via gavage for 14days before paracetamol (2000mg/kg, p.o.) treatment. After the experiment, the levels of serum biochemical parameters and enzymatic antioxidant levels were determined. Furthermore, liver tissues were analyzed histopathologically. Additionally, the molecular docking studies of the identified compounds against PXR and FXR proteins were also performed. The assessment revealed that the acetone extract significantly reduced the elevated levels of SGPT, SGOT and ALP in serum. Moreover, the enzymatic antioxidants such as SOD, CAT and LPO were also retained normally by the plant extract. From histopathological analysis, it was clearly evident that the cellular architecture of plant extract treated rat liver tissues were not affected by the paracetamol induction at the higher dose. The results of docking studies also revealed that the identified compounds showed steric interactions (between nonpolar atoms) with amino acid groups. Collectively, the present study suggests that P. leschenaultii leaves extract protects the liver from paracetamol induced hepatic damage.

Molecular Hybridization is an approach in rational drug design where new chemical entities are obtained by combining two or more pharmacophoric units from different bioactive compounds into a single molecule. Through this approach, medicinal chemists hope that the new hybrid derivative presents: better affinity and efficacy when compared to the parent drugs; a modified selectivity profile with improvement over pharmacokinetic and pharmacodynamic restrictions; dual or multiple modes of action; reduction of undesirable side effects; decreases in drug-drug interactions; reduced emergence or spread of drug resistance in microorganisms and protozoans; and lower cost. The approach has been successfully used by many research groups around the world and has had very promising results with diseases having multifactorial profiles, like Alzheimer´s, Parkinson´s disease, cancer, inflammation, and hypertension among others. The purpose of this paper is to conduct an updated review of molecular hybridization and multitarget profiling (a rational drug design approach), and its applications to the design and discovery of novel hybrid compounds with anti-inflammatory, antimicrobial, anticancer and antiprotozoal (leishmaniasis, malaria, and schistosomiasis) activities over the last six years.

Made available in DSpace on 2019-10-06T16:45:21Z (GMT). No. of bitstreams: 0 Previous issue date: 2019-11-01 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Financiadora de Estudos e Projetos The search for new drugs with anti-inflammatory properties remains a challenge for modern medicine. Among the various strategies for drug discovery, deriving new chemical entities from known bioactive natural and/or synthetic compounds remains a promising approach. Here, we designed and synthesized CVIB, a codrug developed by association of carvacrol (a phenolic monoterpene) with ibuprofen (a non-steroidal anti-inflammatory drug). In silico pharmacokinetic and physicochemical properties evaluation indicated low aqueous solubility (LogP ≥5.0). Nevertheless, the hybrid presented excellent oral bioavailability, gastrointestinal tract absorption, and low toxicity. CVIB did not present cytotoxicity in peripheral blood mononuclear cells (PBMCs), and promoted a significant reduction in IL-2, IL-10, IL-17, and IFN-γ cytokine levels in vitro. The LD50 was estimated to be approximately 5000 mg/kg. CVIB was stable and detectable in human plasma after 24 h. In vivo anti-inflammatory evaluations revealed that CVIB at 10 and 50 mg/kg i.p. caused a significant decrease in total leukocyte count (p < 0.01) and provoked a significant reduction in IL-1β (p < 0.01). CVIB at 10 mg/kg i.p. efficiently decreased inflammatory parameters better than the physical mixture (carvacrol + ibuprofen 10 mg/kg i.p.). The results suggest that the codrug approach is a good option for drug design and development, creating the possibility of combining NSAIDs with natural products in order to obtain new hybrid drugs may be useful for treatment of inflammatory diseases. Laboratory of Synthesis and Drug Delivery State University of Paraiba Post-Graduation Program in Natural and Synthetic Bioactive Products Federal University of Paraiba Laboratory of Immunomodulation and Novel Therapeutic Approaches Federal University of Pernambuco Laboratory of Neurosciences and Pharmacological Assays (LANEF) University of Sergipe Teaching and Research Management - University Hospital Federal University of Paraiba Department of Antibiotics Center for Biosciences Federal University of Pernambuco Laboratory of Toxicology São Paulo State University (UNESP) School of Pharmaceutical Sciences Health Research and Education Center (NUPADS) Federal University of Mato Grosso Université de Nantes Cibles et Médicaments des Infections et du Cancer IICiMed EA 1155 Laboratory of Toxicology São Paulo State University (UNESP) School of Pharmaceutical Sciences CNPq: 304112/2017-8 CNPq: 306115/2017-4 CNPq: 308590/2017-1

Natural products are compounds extracted from plants, marine organisms, fungi or bacteria. Many researches for new drugs are based on these natural molecules, mainly by beneficial effects on health, health, efficacy, and therapeutic safety. Leishmaniosis, Chagas disease and African sleeping sickness are neglected diseases caused by the Leishmania and Trypanosoma ssp. parasites. These infections mainly affect population of developing countries; they have different symptoms, and may often lead to death. The therapeutic drugs available to treat these diseases are either obsolete, toxic, or have questionable efficacy, possibly through encountering resistance. Discovery of new, safe, effective, and affordable molecules is urgently needed. Natural organisms, as marine metabolites, alkaloids, flavonoids, steroids, terpene and coumarins provide innumerable molecules with the potential to treat these diseases. This study examines studies of natural bioactive compounds as antileishmanial and antitrypanosomal agents.

The anti-hyperalgesic effect of the complex containing α-terpineol (αTPN) and β-cyclodextrin (βCD) was analyzed in a non-inflammatory chronic muscle pain model, as well as its mechanism of action through docking study for a possible interaction with receptors. The αTPN-βCD complex was prepared and characterized through the thermogravimetry/derivate thermogravimetry (TG/DTG), Fourier transform infrared spectroscopy (FTIR) and scanning electron microscope (SEM). The model of chronic muscle pain was induced by two injections of pH 4.0 saline (20 μl) into the left gastrocnemius 5 days apart. After confirming hyperalgesia, male mice were treated with αTPN-βCD (25, 50 or 100 mg/kg; p.o.) or vehicle (saline 0.9%, p.o.) daily for 10 days. 1 h after the mechanical hyperalgesia, motor performance was evaluated. In addition, the systemic administration of naloxone and ondansetron tested the analgesic effect on the active opioid and serotonin receptors, respectively. The characterization tests indicated that αTPN was efficiently incorporated into βCD. The oral treatment with αTPN-βCD, at all doses tested, produced a significant (p < 0.001) decrease in the mechanical hyperalgesia, without causing any alteration in the force and in motor performance. This analgesic effect was reversed by the systemic administration of naloxone or ondansetron. These findings are corroborated by the docking study described in the present study, which verified a possible interaction of αTPN-βCD with opioid (MU, Kappa, Delta) and 5-HT receptors. Thus, it can be concluded that αTPN-βCD reduced the hyperalgesia followed by the chronic muscle pain model, probably evoked by the descending inhibitory pain system, specifically by opioid and serotoninergic receptors.

This work aimed to characterize and evaluate the antihypertensive effect of the (-)-β-pinene/β-cyclodextrin (βP/β-CD) complex. The complex was prepared through physical mixture and slurry complexation methods and was analyzed through differential scanning calorimetry, thermogravimetry/derivative thermogravimetry, fourier transform infrared spectroscopy, diffraction X-ray, docking and scanning electron microscopy. Normotensive or L-NAME-induced hypertensive rats were used in pharmacological experiments. Mean arterial pressure (MAP) was determined with direct blood pressure measurements from the abdominal aorta. The drugs were orally administrated and their effects were recorded during 48 hours. Vascular effects of βP were evaluated in isolated ring of mesenteric artery. The physicochemical characterization showed βP/β-CD complex formation. In hypertensive rats (MAP = 156±16 mmHg), the complex, but not βP alone, promoted hypotension at 36 and 48 hours after administration (MAP = 124±3 and 110±5 mmHg, respectively). In arterial rings, βP vasorelaxed rings precontracted with phenylephrine (Emax = 105±6%), which was not changed after the removal of the vascular endothelium (Emax = 108±4%), after the pre-contraction with KCl 80 mM (Emax = 107±8%) or S(-)-BayK8644 (Emax = 107±5%), or after incubation with TEA (Emax = 113±4%). Finally, βP inhibited CaCl2- and sodium-orthovanadate-induced contractions. In conclusion, the slurry complexation method was the best among them. Pharmacological results demonstrated that the complex promoted antihypertensive effect. Furthermore, βP induced endothelium- independent vasorelaxation possibly caused by the inhibition of the Ca2+ influx through L-type Ca2+ channel associated to a decrease in calcium sensitivity.

Background Diseases perceived as neglected tropical infections are generally caused by parasites which reach poor, underserved populations (primarily infrastructure), cause serious damage to health, and many deaths. AIDS and tuberculosis, (although not classified as neglected by WHO), are discriminated against infections which cause great social damage. The drugs currently used to treat these diseases do not have the desired effectiveness, enable the emergence of resistant strains, and in most cases are difficult to obtain. Few pharmaceutical companies are investing in new drug research for neglected diseases, for lack of financial return. This review reports the major neglected diseases, AIDS, tuberculosis, their targets, and research on multi-target drugs. Methods The studies for new drugs against these infections involve in silico methods, synthesis, structural determinations, analytical analysis and other experimental assays. Results A new single compound, forecasting possible pharmacodynamic and pharmacokinetic interactions becomes a simpler process; it is also believed that these drugs are safer and more efficient, since they act with synergism on different targets. It occurs but the emergence of new resistant strains and side effects. Conclusion Multi-target drugs represent a new alternative to find new lead compounds. A ligand that targets two or more receivers may be seen as a potential drug, combating infection by different routes.