Current Approaches to Drug Discovery for Chagas Disease: Methodological Advances

2019 ◽  
Vol 22 (8) ◽  
pp. 509-520
Author(s):  
Cauê B. Scarim ◽  
Chung M. Chin
Keyword(s):  
Drug Discovery ◽  
Chagas Disease ◽  
Drug Candidates ◽  
Lead Compounds ◽  
New Drug ◽  
Compound Libraries ◽  
Screening Assays ◽  
Cruzi Infection

Background: In recent years, there has been an improvement in the in vitro and in vivo methodology for the screening of anti-chagasic compounds. Millions of compounds can now have their activity evaluated (in large compound libraries) by means of high throughput in vitro screening assays. Objective: Current approaches to drug discovery for Chagas disease. Method: This review article examines the contribution of these methodological advances in medicinal chemistry in the last four years, focusing on Trypanosoma cruzi infection, obtained from the PubMed, Web of Science, and Scopus databases. Results: Here, we have shown that the promise is increasing each year for more lead compounds for the development of a new drug against Chagas disease. Conclusion: There is increased optimism among those working with the objective to find new drug candidates for optimal treatments against Chagas disease.

scholarly journals Of Drugs and Trypanosomatids: New Tools and Knowledge to Reduce Bottlenecks in Drug Discovery

Genes ◽  
2020 ◽  
Vol 11 (7) ◽  
pp. 722 ◽  
Author(s):  
Arijit Bhattacharya ◽  
Audrey Corbeil ◽  
Rubens L. do Monte-Neto ◽  
Christopher Fernandez-Prada
Keyword(s):  
Drug Discovery ◽  
Trypanosoma Brucei ◽  
Leishmania Species ◽  
Lead Compounds ◽  
Technological Advances ◽  
Compound Screening ◽  
Trypanosomatid Parasites ◽  
Novel Drug

Leishmaniasis (Leishmania species), sleeping sickness (Trypanosoma brucei), and Chagas disease (Trypanosoma cruzi) are devastating and globally spread diseases caused by trypanosomatid parasites. At present, drugs for treating trypanosomatid diseases are far from ideal due to host toxicity, elevated cost, limited access, and increasing rates of drug resistance. Technological advances in parasitology, chemistry, and genomics have unlocked new possibilities for novel drug concepts and compound screening technologies that were previously inaccessible. In this perspective, we discuss current models used in drug-discovery cascades targeting trypanosomatids (from in vitro to in vivo approaches), their use and limitations in a biological context, as well as different examples of recently discovered lead compounds.

scholarly journals In Silico Identification of New Targets for Diagnosis, Vaccine, and Drug Candidates against Trypanosoma cruzi

2020 ◽  
Vol 2020 ◽  
pp. 1-15
Author(s):  
Rafael Obata Trevisan ◽  
Malú Mateus Santos ◽  
Chamberttan Souza Desidério ◽  
Leandro Gomes Alves ◽  
Thiago de Jesus Sousa ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Drug Targets ◽  
Hot Spot ◽  
Mhc I ◽  
Drug Candidates ◽  
Subtractive Genomics

Chagas disease is a neglected tropical disease caused by the parasite Trypanosoma cruzi. Despite the efforts and distinct methodologies, the search of antigens for diagnosis, vaccine, and drug targets for the disease is still needed. The present study is aimed at identifying possible antigens that could be used for diagnosis, vaccine, and drugs targets against T. cruzi using reverse vaccinology and molecular docking. The genomes of 28 T. cruzi strains available in GenBank (NCBI) were used to obtain the genomic core. Then, subtractive genomics was carried out to identify nonhomologous genes to the host in the core. A total of 2630 conserved proteins in 28 strains of T. cruzi were predicted using OrthoFinder and Diamond software, in which 515 showed no homology to the human host. These proteins were evaluated for their subcellular localization, from which 214 are cytoplasmic and 117 are secreted or present in the plasma membrane. To identify the antigens for diagnosis and vaccine targets, we used the VaxiJen software, and 14 nonhomologous proteins were selected showing high binding efficiency with MHC I and MHC II with potential for in vitro and in vivo tests. When these 14 nonhomologous molecules were compared against other trypanosomatids, it was found that the retrotransposon hot spot (RHS) protein is specific only for T. cruzi parasite suggesting that it could be used for Chagas diagnosis. Such 14 proteins were analyzed using the IEDB software to predict their epitopes in both B and T lymphocytes. Furthermore, molecular docking analysis was performed using the software MHOLline. As a result, we identified 6 possible T. cruzi drug targets that could interact with 4 compounds already known as antiparasitic activities. These 14 protein targets, along with 6 potential drug candidates, can be further validated in future studies, in vivo, regarding Chagas disease.

scholarly journals Marine Power on Cancer: Drugs, Lead Compounds, and Mechanisms

Marine Drugs ◽  
2021 ◽  
Vol 19 (9) ◽  
pp. 488
Author(s):  
Lichuan Wu ◽  
Ke Ye ◽  
Sheng Jiang ◽  
Guangbiao Zhou
Keyword(s):  
Mechanisms Of Action ◽  
Malignant Neoplasms ◽  
Drug Candidates ◽  
Lead Compounds ◽  
Anticancer Effects ◽  
The Earth ◽  
Novel Drugs ◽  
Marine Compounds

Worldwide, 19.3 million new cancer cases and almost 10.0 million cancer deaths occur each year. Recently, much attention has been paid to the ocean, the largest biosphere of the earth that harbors a great many different organisms and natural products, to identify novel drugs and drug candidates to fight against malignant neoplasms. The marine compounds show potent anticancer activity in vitro and in vivo, and relatively few drugs have been approved by the U.S. Food and Drug Administration for the treatment of metastatic malignant lymphoma, breast cancer, or Hodgkin′s disease. This review provides a summary of the anticancer effects and mechanisms of action of selected marine compounds, including cytarabine, eribulin, marizomib, plitidepsin, trabectedin, zalypsis, adcetris, and OKI-179. The future development of anticancer marine drugs requires innovative biochemical biology approaches and introduction of novel therapeutic targets, as well as efficient isolation and synthesis of marine-derived natural compounds and derivatives.

scholarly journals Cryptosporidiosis: A Potential Anti-diarrheal Natural Product Drug Discovery Journey in Ghana, West Africa

2020 ◽  
pp. 85-93
Author(s):  
Senyo K. Botchie ◽  
Andrew G. Mtewa ◽  
Irene Ayi
Keyword(s):  
Developing Countries ◽  
Natural Products ◽  
Drug Discovery ◽  
Drug Development ◽  
Natural Product ◽  
Causative Organism ◽  
Drug Candidates ◽  
Cause Of Deaths

The overwhelming resistance to current drugs and the exhaustion of drug development interventions, as well as synthetic libraries, have compelled researchers to resort to the use of novel drug candidates derived from natural products. Cryptosporidium, the causative organism of Cryptosporidiosis, is no exception. The diarrhea-causing parasite is known to be the leading cause of deaths in children below age 5 in developing countries like Ghana and second to rotavirus as the causative agent for diarrhea in newborn calves and infants. Currently, the only FDA approved drug for the treatment of Cryptosporidiosis is Nitazoxanide. It is, therefore, needful to develop novel alternative candidates as it could aid in the decrease in child mortality and malnutrition in developing countries. Even though there have been significant limitations into anti-cryptosporidial drug development in vitro and in vivo, essential advancements are being made of which this article addresses the need for research into natural products. Some studies outlined in this paper has stated potential plant extracts showing anti-cryptosporidiosis efficacy. With the wealth of medicinal plant products and Cryptosporidium in vitro culture expertise available in our labs at Noguchi Memorial Institute for Medical research we are certain of making potential significant strides in the world of natural product Cryptosporidium drug discovery in Africa.

scholarly journals Big Data and Artificial Intelligence Modeling for Drug Discovery

2020 ◽  
Vol 60 (1) ◽  
pp. 573-589 ◽  
Author(s):  
Hao Zhu
Keyword(s):  
Artificial Intelligence ◽  
Big Data ◽  
Drug Discovery ◽  
Data Sets ◽  
Modeling And Analysis ◽  
The Road ◽  
Drug Candidates ◽  
Modeling Studies

Due to the massive data sets available for drug candidates, modern drug discovery has advanced to the big data era. Central to this shift is the development of artificial intelligence approaches to implementing innovative modeling based on the dynamic, heterogeneous, and large nature of drug data sets. As a result, recently developed artificial intelligence approaches such as deep learning and relevant modeling studies provide new solutions to efficacy and safety evaluations of drug candidates based on big data modeling and analysis. The resulting models provided deep insights into the continuum from chemical structure to in vitro, in vivo, and clinical outcomes. The relevant novel data mining, curation, and management techniques provided critical support to recent modeling studies. In summary, the new advancement of artificial intelligence in the big data era has paved the road to future rational drug development and optimization, which will have a significant impact on drug discovery procedures and, eventually, public health.

Flavonoids as P-gp Inhibitors: A Systematic Review of SARs

2019 ◽  
Vol 26 (25) ◽  
pp. 4799-4831 ◽  
Author(s):  
Jiahua Cui ◽  
Xiaoyang Liu ◽  
Larry M.C. Chow
Keyword(s):  
Molecular Mechanisms ◽  
Metastatic Cancer ◽  
Drug Candidates ◽  
Chemical Structures ◽  
Transporter Family ◽  
Promising Area ◽  
New Generation ◽  
Nontoxic Inhibitors

P-glycoprotein, also known as ABCB1 in the ABC transporter family, confers the simultaneous resistance of metastatic cancer cells towards various anticancer drugs with different targets and diverse chemical structures. The exploration of safe and specific inhibitors of this pump has always been the pursuit of scientists for the past four decades. Naturally occurring flavonoids as benzopyrone derivatives were recognized as a class of nontoxic inhibitors of P-gp. The recent advent of synthetic flavonoid dimer FD18, as a potent P-gp modulator in reversing multidrug resistance both in vitro and in vivo, specifically targeted the pseudodimeric structure of the drug transporter and represented a new generation of inhibitors with high transporter binding affinity and low toxicity. This review concerned the recent updates on the structure-activity relationships of flavonoids as P-gp inhibitors, the molecular mechanisms of their action and their ability to overcome P-gp-mediated MDR in preclinical studies. It had crucial implications on the discovery of new drug candidates that modulated the efflux of ABC transporters and also provided some clues for the future development in this promising area.

The Role of nitro (NO2-), chloro (Cl), and fluoro (F) Substitution in the Design of Antileishmanial and Antichagasic Compounds

2020 ◽  
Vol 21 ◽  
Author(s):  
Boniface Pone ◽  
Ferreira Igne Elizabeth
Keyword(s):  
Chagas Disease ◽  
Mammalian Cells ◽  
Neglected Tropical Diseases ◽  
New Drugs ◽  
Pharmacokinetic Studies ◽  
Scientific Publications ◽  
Antitrypanosomal Activity ◽  
Chemical Groups

: Neglected tropical diseases (NTDs) are responsible for over 500,000 deaths annually and are characterized by multiple disabilities. Leishmaniasis and Chagas disease are among the most severe NTDs, and are caused by the Leishmania sp, and Trypanosoma cruzi, respectively. Glucantime, pentamidine and miltefosine are commonly used to treat leishmaniasis, whereas nifurtimox, benznidazole are current treatments for Chagas disease. However, these treatments are associated with drug resistance, and severe side effects. Hence, the development of synthetic products, especially those containing N02, F, or Cl, which chemical groups are known to improve the biological activity. The present work summarizes the information on the antileishmanial and antitrypanosomal activity of nitro-, chloro-, and fluoro-synthetic derivatives. Scientific publications referring to halogenated derivatives in relation to antileishmanial and antitrypanosomal activities were hand searched in databases such as SciFinder, Wiley, Science Direct, PubMed, ACS, Springer, Scielo, and so on. According to the literature information, more than 90 compounds were predicted as lead molecules with reference to their IC50/EC50 values in in vitro studies. It is worth to mention that only active compounds with known cytotoxic effects against mammalian cells were considered in the present study. The observed activity was attributed to the presence of nitro-, fluoro- and chloro-groups in the compound backbone. All in all, nitro and h0alogenated derivatives are active antileishmanial and antitrypanosomal compounds and can serve as baseline for the development of new drugs against leishmaniasis and Chagas disease. However, efforts on in vitro and in vivo toxicity studies of the active synthetic compounds is still needed. Pharmacokinetic studies, and the mechanism of action of the promising compounds need to be explored. The use of new catalysts and chemical transformation can afford unexplored halogenated compounds with improved antileishmanial and antitrypanosomal activity.

Design and synthesis of mannich base-type derivatives containing imidazole and benzimidazole as lead compounds for drug discovery in Chagas Disease

2021 ◽  
pp. 113646
Author(s):  
Iván Beltran-Hortelano ◽  
Richard L. Atherton ◽  
Mercedes Rubio-Hernández ◽  
Julen Sanz-Serrano ◽  
Verónica Alcolea ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Chagas Disease ◽  
Mannich Base ◽  
Design And Synthesis ◽  
Lead Compounds

scholarly journals Exploration of in vitro thrombolytic, anthelminthic, cytotoxic and in vivo anxiolytic potentials with phytochemical screening of flowers of Brassica nigra

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Mohammad Sarowar Uddin ◽  
Md. Shalahuddin Millat ◽  
Mohammad Safiqul Islam ◽  
Md. Saddam Hussain ◽  
Md. Giash Uddin ◽  
...  
Keyword(s):  
Brassica Nigra ◽  
Anxiolytic Activity ◽  
Clot Lysis ◽  
Dependent Manner ◽  
Standard Drug ◽  
Lead Compounds ◽  
Lysis Activity ◽  
Test Models

Abstract Background Brassica nigra is a plant of Brassicaceae family, which possesses numerous medicinal values. Our present study is intended to assess the potential in vitro thrombolytic, anthelminthic, cytotoxic and in vivo anxiolytic properties of MCE of B. nigra flowers. MCE was fractioned for separating the compound on the basis of polarity by using chloroform, n-hexane and ethyl acetate solvent. Thrombolytic and anthelminthic activities were explained by collecting human erythrocytes and earthworms as test models, respectively. Anxiolytic activity was evaluated by elevated plus maze and hole board models while cytotoxic test was conducted through brine shrimp lethality bioassay. Results MCE revealed the presence of alkaloids, flavonoids, tannin, diterpenes, glycosides, carbohydrates, phenols, fixed oils and fat. In case of thrombolytic test, the MCE, CSF, ASF and n-HSF had produced maximum clot lysis activity at 5 and 10 mg/ml dose conditions. Two different concentrations (10 and 20 mg/ml) of MCE and its fractions showed significant (p < 0.05) anthelminthic activities in a dose-dependent manner. Significant anxiolytic activity was observed for all fractions which was comparable to the standard drug diazepam (p < 0.05). Again, the cytotoxic screening also presented good potentials for all fractions. Conclusion From the findings of present study, we can conclude that MCE of B. nigra flowers and its fraction possess significant anxiolytic, anthelmintic, anticancer and thrombolytic properties which may be a good candidate for treating these diseases through the determination of bio-active lead compounds.

scholarly journals Predicting Absorption-Distribution Properties of Neuroprotective Phosphine-Borane Compounds Using In Silico Modeling and Machine Learning

Molecules ◽  
2021 ◽  
Vol 26 (9) ◽  
pp. 2505
Author(s):  
Raheem Remtulla ◽  
Sanjoy Kumar Das ◽  
Leonard A. Levin
Keyword(s):  
Machine Learning ◽  
Neural Networks ◽  
In Silico ◽  
Disulfide Bonds ◽  
Oral Absorption ◽  
In Vivo Studies ◽  
Drug Candidates ◽  
In Silico Methods

Phosphine-borane complexes are novel chemical entities with preclinical efficacy in neuronal and ophthalmic disease models. In vitro and in vivo studies showed that the metabolites of these compounds are capable of cleaving disulfide bonds implicated in the downstream effects of axonal injury. A difficulty in using standard in silico methods for studying these drugs is that most computational tools are not designed for borane-containing compounds. Using in silico and machine learning methodologies, the absorption-distribution properties of these unique compounds were assessed. Features examined with in silico methods included cellular permeability, octanol-water partition coefficient, blood-brain barrier permeability, oral absorption and serum protein binding. The resultant neural networks demonstrated an appropriate level of accuracy and were comparable to existing in silico methodologies. Specifically, they were able to reliably predict pharmacokinetic features of known boron-containing compounds. These methods predicted that phosphine-borane compounds and their metabolites meet the necessary pharmacokinetic features for orally active drug candidates. This study showed that the combination of standard in silico predictive and machine learning models with neural networks is effective in predicting pharmacokinetic features of novel boron-containing compounds as neuroprotective drugs.

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