Drug discovery and computational strategies in the multitarget drugs era

The pharmaceutical industry is increasingly joining chemoinformatics in the search for the development of new drugs to be used in the treatment of diseases. These computational studies have the advantage of being less expensive and optimize the study time, and thus the interest in this area is increasing. Among the techniques used is the development of multitarget directed ligands (MTDLs), which has become an ascending technique, mainly due to the improvement in the quality of treatment involving several drugs. Multitarget therapy is more effective than traditional drug therapy that emphasizes maximum selectivity for a single target. In this review a multitarget drug survey was carried out as a promising strategy in several important diseases: neglected diseases, neurodegenerative diseases, AIDS, and cancer. In addition, we discuss Computer-Aided Drug Design (CADD) techniques as a tool in the projection of multitarget compounds against these diseases

13C NMR spectral data and molecular descriptors to predict the antioxidant activity of flavonoids

Tissue damage due to oxidative stress is directly linked to development of many, if not all, human morbidity factors and chronic diseases. In this context, the search for dietary natural occurring molecules with antioxidant activity, such as flavonoids, has become essential. In this study, we investigated a set of 41 flavonoids (23 flavones and 18 flavonols) analyzing their structures and biological antioxidant activity. The experimental data were submitted to a QSAR (quantitative structure-activity relationships) study. NMR 13C data were used to perform a Kohonen self-organizing map study, analyzing the weight that each carbon has in the activity. Additionally, we performed MLR (multilinear regression) using GA (genetic algorithms) and molecular descriptors to analyze the role that specific carbons and substitutions play in the activity.Danos aos tecidos devido ao estresse oxidativo estão diretamente ligados ao desenvolvimento de muitos, senão todos, os fatores de sedentarismo e de doenças crônicas. Neste contexto, a busca de moléculas naturais, que participam da nossa dieta e que possuam atividade antioxidante, flavonóides, torna-se de grande interesse. Neste estudo, nós investigamos um conjunto de 41 flavonóides (23 flavonas e 18 flavonóis), relacionando suas estruturas e atividade antioxidante. Os dados experimentais foram submetidos à análise de QSAR (relações quantitativas estrutura-atividade). Dados de RMN 13C foram utilizados para realizar um estudo do mapa auto-organizável de Kohonen, analisando o peso que cada carbono tem na atividade. Além disso, realizamos uma MLR (regressão múltipla) usando GA (algoritmos genéticos) e descritores moleculares para avaliar a influência de carbonos e substituições na atividade

Sesquiterpene Lactones with Anti-Hepatitis C Virus Activity Using Molecular Descriptors

Hepatitis C is a worldwide public health problem. The available therapies are limited by their partial effectiveness and with meaningful side-effects. Sesquiterpene lactones (SLs) are a group of natural products with a wide variety of chemical structures and biological activities associated. There are few studies about the influence of the molecular structure of SLs for the anti-hepatitis C virus activity. In the present work, SLs are investigated in a subgenomic RNA replicon assay system and were analyzed using multiple linear regression along with self-organizing maps with DRAGON descriptors in order to identify the structural requirements for their biological activity and to predict the inhibitory potency of SLs. Characteristics such as stereochemistry and electronic effects demonstrated to be important for their anti-HCV activity, and the SOM produced a clear separation betwenn active and inactive compounds. Therefore, it is possible to use this map as a filter for virtual screening to predict the anti-HCV activity of SLs.Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq

Modelagem molecular aplicada ao desenvolvimento de moléculas com atividade antioxidante visando ao uso cosmético

Some hypotheses and constants studies are made with intention to elucidate the aging process. To prevent and to attenuate the cutaneous aging it becomes necessary to strengthen our endogenous antioxidant natural defenses. Diverse exogenous antioxidant substances, as vitamins, vegetal extracts and others, have been used by the Cosmetology in antiaging products. The objective of this paper is to show how the Molecular Modeling can be an useful tool in the research for new antioxidant cosmetic substances to face the cutaneous aging.Várias hipóteses e constantes estudos são realizados com o intuito de elucidar o envelhecimento cutâneo. Para prevenir e contornar este processo torna-se necessário reforçar nossas defesas naturais antioxidantes endógenas. Diversas substâncias antioxidantes exógenas, como vitaminas, extratos vegetais, dentre outras, são utilizadas pela Cosmetologia nos produtos antienvelhecimento. O objetivo deste artigo é apresentar de que forma a Modelagem Molecular pode ser uma ferramenta útil na pesquisa por novas substâncias cosméticas antioxidantes para combater o envelhecimento cutâneo

Anxiolytic Effect of Citrus aurantium

The objective of this study was to investigate the anxiolytic effects of the essential oil (EO) of Citrus aurantium L. in patients experiencing crack withdrawal. This was developed with internal users in therapeutic communities in Paraíba, Brazil. The test population consisted of 51 volunteers, subdivided into three groups. To elicit anxiety, the Simulated Public Speaking (SPS) method was used. Physiological measures were assessed at specific phases during the experiment using appropriate equipment. Psychological measures of anxiety were assessed using the Trait-State Anxiety Inventory (IDATE) and the Analog Smoke Scale (HAS). EO was administered by nebulization. The experiment was developed in individual sessions and consolidated to four phases. The results demonstrated that the test subjects in the groups that were given the EO maintained controlled anxiety levels during SPS, when compared to the Control Group (no treatment). Subjects who used the EO also maintained levels of “discomfort” and “cognitive impairment” during SPS. It was concluded that individuals who are experiencing internal crack cocaine withdrawal present high anxiety traits and that nebulization of the EO of Citrus aurantium L. provided an acute anxiolytic effect in crack cocaine users exposed to SPS

Anxiolytic and antinociceptive-like effects of cinnamic alcohol by possible GABAergic pathway modulation: In vivo and in silico studies / Efeitos ansiolítico e antinociceptivo do álcool cinâmico por possível modulação da via GABAérgica: Estudos in vivo e in sílico

Introduction: Cinnamic alcohol (CA) is a phenylpropanoid found in the bark of Cinnamomum verum J.Presl (cinnamon) an ancient spice. Our main objective was to evaluate the central effects of CA in anxiety and pain models using in vivo and in silico studies. Methods: initially, Swiss male mice (Mus musculus) were treated intraperitoneally with CA at 6.25, 12.5 and 25 mg/kg, and underwent rota rod, elevated plus-maze, and formalin induced nociception tests. Results: in the rota rod test, there was no change in the performance of the animals treated with CA (6.25, 12.5, 25 mg/kg), not indicating a myo-relaxant or sedative effect. In the elevated plus-maze test, CA (6.25, 12.5, 25 mg/kg), an increased the number of entries and the length of stay of the animals in the open arms was observed. In the formalin test, the CA-treated animals (6.25, 12.5, 25 mg/kg) presented reduced paw licking behavior in the first and second phase of the test. Finally, the in silico studies (docking and molecular dynamics) indicated a positive interaction between CA and the GABAA receptor. Limitations: This is a non-clinical study, so all data are preliminary. Conclusions: thus, the results suggest that CA has anxiolytic and antinociceptive-like effects in mice, probably due to GABAergic system modulation.

SYNTHESIS, IN SILICO CHARACTERIZATION AND EX VIVO EVALUATION OF THE NOVEL ORGANIC NITRATE NDIBP AS A POTENTIAL VASORELAXANT AGENT

Objective: This study aimed to describe the synthesis and biological/pharmacokinetic potential of the 1,3-diisobutoxypropan-2-yl nitrate (NDIBP) using in silico and ex vivo approaches. Methods: The compound was characterized by Fourier-transform infrared spectroscopy and 1H and 13C- nuclear magnetic resonance spectra. NDIBP biological activity spectrum was obtained by Prediction of Activity Spectra for Substances (PASS). The pharmacological effect was validated in ex vivo studies using mesenteric artery. Drug-like properties and Absorption Distribution Metabolism Excretion and Toxicity (ADMET) studies were carried out by pkCSM (Predicting Small-Molecule Pharmacokinetic Properties Using Graph-Based Signatures) software. Results: PASS prediction indicated NDIBP as nitric oxide (NO) donor with vasodilator effect. Ex vivo studies validated PASS analysis and showed the NDIBP vasorelaxant activity in mesenteric arteries. Physicochemical parameters and ADMET prediction suggested that NDIBP is a drug-like molecule with a good theoretical oral bioavailability, good absorption in the gastrointestinal tract, and a low distribution in the tissues. Conclusion: All the data indicated that NDIBP possesses biological activities and drug-like properties to be considered as a vasorelaxant agent and a good candidate for further investigation in the treatment of arterial hypertension and drug development studies

Cytotoxic and Schistosomidal Activities of Extract, Fractions and Isolated Compounds from Zanthoxylum Leprieurii (Rutaceae)

Schistosomiasis is a major and chronic neglected tropical disease. The existing treatment does not kill immature schistosomes and have serious adverse side effect.  It is well known that some parasites are responsible for causing specific cancers in humans including bladder cancer from Schistosoma haematobium infection. So, novel drugs discovery is an urgent need. In this study, were evaluated in vitro the cytotoxic on human hepatocarcinoma (HepG2) and normal cells (Chang liver), and the schistosomicidal properties of crude extract, fractions and isolated compounds (1-Hydroxy-3-methoxy-N-methylacridone (1) described in this species from Cameroon for the first time, Scoparone (2), and Arborinine (3)) from powdered fruits of Zanthoxylum leprieurii (Rutaceae). All fractions: hexanic (FH), methylene chloride (FC), ethyl acetate (FA) and methanolic (FM) killed all the cercariae within 2 hours exposure and presents LC50 values between 2 and 3 μg/ml; Compounds 1 and 3 also displayed a good in vitro schistosomicidal activity against cercariae with LC50 values of 78.78 and 6.98 μg/mL, respectively. For antitumor activity compounds 1-3 and fraction FC presents good activity with IC50 values range 18.27 - 74.61 μg/mL on HepG2 cells, however most of these were more toxic on Chang cells than to HepG2 cells, with only exception for compound 2. The acridone Arborinine (3) can constitute a good lead for the research of schistosomiasis alternative therapy, and the coumarin Scoparone (2) can be used in drug design as scaffold for design new potential anticancer agents

Study of physiochemical properties and criteria for obtaining and validation of QSAR models of similar semicarbazonas set with antichagasic activity, selected of literature

O desenvolvimento tecnológico observado nos últimos anos e o avanço na aquisição de dados para os sistemas tanto químicos como biológicos tem gerado um grande número de informações. Como consequência, nos últimos anos, procuram-se ferramentas, fundamentalmente matemáticas, que permitam decodificar este volume imenso de informações, em termos estruturais e biológicos. Embora diversos parâmetros estatísticos e métodos de seleção de modelos e de variáveis tenham sido descritos, mais recentemente, são encontradas propostas de novas ferramentas visando assegurar tanto a qualidade de predição do modelo como a elucidação de algum mecanismo a partir do modelo gerado. Com relação aos estudos de compostos antichagásicos, é grande o número de dados disponíveis, na literatura, nos diferentes aspectos pesquisados.A cruzipaína, também chamada de cruzaína, é a principal cisteína protease do Trypanosoma cruzi e sua inibição tem se mostrado capaz de inibir o desenvolvimento intracelular do protozoário. Neste trabalho foram selecionados da literatura original 90 compostos, incluindo-se 29 alfa-(N)-heterocíclica carboxaldeído tiossemicarbazonas substituídas, com atividade inibitória frente a ribonucleotídeo redutase (IRNR) (série I; compostos I.1. a I.29); 37 tiossemicarbazonas substituídas na cadeia lateral e no anel aromático (série II; compostos II.1 a II.37) e, 61 compostos estruturalmente diferentes (série III; compostos II.1 a III.61, sendo 45 tiossemicarbazonas das quais 37 da série II e, 16 derivados de isatinas). As séries II e III apresentam atividade inibitória frente à cruzaína, uma cisteína protease do T.cruzi. E a série I, embora, apresente atividade inibitória frente a ribonucleotídeo redutase (IRNR) de células H.Ep.-2, é, no entanto, estruturalmente similar às séries II e III. E, ainda mais, os modelos gerados nesta dissertação para a série I foram incluídos na tese de doutorado de H.Ishiki. Cada uma das séries foi dividida em 3 séries de treinamento (A, B e C) com suas correspondentes séries de teste. A seguir, a partir das estruturas representadas em 3 dimensões das moléculas, foram gerados 1497 descritores através do programa DRAGON (v. 3.0) para cada série (I, II e III). Estes descritores foram submetidos a um pré-tratamento de dados, excluindo-se aqueles que não contribuiriam para as análises PLS - Partial Least Squares (mínimos quadrados parciais). Através das análises PLS foram selecionados os descritores mais significativos das equações de regressão linear, que a seguir foram submetidos a uma análise de freqüência, ou seja, foram selecionados os descritores presentes em pelo menos em 2 dos 3 modelos obtidos das séries de treinamento (A, B e C). A partir destes descritores selecionados foram obtidos modelos de QSAR clássico com 5 descritores que foram validados por três filtros. Estes modelos de QSAR validados, apresentaram valores de coeficiente de correlação (r) e do quadrado do coeficiente de predição interna (Qcv2) maiores que 0,9 e 0,7 respectivamente.It has been observed an enormous improvement in the methods concerning data generation, leading to a large amount of information, especially for chemical and biological systems. Through these developments, it becomes relevant to have reliable methods, mainly new mathematical tools, for structure-activity relationship (SAR) data examination, which means that there is a need for developing datasets screening tools. Although a huge number of descriptors and methods for selection have been described in the literature, it becomes a crucial aspect to develop new concepts and tools that assure selection of relevant information as well as a high predictive power for the generated QSAR models. Concerning antichagasic compounds, in the literature, there is a huge number of data in anti Chagas disease drug research fields. Cruzain, known also as cruzipain, is the major cysteine protease of T. cruzi. The protease is expressed in all life cycle stages of the parasite. Therefore, cruzain is essential for replication of the intracellular parasite. Thus, cruzain is an appealing target for new antitrypanosomal chemotherapy. In this work, it has been taken from selected literature 90 compounds, including 29 substituted alpha-(N)- heterocyclic carboxaldehyde thiosemicarbazones, (set I, compounds I.1 to I. 29) and 37 substituted thiosemicarbazones (set II, compounds II.1 to II.37) and 61 structurally different compounds (set III, compounds II.1 to III.61, namely 45 thiosemicarbazones (37 from set II) and 16 isatin derivatives). Sets II and III showed inhibitory activity against cruzain, a cysteine protease of T. cruzi. Although set I compounds showed inhibitory activity against ribonucleotide reductase enzyme of H.Ep.-2 cells they have been included in this study taking into account that they are structurally similar to sets II and III, studied by H. Ishiki in his PhD thesis. Each set was divided in 3 training sets (A, B and C) with its corresponding test sets. Initially, 1497 descriptors have been obtained by means of DRAGON program (v.3.0) using 3D structures of sets I, II and III compounds. In a second step to reduce the data size, all descriptors have been submitted to a pre-treatment, including the use of different filters, followed by PLS analyses with external validation. Relevant descriptors have been selected using PLS followed by frequency analysis. That means, it has been selected descriptors, which were present at least in 2 or 3 models, generated from training sets (A, B an C). These descriptors have been used to generate QSAR models with up to 5 descriptors. The QSAR models had been validated by three filters. Values of correlation coefficient (r) and the squared correlation coefficient of internal predictions (Qcv2) were higher than 0.9 and 0.7, respectively, for the validated QSAR models