Computer-Aided Drug Design Using Sesquiterpene Lactones as Sources of New Structures with Potential Activity against Infectious Neglected Diseases

This review presents an survey to the biological importance of sesquiterpene lactones (SLs) in the fight against four infectious neglected tropical diseases (NTDs)—leishmaniasis, schistosomiasis, Chagas disease, and sleeping sickness—as alternatives to the current chemotherapies that display several problems such as low effectiveness, resistance, and high toxicity. Several studies have demonstrated the great potential of some SLs as therapeutic agents for these NTDs and the relationship between the protozoal activities with their chemical structure. Recently, Computer-Aided Drug Design (CADD) studies have helped increase the knowledge of SLs regarding their mechanisms, the discovery of new lead molecules, the identification of pharmacophore groups and increase the biological activity by employing in silico tools such as molecular docking, virtual screening and Quantitative-Structure Activity Relationship (QSAR) studies

Identification of Kaurane-Type Diterpenes as Inhibitors of Leishmania Pteridine Reductase I

The current treatments against Leishmania parasites present high toxicity and multiple side effects, which makes the control and elimination of leishmaniasis challenging. Natural products constitute an interesting and diverse chemical space for the identification of new antileishmanial drugs. To identify new drug options, an in-house database of 360 kauranes (tetracyclic diterpenes) was generated, and a combined ligand- and structure-based virtual screening (VS) approach was performed to select potential inhibitors of Leishmania major (Lm) pteridine reductase I (PTR1). The best-ranked kauranes were employed to verify the validity of the VS approach through LmPTR1 enzyme inhibition assay. The half-maximal inhibitory concentration (IC50) values of selected bioactive compounds were examined using the random forest (RF) model (i.e., 2β-hydroxy-menth-6-en-5β-yl ent-kaurenoate (135) and 3α-cinnamoyloxy-ent-kaur-16-en-19-oic acid (302)) were below 10 μM. A compound similar to 302, 3α-p-coumaroyloxy-ent-kaur-16-en-19-oic acid (302a), was also synthesized and showed the highest activity against LmPTR1. Finally, molecular docking calculations and molecular dynamics simulations were performed for the VS-selected, most-active kauranes within the active sites of PTR1 hybrid models, generated from three Leishmania species that are known to cause cutaneous leishmaniasis in the new world (i.e., L. braziliensis, L. panamensis, and L. amazonensis) to explore the targeting potential of these kauranes to other species-dependent variants of this enzyme

Estudos quimiotaxonômicos e triagem virtual de sesquiterpenos lactonizados isolados da família asteraceae com potencial atividade leishmanicida e tripanocida

Leishmaniasis and American trypanosomiasis are the neglected diseases that affect a large percentage of the Brazil and Colombia population. Some of the difficulties for the control and elimination of these diseases are the limitation and inefficacy of the current treatments mainly in the chronic phases. Natural products are potential sources of new and selective agents for the treatment of tropical diseases caused by protozoa and other parasites. Asteraceae family has allowed the isolation of a great variety of substances that exhibit diverses biological activities, among them, sesquiterpenes lactones, which have not been studied yet deepth, but present a great potential of antiprotozoal activity. Computational methods have emerged, as an important tool in the field of medicinal chemistry, improving the effectiveness of processes to develop of new treatments, reducing costs and resources. Therefore, this study aims use, create and combine several methodologies of virtual screening of a natural products database through molecular docking, and machine learning algorithms using molecular descriptors, in order to find sesquiterpenes lactones with potential trypanocidal and leishmanicidal activity. In Chapter 2, is presented a review of the biological importance of sesquiterpenes lactones in the fight against neglected diseases including some investigations performed with in silico tools in the search of new molecules with leishmanicidal and antichagasic activity. Chapter 3 presents a modern and innovative web tool for database managing of secondary metabolites, called SISTEMATX, which was developed in the cheminformatics laboratory of the Federal University of Paraíba. The last two chapters, present computational studies aimed at finding structures with potential antichagasic and leishmanicidal multitarget activity, using an in-house databank (SISTEMATX) consisting of 1,306 sesquiterpenes lactones. Random forest classificatory models built for each one of the parasitic forms of T. cruzi and L. donovani reached a predictive power above of 75,4% of accuracy. By ligand-based virtual screening, the number of structures classified as active were: 34, 17 and 420 for amastigotes, trypomastigotes and epimastigotes of T. cruzi, as well as, 741 and 11 for amastigotes and promastigotes of L. donovani. Likewise, structure-based virtual screening was performed by molecular docking of the same set of molecules using eight target enzymes of T. cruzi and four proteins of L. donovani, including a homology model of Pteridine reductase 1 (LdPTR1). Finally, by means of a consensus analysis of the two techniques, it was sought to normalize the probability values, to verify potentially active compounds against these two neglected diseases and to establish their possible mechanism of action.Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPqA leishmaniose e a tripanossomíase americana são as doenças negligenciadas que afetam em maior percentagem à população do Brasil e da Colômbia. Algumas das principais dificuldades para o controle e eliminação destas doenças são a limitação e ineficácia dos atuais tratamentos usados, principalmente nas fases crónicas. Os produtos naturais são potenciais fontes de novos e seletivos agentes para o tratamento de doenças tropicais causados por protozoários e outros parasitos. A família Asteraceae tem permitido o isolamento de uma grande variedade de substâncias que exibem diversas atividades biológicas entre estes, sesquiterpenos lactonizados que ainda não têm sido estudados com profundidade, mas apresentam um grande potencial de atividade antiprotozoária. Os métodos computacionais, têm emergido, como uma importante ferramenta na área da química medicinal, melhorando a eficiência de múltiplos processos para o desenvolvimento de novos tratamentos, reduzindo custos e recursos. Portanto, este estudo tem como objetivo, utilizar, criar e combinar diversas metodologias de triagem virtual de banco de dados de produtos naturais através de docking molecular e aprendizado de máquina utilizando descritores moleculares para propor sesquiterpenos lactonizados com potencial atividade leishmanicida e tripanocida multialvo. No capítulo 2, apresenta-se uma revisão da importância biológica dos sesquiterpenos lactonizados na luta contra as doenças negligenciadas incluindo algumas investigações desenvolvidas com ferramentas in silico na busca de novas moléculas com atividade leishmanicida e antichagásica. O capitulo 3, apresenta uma moderna e inovadora ferramenta web para o gerenciamento do banco de dados de metabolitos secundários, chamada SISTEMATX a qual foi desenvolvida no laboratório de quimioinformática da Universidade federal da Paraíba. Os últimos dois capítulos, mostram estudos computacionais dirigidos a busca de estruturas com potencial atividade antichagásica e leishmanicida multialvo, usando um banco de dados próprio (SISTEMATX) constituído por 1,306 SLs. Os modelos classificatórios Random forest construídos para cada uma das formas parasitarias de T. cruzi e L. donovani alcançaram um poder preditivo acima de 75,4% de acurácia. Mediante a triagem virtual baseada na estrutura do ligante, o número de estruturas classificadas como ativas foram: 34, 17 e 420 para amastigotas, tripomastigotas e epimastigotas de T. cruzi, assim como, 741 e 11 para amastigotas e promastigotas de L. donovani. Estudos de triagem virtual baseado na estrutura do receptor foram realizados mediante docking molecular do mesmo banco de moléculas usando 8 enzimas alvos do T. cruzi e 4 proteínas de L. donovani, incluindo um modelo de homologia de Redutase de pteridina 1 (LdPTR1). Finalmente, mediante uma análise de consenso das duas técnicas, buscou-se normalizar os valores de probabilidades, para verificar compostos potencialmente ativos contra estas duas doenças negligenciadas e estabelecer o possível mecanismo de ação destes

Computer-Aided Drug Design Using Sesquiterpene Lactones as Sources of New Structures with Potential Activity against Infectious Neglected Diseases

This review presents an survey to the biological importance of sesquiterpene lactones (SLs) in the fight against four infectious neglected tropical diseases (NTDs)—leishmaniasis, schistosomiasis, Chagas disease, and sleeping sickness—as alternatives to the current chemotherapies that display several problems such as low effectiveness, resistance, and high toxicity. Several studies have demonstrated the great potential of some SLs as therapeutic agents for these NTDs and the relationship between the protozoal activities with their chemical structure. Recently, Computer-Aided Drug Design (CADD) studies have helped increase the knowledge of SLs regarding their mechanisms, the discovery of new lead molecules, the identification of pharmacophore groups and increase the biological activity by employing in silico tools such as molecular docking, virtual screening and Quantitative-Structure Activity Relationship (QSAR) studies

Kaurane-Type Diterpenoids as Potential Inhibitors of Dihydrofolate Reductase-Thymidylate Synthase in New World <i>Leishmania</i> Species

The bifunctional enzyme Dihydrofolate reductase-thymidylate synthase (DHFR-TS) plays a crucial role in the survival of the Leishmania parasite, as folates are essential cofactors for purine and pyrimidine nucleotide biosynthesis. However, DHFR inhibitors are largely ineffective in controlling trypanosomatid infections, largely due to the presence of Pteridine reductase 1 (PTR1). Therefore, the search for structures with dual inhibitory activity against PTR1/DHFR-TS is crucial in the development of new anti-Leishmania chemotherapies. In this research, using the Leishmania major DHFR-TS recombinant protein, enzymatic inhibitory assays were performed on four kauranes and two derivatives that had been previously tested against LmPTR1. The structure 302 (6.3 µM) and its derivative 302a (4.5 µM) showed the lowest IC50 values among the evaluated molecules. To evaluate the mechanism of action of these structures, molecular docking calculations and molecular dynamics simulations were performed using a DHFR-TS hybrid model. Results showed that hydrogen bond interactions are critical for the inhibitory activity against LmDHFR-TS, as well as the presence of the p-hydroxyl group of the phenylpropanoid moiety of 302a. Finally, additional computational studies were performed on DHFR-TS structures from Leishmania species that cause cutaneous and mucocutaneous leishmaniasis in the New World (L. braziliensis, L. panamensis, and L. amazonensis) to explore the targeting potential of these kauranes in these species. It was demonstrated that structures 302 and 302a are multi-Leishmania species compounds with dual DHFR-TS/PTR1 inhibitory activity

A new synthetic peptide having two target of antibacterial action in E. coli ML35

The increased resistance of microorganisms to the different antimicrobials available to today has highlighted the need to find new therapeutic agents, including natural and/or synthetic antimicrobial peptides. This study has evaluated the antimicrobial activity of synthetic peptide 35409 (RYRRKKKMKKALQYIKLLKE) against S. aureus ATCC 29213, P. aeruginosa ATCC 15442 and E. coli ML 35 (ATCC 43827). The results have shown that peptide 35409 inhibited the growth of these three bacterial strains, having 16 fold greater activity against E. coli and P. aeruginosa, but requiring less concentration regarding E. coli (22 µM). When analyzing this activity against E. coli compared to time taken, it was found that this peptide inhibited bacterial growth during the first 60 min and reduced CFU/mL 1 log after 120 min had elapsed. This antimicrobial peptide permeabilized the E. coli membrane by interaction with membrane phospholipids, mainly phosphatidylethanolamine, inhibited cell division and induced filamentation, suggesting two different targets of action within a bacterial cell. Cytotoxicity studies revealed that peptide 35409 had low hemolytic activity and was not cytotoxic for two human cell lines. We would thus propose, in the light of these findings, that the peptide 35409 sequence should provide a promising template for designing broad-spectrum antimicrobial peptides

SistematX, an Online Web-Based Cheminformatics Tool for Data Management of Secondary Metabolites

The traditional work of a natural products researcher consists in large part of time-consuming experimental work, collecting biota to prepare and analyze extracts and to identify innovative metabolites. However, along this long scientific path, much information is lost or restricted to a specific niche. The large amounts of data already produced and the science of metabolomics reveal new questions: Are these compounds known or new? How fast can this information be obtained? To answer these and other relevant questions, an appropriate procedure to correctly store information on the data retrieved from the discovered metabolites is necessary. The SistematX (http://sistematx.ufpb.br) interface is implemented considering the following aspects: (a) the ability to search by structure, SMILES (Simplified Molecular-Input Line-Entry System) code, compound name and species; (b) the ability to save chemical structures found by searching; (c) compound data results include important characteristics for natural products chemistry; and (d) the user can find specific information for taxonomic rank (from family to species) of the plant from which the compound was isolated, the searched-for molecule, and the bibliographic reference and Global Positioning System (GPS) coordinates. The SistematX homepage allows the user to log into the data management area using a login name and password and gain access to administration pages. In this article, we introduced a modern and innovative web interface for the management of a secondary metabolite database. With its multiplatform design, it is able to be properly consulted via the internet and managed from any accredited computer. The interface provided by SistematX contains a wealth of useful information for the scientific community about natural products, highlighting the locations of species from which compounds are isolated

Selene-Ethylenelacticamides and <i>N</i>-Aryl-Propanamides as Broad-Spectrum Leishmanicidal Agents

The World Health Organization classifies Leishmania as one of the 17 “neglected diseases” that burden tropical and sub-tropical climate regions with over half a million diagnosed cases each year. Despite this, currently available anti-leishmania drugs have high toxicity and the potential to be made obsolete by parasite drug resistance. We chose to analyze organoselenides for leishmanicidal potential given the reduced toxicity inherent to selenium and the displayed biological activity of organoselenides against Leishmania. Thus, the biological activities of 77 selenoesters and their N-aryl-propanamide derivatives were predicted using robust in silico models of Leishmania infantum, Leishmania amazonensis, Leishmania major, and Leishmania (Viannia) braziliensis. The models identified 28 compounds with >60% probability of demonstrating leishmanicidal activity against L. infantum, and likewise, 26 for L. amazonesis, 25 for L. braziliensis, and 23 for L. major. The in silico prediction of ADMET properties suggests high rates of oral absorption and good bioavailability for these compounds. In the in silico toxicity evaluation, only seven compounds showed signs of toxicity in up to one or two parameters. The methodology was corroborated with the ensuing experimental validation, which evaluated the inhibition of the Promastigote form of the Leishmania species under study. The activity of the molecules was determined by the IC50 value (µM); IC50 values 50 values Leishmania species under study, with compound NC34 presenting the strongest parasite inhibition profile. Furthermore, the methodology used was effective, as many of the compounds with the highest probability of activity were confirmed by the in vitro tests performed