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Inflammation is a natural process that occurs in the organism in response to harmful external agents. Despite being considered beneficial, exaggerated cases can cause severe problems for the body. The main inflammatory manifestations are pain, increased temperature, edema, decreased mobility, and quality of life for affected individuals. Diseases such as arthritis, cancer, allergies, infections, arteriosclerosis, neurodegenerative diseases, and metabolic problems are mainly characterized by an exaggerated inflammatory response. Inflammation is related to two categories of substances: pro- and anti-inflammatory mediators. Among the pro-inflammatory mediators is Tumor Necrosis Factor-α (TNF-α). It is associated with immune diseases, cancer, and psychiatric disorders which increase its excretion. Thus, it becomes a target widely used in discovering new antiinflammatory drugs. In this context, secondary metabolites biosynthesized by plants have been used for thousands of years and continue to be one of the primary sources of new drug scaffolds against inflammatory diseases. To decrease costs related to the drug discovery process, Computer-Aided Drug Design (CADD) techniques are broadly explored to increase the chances of success. In this review, the main natural compounds derived from alkaloids, flavonoids, terpene, and polyphenols as promising TNF-α inhibitors will be discussed. Finally, we applied a molecular modeling protocol involving all compounds described here, suggesting that their interactions with Tyr59, Tyr119, Tyr151, Leu57, and Gly121 residues are essential for the activity. Such findings can be useful for research groups worldwide to design new anti-inflammatory TNF-α inhibitors.

Abstract: Drug design and discovery is a process that requires high financial costs and is timeconsuming. For many years, this process focused on empirical pharmacology. However, over the years, the target-based approach allowed a significant discovery in this field, initiating the rational design era. In view, to decrease the time and financial cost, rational drug design is benefited by increasing computer engineering and software development, and computer-aided drug design (CADD) emerges as a promising alternative. Since the 1970s, this approach has been able to identify many important and revolutionary compounds, like protease inhibitors, antibiotics, and others. Many anticancer compounds identified through this approach have shown their importance, being CADD essential in any drug discovery campaign. Thus, this perspective will present the prominent successful cases utilizing this approach and entering into the next stage of drug design. We believe that drug discovery will follow the progress in bioinformatics, using high-performance computing with molecular dynamics protocols faster and more effectively. In addition, artificial intelligence and machine learning will be the next process in the rational design of new drugs. Here, we hope that this paper generates new ideas and instigates research groups worldwide to use these methods and stimulate progress in drug design.

Abstract: The Flaviviridae virus family consists of the genera Hepacivirus, Pestivirus, and Fla-vivirus, with approximately 70 viral types that use arthropods as vectors. Among these diseases, dengue (DENV) and zika virus (ZIKV) serotypes stand out, responsible for thousands of deaths worldwide. Due to the significant increase in cases, the World Health Organization (WHO) declared DENV a potential threat for 2019 due to being transmitted by infected travelers. Furthermore, ZIKV also has a high rate of transmissibility, highlighted in the outbreak in 2015, generating consequenc-es such as Guillain-Barré syndrome and microcephaly. According to clinical outcomes, those in-fected with DENV can be asymptomatic, and in other cases, it can be lethal. On the other hand, ZIKV has severe neurological symptoms in newborn babies and adults. More serious symptoms in-clude microcephaly, brain calcifications, intrauterine growth restriction, and fetal death. Despite these worrying data, no drug or vaccine is approved to treat these diseases. In the drug discovery process, one of the targets explored against these diseases is the NS2B-NS3 complex, which pre-sents the catalytic triad His51, Asp75, and Ser135, with the function of cleaving polyproteins, with specificity for basic amino acid residues, Lys- Arg, Arg-Arg, Arg-Lys or Gln-Arg. Since NS3 is highly conserved in all DENV serotypes and plays a vital role in viral replication, this complex is an excellent drug target. In recent years, computer-aided drug discovery (CADD) is increasingly essen-tial in drug discovery campaigns, making the process faster and more cost-effective, mainly ex-plained by discovering new drugs against DENV and ZIKV. Finally, the main advances in compu-tational methods applied to discover new compounds against these diseases will be presented here. In fact, molecular dynamics simulations and virtual screening is the most explored approach, providing several hit and lead compounds that can be used in further optimizations. In addition, fragment-based drug design and quantum chemistry/molecular mechanics (QM/MM) provides new insights for developing anti-DENV/ZIKV drugs. We hope that this review offers further helpful in-formation for researchers worldwide and stimulates the use of computational methods to find a promising drug for treating DENV and ZIKV.

ABSTRACT: The discovery of antibiotics was a revolutionary feat that provided countless health bene-fits. The identification of penicillin by Alexander Fleming initiated the era of antibiotics, represent-ed by constant discoveries that enabled effective treatments for the different classes of diseases caused by bacteria. However, the indiscriminate use of these drugs allowed the emergence of re-sistance mechanisms of these microorganisms against the available drugs. In addition, the constant discoveries in the 20th century generated a shortage of new molecules, worrying health agencies and professionals about the appearance of multidrug-resistant strains against available drugs. In this context, the advances of recent years in molecular biology and microbiology have allowed new per-spectives in drug design and development, using the findings related to the mechanisms of bacterial resistance to generate new drugs that are not affected by such mechanisms and supply new mole-cules to be used to treat resistant bacterial infections. Besides, a promising strategy against bacterial resistance is the combination of drugs through adjuvants, providing new expectations in designing new antibiotics and new antimicrobial therapies. Thus, this manuscript will address the main mech-anisms of bacterial resistance under the understanding of medicinal chemistry, showing the main active compounds against efflux mechanisms, and also the application of the use of drug delivery systems, and finally, the main potential natural products as adjuvants or with promising activity against resistant strains.

Since December 2019, the new Coronavirus disease (COVID-19) caused by the etiological agent SARS-CoV-2 has been responsible for several cases worldwide, becoming pandemic in March 2020. Pharmaceutical companies and academics have joined their efforts to discover new therapies to control the disease since there are no specific drugs to combat this emerging virus. Thus, several tar-gets have been explored; among them, the transmembrane protease serine 2 (TMPRSS2) has gained greater interest in the scientific community. In this context, this review will describe the importance of TMPRSS2 protease and the significant advances in virtual screening focused on discovering new inhibitors. In this review, it was observed that molecular modeling methods could be powerful tools in identifying new molecules against SARS-CoV-2. Thus, this review could be used to guide re-searchers worldwide to explore the biological and clinical potential of compounds that could be promising drug candidates against SARS-CoV-2, acting by inhibition of TMPRSS2 protein.

Graphical abstract, Highlights • 25H-NBOMe and 25H-NBOH recreational drugs induces abnormal formation in zebrafish embryos. • Biophysical and theoretical studies indicate that these drugs have affinity for the DNA major groove. • The toxicity observed in the zebrafish embryos and DNA interaction may be correlated., Toxicological effects of 25H-NBOMe and 25H-NBOH recreational drugs on zebrafish embryos and larvae at the end of 96 h exposure period were demonstrated. 25H-NBOH and 25H-NBOMe caused high embryo mortality at 80 and 100 µg mL−1, respectively. According to the decrease in the concentration tested, lethality decreased while non-lethal effects were predominant up to 10 and 50 µg mL−1 of 25H-NBOH and 25H-NBOMe, respectively, including spine malformation, egg hatching delay, body malformation, otolith malformation, pericardial edema, and blood clotting. We can disclose that these drugs have an affinity for DNA in vitro using biophysical spectroscopic assays and molecular modeling methods. The experiments demonstrated that 25H-NBOH and 25H-NBOMe bind to the unclassical major groove of ctDNA with a binding constant of 27.00 × 104 M−1 and 5.27 × 104 M−1, respectively. Furthermore, these interactions lead to conformational changes in the DNA structure. Therefore, the results observed in the zebrafish embryos and DNA may be correlated.

In recent years, the world has faced several outbreaks caused by viral diseases, resulting in deaths and comorbidities, harming the health of the population. Due to the “constant” discovery of new antivirals, vaccines, hygiene habits, and basic sanitation, society had the false impression of being free from these diseases. However, since the 1980s, various outbreaks have occurred, such as HIV (Human immunodeficiency virus) and recently, ZIKV (Zika virus), CHIKV (Chikungunya virus), and EBOV (Ebola virus) have increased the concern about such pathogens, resulting in advances in drug discovery. In addition, the SARS-CoV-2 outbreak responsible for 27,417,497 cases, and 894,241 deaths (to date, September 9th, 2020), showed how scientists should advance to end this disease so damaging to the global health and economy. In this context, researches focused on drug development have been improved in recent years. Thus, it is essential to use computational approaches to accelerate drug discovery in laboratories. Based on this, structure-based drug design (SBDD) techniques constitute the most used computer-aided approaches for discovering and developing new drugs. Among these techniques, molecular dynamics (MD) simulations have been essential steps and their use in virtual screening studies is considered indispensable. The MD considers the macromolecule flexibility using Newtonian principles applied to proteins, enzymes, membranes, nucleic acids, and other systems. Thus, it is possible to analyze protein-ligand interactions, and also the affinity energy that a determined ligand exhibits towards its target. Such information is indispensable for designing and optimizing new active agents. This chapter will be addressed to concepts and applications of MD simulations, as well as their applications in the discovery of drugs against Coronaviruses (SARS-, MERS-CoV, and SARSCoV-2); Influenza (INFV); Chikungunya (CHIKV); Zika (ZIKV); Dengue (DENV); Ebola (EBOV); and human immunodeficiency virus (HIV), constituting a great source of helpful information that could be utilized for designing new compounds against these diseases.

Over recent years, many outbreaks caused by (re)emerging RNA viruses have been reported worldwide, including life-threatening Flaviviruses, such as Dengue (DENV) and Zika (ZIKV). Currently, there is only one licensed vaccine against Dengue, Dengvaxia®. However, its administration is not recommended for children under nine years. Still, there are no specific inhibitors available to treat these infectious diseases. Among the flaviviral proteins, NS5 RNA-dependent RNA polymerase (RdRp) is a metalloenzyme essential for viral replication, suggesting that it is a promising macromolecular target since it has no human homolog. Nowadays, several NS5 RdRp inhibitors have been reported, while none inhibitors are currently in clinical development. In this context, this review constitutes a comprehensive work focused on RdRp inhibitors from natural, synthetic, and even repurposing sources. Furthermore, their main aspects associated with the structure-activity relationship (SAR), proposed mechanisms of action, computational studies, and other topics will be discussed in detail.

Inflammation is a natural reaction to external stimuli to protect the organism. However, if it is exaggerated, it can cause severe physiopathological damage, linked to diseases like rheumatoid arthritis, cancer, diabetes, allergies, and infections. Inflammation is mainly characterized by pain, increased temperature, flushing, and edema, which can be controlled using anti-inflammatory drugs. In this context, prostaglandin E

Measles virus (MV) is an infectious disease related to thousands of deaths in previous outbreaks. Health agencies estimated that approximately 42% of countries would have the eradication of this pathogen. However, the virus remains as a challenging health problem for countries’ economies. This pathogen is highly transmissible via the respiratory droplets of infected individuals, which remain in the air and surfaces for several hours, increasing its rate of transmission. Prophylactic vaccination is the most effective strategy in controlling this infection. In recent years, political-economic factors and the anti-vaccine movement have contributed to its reemergence. Despite apparently being a controlled disease, these factors contributed to the increase in the number of cases, including fatalities. Also, there is still no drug used in the disease’s clinical management, justifying the investment in new alternatives. This chapter will be addressed to the main advances in new therapies against MV, highlighting hit compounds, focusing on non- and nucleoside, peptide, quinoline, retinoid analogs, and other derivatives. Besides the main advances in biological approaches such as glycosaminoglycan and interferon; also immunological approaches exist such as plant-and peptide-based vaccines. Nucleoside and non-nucleoside analogs are the most explored chemical agents, resulting in several promising molecules. Also, natural products could be effective in controlling MV. Finally, advances in immunological strategies, such as discovering new vaccines show that (despite a vaccine’s existence) it is necessary to find another more effective and accepted by the population, leading to the definitive eradication of this disease.

Background: Leishmaniasis is a worldwide health problem, highly endemic in developing countries. Among the four main clinical forms of the disease, visceral leishmaniasis is the most severe, fatal in 95% of cases. The undesired side-effects from first-line chemotherapy and the reported drug resistance search for effective drugs that can replace or supplement those currently used an urgent need. Aminoguanidine hydrazones (AGH's) have been explored for exhibiting a diverse spectrum of biological activities, in particular the antileishmanial activity of MGBG. The bioisosteres thiosemicarbazones (TSC's) offer a similar biological activity diversity, including antiprotozoal effects against Leishmania species and Trypanosoma cruzi. Objective: Considering the impact of leishmaniasis worldwide, this work aimed to design, synthesize, and perform a screening upon L. chagasi amastigotes and for the cytotoxicity of the small "in-house" library of both AGH and TSC derivatives and their structurally-related compounds. Method: A set of AGH's (3-7), TSC's (9, 10), and semicarbazones (11) were initially synthesized. Subsequently, different semi-constrained analogs were designed and also prepared, including thiazolidines (12), dihydrothiazines (13), imidazolines (15), pyrimidines (16, 18) azines (19, 20), and benzotriazepinones (23-25). All intermediates and target compounds were obtained with satisfactory yields and exhibited spectral data consistent with their structures. All final compounds were evaluated against L. chagasi amastigotes and J774.A1 cell line. Molecular docking was performed towards trypanothione reductase using GOLD® software. Result: The AGH's 3i, 4a, and 5d, and the TSC's 9i, 9k, and 9o were selected as valuable hits. These compounds presented antileishmanial activity compared with pentamidine, showing IC50 values ranged from 0.6 to 7.27 μM, maximal effects up to 55.3%, and satisfactory SI values (ranged from 11 to 87). On the other hand, most of the resulting semi-constrained analogs were found cytotoxic or presented reduced antileishmanial activity. In general, TSC class is more promising than its isosteric AGH analogs, and the beneficial aromatic substituent effects are not similar in both series. In silico studies have suggested that these hits are capable of inhibiting the trypanothione reductase from the amastigote forms. Conclusion: The promising antileishmanial activity of three AGH’s and three TSC’s was characterized. These compounds presented antileishmanial activity compared with PTD, showing IC50 values ranged from 0.6 to 7.27 μM, and satisfactory SI values. Further pharmacological assays involving other Leishmania strains are under progress, which will help to choose the best hits for in vivo experiments.

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

Background: Viral diseases are responsible for several deaths around the world. Over the past few years, the world has seen several outbreaks caused by viral diseases that, for a long time, seemed to possess no risk. These are diseases that have been forgotten for a long time and, until nowadays, there are no approved drugs or vaccines, leading the pharmaceutical industry and several research groups to run out of time in the search for new pharmacological treatments or prevention methods. In this context, drug repurposing proves to be a fast and economically viable technique, considering the fact that it uses drugs that have a well-established safety profile. Thus, in this review, we present the main advances in drug repurposing and their benefit for searching new treatments against emerging viral diseases. Methods: We conducted a search in the bibliographic databases (Science Direct, Bentham Science, PubMed, Springer, ACS Publisher, Wiley, and NIH’s COVID-19 Portfolio) using the keywords "drug repurposing", "emerging viral infections" and each of the diseases reported here (CoV; ZIKV; DENV; CHIKV; EBOV and MARV) as an inclusion/exclusion criterion. A subjective analysis was performed regarding the quality of the works for inclusion in this manuscript. Thus, the selected works were those that presented drugs repositioned against the emerging viral diseases presented here by means of computational, high-throughput screening or phenotype-based strategies, with no time limit and of relevant scientific value. Results: 291 papers were selected, 24 of which were CHIKV; 52 for ZIKV; 43 for DENV; 35 for EBOV; 10 for MARV; and 56 for CoV and the rest (72 papers) related to the drugs repurposing and emerging viral diseases. Among CoV-related articles, most were published in 2020 (31 papers), updating the current topic. Besides, between the years 2003 - 2005, 10 articles were created, and from 2011 – 2015, there were 7 articles, portraying the outbreaks that occurred at that time. For ZIKV, similar to CoV, most publications were during the period of outbreaks between the years 2016 - 2017 (23 articles). Similarly, most CHIKV (13 papers) and DENV (14 papers) publications occur at the same time interval. For EBOV (13 papers) and MARV (4 papers), they were between the years 2015 - 2016. Through this review, several drugs were highlighted that can be evolved in vivo and clinical trials as possible used against these pathogens showed that remdesivir represent potential treatments against CoV. Furthermore, ribavirin may also be a potential treatment against CHIKV; sofosbuvir against ZIKV; celgosivir against DENV, and favipiravir against EBOV and MARV, representing new hopes against these pathogens. Conclusions: The conclusions of this review manuscript show the potential of the drug repurposing strategy in the discovery of new pharmaceutical products, as from this approach, drugs could be used against emerging viral diseases. Thus, this strategy deserves more attention among research groups and is a promising approach to the discovery of new drugs against emerging viral diseases and also other diseases.

Objetivo: Compilar dados da literatura científica acerca dos principais compostos indólicos com potencial anticâncer desenvolvidos nos últimos anos. Métodos: Foram utilizados os seguintes bancos de dados: PubMed (US National Library of Medicine National Institute of Health), Science Direct, SciFinder e Bentham Science, no período de 2007 de 2020 com os descritores indole AND anticâncer. Os estudos elegíveis retratavam da temática da pesquisa, publicados em inglês com texto completo disponível. Resultados: Foi mostrado que os indóis são compostos que apresentam potente atividade contra diversas linhagens de tumor (MDA-MB-231; HL-60; CCRF-CEM; K-562, MOLT-4; RPMI-8226, dentre outras) inibindo diferentes mecanismos responsáveis pela manutenção ou propagação da neoplasia (inibição da polimerização dos microtúbulos; enzima topoisomerase I; e intercalação com DNA das células tumorais) apresentando variadas estruturas químicas: desde indóis substituídos com estruturas simplificadas, até híbridos moleculares. Adicionalmente, os resultados de concentração inibitória 50 (IC50) mostraram compostos com inibição na escala nanomolar e índice de seletividade significativo, representando uma classe promissora. Considerações finais: O estudo fez um levantamento dos principais hits indólicos, passíveis de gerar novos compostos leads para a descoberta de fármacos com o objetivo de avançar nas pesquisas para produção de novos agentes antineoplásicos, com maior eficácia e menor incidência de efeitos colaterais.