scholarly journals Benzimidazole Derivatives as New and Selective Inhibitors of Arginase from Leishmania mexicana with Biological Activity against Promastigotes and Amastigotes

2021 ◽  
Vol 22 (24) ◽  
pp. 13613
Author(s):  
Irene Betancourt-Conde ◽  
Claudia Avitia-Domínguez ◽  
Alicia Hernández-Campos ◽  
Rafael Castillo ◽  
Lilián Yépez-Mulia ◽  
...  
Keyword(s):  
Biological Activity ◽  
In Silico ◽  
Cytotoxic Effect ◽  
New Drugs ◽  
Dynamics Simulation ◽  
Benzimidazole Derivatives ◽  
Leishmania Mexicana ◽  
Arginase 1 ◽  
Excellent Starting Point ◽  
Starting Point

Leishmaniasis is a disease caused by parasites of the Leishmania genus that affects 98 countries worldwide, 2 million of new cases occur each year and more than 350 million people are at risk. The use of the actual treatments is limited due to toxicity concerns and the apparition of resistance strains. Therefore, there is an urgent necessity to find new drugs for the treatment of this disease. In this context, enzymes from the polyamine biosynthesis pathway, such as arginase, have been considered a good target. In the present work, a chemical library of benzimidazole derivatives was studied performing computational, enzyme kinetics, biological activity, and cytotoxic effect characterization, as well as in silico ADME-Tox predictions, to find new inhibitors for arginase from Leishmania mexicana (LmARG). The results show that the two most potent inhibitors (compounds 1 and 2) have an I50 values of 52 μM and 82 μM, respectively. Moreover, assays with human arginase 1 (HsARG) show that both compounds are selective for LmARG. According to molecular dynamics simulation studies these inhibitors interact with important residues for enzyme catalysis. Biological activity assays demonstrate that both compounds have activity against promastigote and amastigote, and low cytotoxic effect in murine macrophages. Finally, in silico prediction of their ADME-Tox properties suggest that these inhibitors support the characteristics to be considered drug candidates. Altogether, the results reported in our study suggest that the benzimidazole derivatives are an excellent starting point for design new drugs against leishmanisis.

scholarly journals Leishmania mexicana Trypanothione Reductase Inhibitors: Computational and Biological Studies

Molecules ◽  
2019 ◽  
Vol 24 (18) ◽  
pp. 3216 ◽  
Author(s):  
Félix Matadamas-Martínez ◽  
Alicia Hernández-Campos ◽  
Alfredo Téllez-Valencia ◽  
Alejandra Vázquez-Raygoza ◽  
Sandra Comparán-Alarcón ◽  
...  
Keyword(s):  
New Drugs ◽  
Dynamics Simulation ◽  
Mammalian Host ◽  
Trypanothione Reductase ◽  
Leishmania Mexicana ◽  
Reductase Inhibitors ◽  
Zinc Database ◽  
Biological Studies ◽  
Starting Point ◽  
Flavoprotein Oxidoreductase

Leishmanicidal drugs have many side effects, and drug resistance to all of them has been documented. Therefore, the development of new drugs and the identification of novel therapeutic targets are urgently needed. Leishmania mexicana trypanothione reductase (LmTR), a NADPH-dependent flavoprotein oxidoreductase important to thiol metabolism, is essential for parasite viability. Its absence in the mammalian host makes this enzyme an attractive target for the development of new anti-Leishmania drugs. Herein, a tridimensional model of LmTR was constructed and the molecular docking of 20 molecules from a ZINC database was performed. Five compounds (ZINC04684558, ZINC09642432, ZINC12151998, ZINC14970552, and ZINC11841871) were selected (docking scores −10.27 kcal/mol to −5.29 kcal/mol and structurally different) and evaluated against recombinant LmTR (rLmTR) and L. mexicana promastigote. Additionally, molecular dynamics simulation of LmTR-selected compound complexes was achieved. The five selected compounds inhibited rLmTR activity in the range of 32.9% to 40.1%. The binding of selected compounds to LmTR involving different hydrogen bonds with distinct residues of the molecule monomers A and B is described. Compound ZINC12151998 (docking score −10.27 kcal/mol) inhibited 32.9% the enzyme activity (100 µM) and showed the highest leishmanicidal activity (IC50 = 58 µM) of all the selected compounds. It was more active than glucantime, and although its half-maximal cytotoxicity concentration (CC50 = 53 µM) was higher than that of the other four compounds, it was less cytotoxic than amphotericin B. Therefore, compound ZINC12151998 provides a promising starting point for a hit-to-lead process in our search for new anti-Leishmania drugs that are more potent and less cytotoxic.

Design of Inhibitors for Glyceraldehyde-3-phosphate Dehydrogenase (GAPDH) Enzyme of Leishmania mexicana

2020 ◽  
Vol 16 (6) ◽  
pp. 784-795
Author(s):  
Krisnna M.A. Alves ◽  
Fábio José Bonfim Cardoso ◽  
Kathia M. Honorio ◽  
Fábio A. de Molfetta
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Binding Site ◽  
Point Of View ◽  
New Drugs ◽  
Leishmania Mexicana ◽  
Receptor Complexes ◽  
Starting Point ◽  
Dynamics Simulations ◽  
Selection Of

Background:: Leishmaniosis is a neglected tropical disease and glyceraldehyde 3- phosphate dehydrogenase (GAPDH) is a key enzyme in the design of new drugs to fight this disease. Objective:: The present study aimed to evaluate potential inhibitors of GAPDH enzyme found in Leishmania mexicana (L. mexicana). Methods: A search for novel antileishmanial molecules was carried out based on similarities from the pharmacophoric point of view related to the binding site of the crystallographic enzyme using the ZINCPharmer server. The molecules selected in this screening were subjected to molecular docking and molecular dynamics simulations. Results:: Consensual analysis of the docking energy values was performed, resulting in the selection of ten compounds. These ligand-receptor complexes were visually inspected in order to analyze the main interactions and subjected to toxicophoric evaluation, culminating in the selection of three compounds, which were subsequently submitted to molecular dynamics simulations. The docking results showed that the selected compounds interacted with GAPDH from L. mexicana, especially by hydrogen bonds with Cys166, Arg249, His194, Thr167, and Thr226. From the results obtained from molecular dynamics, it was observed that one of the loop regions, corresponding to the residues 195-222, can be related to the fitting of the substrate at the binding site, assisting in the positioning and the molecular recognition via residues responsible for the catalytic activity. Conclusion:: he use of molecular modeling techniques enabled the identification of promising compounds as inhibitors of the GAPDH enzyme from L. mexicana, and the results obtained here can serve as a starting point to design new and more effective compounds than those currently available.

scholarly journals Bioprospecting Antiproliferative Marine Microbiota From Submarine Volcano Tagoro

2021 ◽  
Vol 8 ◽  
Author(s):  
Sara García-Davis ◽  
Carolina P. Reyes ◽  
Irene Lagunes ◽  
José M. Padrón ◽  
Eugenio Fraile-Nuez ◽  
...  
Keyword(s):  
Human Life ◽  
Marine Reserve ◽  
Marine Ecosystem ◽  
New Drugs ◽  
Small Scale ◽  
Bacterial Strains ◽  
Submarine Volcano ◽  
Physical Chemical ◽  
Excellent Starting Point ◽  
Starting Point

Marine ecosystems are unique and rich reservoirs of biodiversity with high potential toward improving the quality of human life. The extreme physical–chemical conditions of the oceans have favored marine organisms to produce a great variety of new molecules as a mechanism to ensure their survival, and such compounds possess great biopharmaceutical interest. In particular, marine microbiota represent a promising and inexhaustible source for the development of new drugs. This work presents the taxonomic study of the samples obtained from the underwater volcano Tagoro, which has allowed us to develop a collection of 182 marine bacterial strains. On October 10th, 2011, at La Restinga–El Mar de Las Calmas Marine Reserve, an underwater eruption gave rise to a novel shallow submarine volcano at 1.8 km south of the island of El Hierro, Canary Islands, Spain. During the first 6 months, extreme physical–chemical perturbations, comprising thermal changes, water acidification, deoxygenation, and metal enrichment, resulted in significant alterations of the marine ecosystem. After March 2012, the submarine volcano Tagoro entered an active hydrothermal phase that involved a release of heat, gases, metals, and micronutrients that continues till our present. During 2016, our research team had the opportunity to participate in one of the monitoring oceanographic cruises carried out in the area in order to isolate microorganisms associated with both rock samples and deep-sea invertebrates over Tagoro submarine volcano. In this study, Proteobacteria revealed as the most abundant Phylum with 70.2% among all isolated strains, followed by Firmicutes 19%, Actinobacteria 9.5%, and Bacteroidetes 1.2%. Furthermore, we present the results of the antiproliferative assays of the extracts obtained from small-scale cultures of selected bacterial strains. An analysis of the effects of culture conditions in the antiproliferative activity showed that strains grown in Marine Broth (MB) presented lower GI50 values than those cultured in a modified medium (MM1). This effect is improved when the strains are incubated under agitation conditions. The antiproliferative potential of genera such as Halobacillus, Kangiella, Photobacterium, and Halomonas is revealed. Their biotechnological development provides an excellent starting point to access novel secondary metabolites and enzymes with potential for pharmaceutical and industrial applications.

scholarly journals Focus Your Screening Library: Rapid Identification of Novel PDE2 Inhibitors with in silico Driven Library Prioritization and MicroScale Thermophoresis

2020 ◽  
Author(s):  
Florian Kaiser ◽  
Maximilian G. Plach ◽  
Thomas Schubert ◽  
V. Joachim Haupt
Keyword(s):  
In Silico ◽  
High Throughput Screening ◽  
Rapid Identification ◽  
Chemical Diversity ◽  
Chemical Library ◽  
Binding Behavior ◽  
Microscale Thermophoresis ◽  
Excellent Starting Point ◽  
Starting Point

Accelerated development of lead structures is of high interest to the pharmaceutical industry in order to decrease development times and costs. We showcase how an intelligent combination of AI-based drug screening with state-of-the-art biophysics drives the rapid identification of novel inhibitor structures with high chemical diversity for cGMP-dependent 3’,5’-cyclic phosphodiesterase (PDE2). The starting point was an off-the-shelve chemical library of two million drug-like compounds. In a single in silico reduction step, we short-listed 125 compounds – the focused library – as potential binders to PDE2 and tested their binding behavior in vitro using MicroScale Thermophoresis (MST). Of this focused library, seven compounds indicated binding to PDE2, translating to a hit rate of 6%. Three of these compounds have affinities in the lower micromolar range. The compound with the highest affinity showed a KD of 10 µM and is thus an excellent starting point for further medicinal chemistry optimization. The results show how innovative and structure-driven in silico approaches and biophysics can be used to accelerate drug discovery and to obtain new molecular scaffolds at a fraction of the costs and time – compared with standard high-throughput screening.

scholarly journals Evaluation Of Potential Cytotoxic Effects Of Herbal Extracts

2015 ◽  
Vol 16 (4) ◽  
pp. 333-342 ◽  
Author(s):  
Ana Radovanovic
Keyword(s):  
Cytotoxic Activity ◽  
Cytotoxic Effect ◽  
Chemical Constituents ◽  
Solvent Polarity ◽  
New Drugs ◽  
Herbal Extract ◽  
Signalling Pathways ◽  
Herbal Extracts ◽  
Starting Point ◽  
Influence Of Solvent

Abstract Herbal medicines have played an important role in treating different diseases since ancient times. Bioactive components of medicinal plants are a good starting point for discovering new drugs such as chemotherapeutics. Currently, there are four classes of plant-derived chemotherapeutic drugs used in clinical practice. However, to discover new potential cytotoxic molecules, the research effort on herbal extracts has not diminished. The aim of this review was to evaluate the chemical constituents of plants that possess cytotoxicity, the signalling pathways responsible for this effect, and the influence of solvent polarity on potential cytotoxic effect and to present the cytotoxic activity of selected herbal extracts. The polyphenolic, anthraquinon, diterpneoid, triterpenoid, flavonoid, betulinic acid and berberine content contributes to cytotoxicity of herbal extracts. The inhibitory effect on cancer cells viability could be a consequence of the non-apoptotic processes, such as cell cycle arrestment, and the apoptotic process in tumour cells through different signalling pathways. The influence of solvent polarity on potential cytotoxic effect of herbal extracts should not be ignored. In general, the best cytotoxic activity was found in nonpolar and moderately polar herbal extracts. The herbal extract with IC50 below 30 μg/ml could be considered a very strong cytotoxic agent. Considering that many antitumor drugs have been discovered from natural products, further research on plants and plant-derived chemicals may result in the discovery of potent anticancer agents.

Application of Computational Techniques to Unravel Structure-Function Relationship and their Role in Therapeutic Development

2018 ◽  
Vol 18 (20) ◽  
pp. 1769-1791 ◽  
Author(s):  
Tara Chand Yadav ◽  
Amit Kumar Srivastava ◽  
Arpita Dey ◽  
Naresh Kumar ◽  
Navdeep Raghuwanshi ◽  
...  
Keyword(s):  
Structure Function ◽  
In Silico ◽  
Density Functional ◽  
New Drugs ◽  
Dynamics Simulation ◽  
Computational Techniques ◽  
Drug Designing ◽  
Structure Function Relationship ◽  
Therapeutic Development ◽  
Function Relationship

Application of computational tools and techniques has emerged as an invincible instrument to unravel the structure-function relationship and offered better mechanistic insights in the designing and development of new drugs along with the treatment regime. The use of in silico tools equipped modern chemist with armamentarium of extensive methods to meticulously comprehend the structural tenacity of receptor-ligand interactions and their dynamics. In silico methods offers a striking property of being less resource intensive and economically viable as compared to experimental evaluation. These techniques have proved their mettle in the designing of potential lead compounds to combat life-threatening diseases such as AIDS, cancer, tuberculosis, malaria, etc. In the present scenario, computer-aided drug designing has ascertained an essential and indispensable gizmo in therapeutic development. This review will present a brief outline of computational methods used at different facets of drug designing and its latest advancements. The aim of this review article is to briefly highlight the methodologies and techniques used in structure-based/ ligand-based drug designing viz., molecular docking, pharmacophore modeling, density functional theory, protein-hydration and molecular dynamics simulation which helps in better understanding of macromolecular events and complexities.

scholarly journals Merged Tacrine-Based, Multitarget-Directed Acetylcholinesterase Inhibitors 2015–Present: Synthesis and Biological Activity

2020 ◽  
Vol 21 (17) ◽  
pp. 5965
Author(s):  
Todd J. Eckroat ◽  
Danielle L. Manross ◽  
Seth C. Cowan
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Biological Activity ◽  
Enzyme Inhibitor ◽  
Acetylcholinesterase Inhibitor ◽  
Acetylcholinesterase Inhibitors ◽  
New Drugs ◽  
Acetylcholinesterase Inhibition ◽  
Future Research ◽  
Starting Point

Acetylcholinesterase is an important biochemical enzyme in that it controls acetylcholine-mediated neuronal transmission in the central nervous system, contains a unique structure with two binding sites connected by a gorge region, and it has historically been the main pharmacological target for treatment of Alzheimer’s disease. Given the large projected increase in Alzheimer’s disease cases in the coming decades and its complex, multifactorial nature, new drugs that target multiple aspects of the disease at once are needed. Tacrine, the first acetylcholinesterase inhibitor used clinically but withdrawn due to hepatotoxicity concerns, remains an important starting point in research for the development of multitarget-directed acetylcholinesterase inhibitors. This review highlights tacrine-based, multitarget-directed acetylcholinesterase inhibitors published in the literature since 2015 with a specific focus on merged compounds (i.e., compounds where tacrine and a second pharmacophore show significant overlap in structure). The synthesis of these compounds from readily available starting materials is discussed, along with acetylcholinesterase inhibition data, relative to tacrine, and structure activity relationships. Where applicable, molecular modeling, to elucidate key enzyme-inhibitor interactions, and secondary biological activity is highlighted. Of the numerous compounds identified, there is a subset with promising preliminary screening results, which should inspire further development and future research in this field.

Two isoprenylated flavonoids from Dorstenia psilurus activate AMPK, stimulate glucose uptake, inhibit glucose production and lower glycemia

2019 ◽  
Vol 476 (24) ◽  
pp. 3687-3704 ◽  
Author(s):  
Aphrodite T. Choumessi ◽  
Manuel Johanns ◽  
Claire Beaufay ◽  
Marie-France Herent ◽  
Vincent Stroobant ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Human Cancer ◽  
Glucose Production ◽  
Liver Mitochondria ◽  
New Drugs ◽  
Structural Isomer ◽  
Rat Liver Mitochondria ◽  
Ionization Mass ◽  
Ampk Activation ◽  
Starting Point

Root extracts of a Cameroon medicinal plant, Dorstenia psilurus, were purified by screening for AMP-activated protein kinase (AMPK) activation in incubated mouse embryo fibroblasts (MEFs). Two isoprenylated flavones that activated AMPK were isolated. Compound 1 was identified as artelasticin by high-resolution electrospray ionization mass spectrometry and 2D-NMR while its structural isomer, compound 2, was isolated for the first time and differed only by the position of one double bond on one isoprenyl substituent. Treatment of MEFs with purified compound 1 or compound 2 led to rapid and robust AMPK activation at low micromolar concentrations and increased the intracellular AMP:ATP ratio. In oxygen consumption experiments on isolated rat liver mitochondria, compound 1 and compound 2 inhibited complex II of the electron transport chain and in freeze–thawed mitochondria succinate dehydrogenase was inhibited. In incubated rat skeletal muscles, both compounds activated AMPK and stimulated glucose uptake. Moreover, these effects were lost in muscles pre-incubated with AMPK inhibitor SBI-0206965, suggesting AMPK dependency. Incubation of mouse hepatocytes with compound 1 or compound 2 led to AMPK activation, but glucose production was decreased in hepatocytes from both wild-type and AMPKβ1−/− mice, suggesting that this effect was not AMPK-dependent. However, when administered intraperitoneally to high-fat diet-induced insulin-resistant mice, compound 1 and compound 2 had blood glucose-lowering effects. In addition, compound 1 and compound 2 reduced the viability of several human cancer cells in culture. The flavonoids we have identified could be a starting point for the development of new drugs to treat type 2 diabetes.

Biological Activity of Trans-Membrane Anion Carriers

2018 ◽  
Vol 25 (30) ◽  
pp. 3560-3576 ◽  
Author(s):  
Massimo Tosolini ◽  
Paolo Pengo ◽  
Paolo Tecilla
Keyword(s):  
Biological Activity ◽  
Membrane Transport ◽  
Anticancer Agents ◽  
Biological Effects ◽  
Structure Activity Relationship ◽  
New Drugs ◽  
Activity Relationship ◽  
Anion Channels ◽  
Cellular Homeostasis ◽  
Structure Activity

Natural and synthetic anionophores promote the trans-membrane transport of anions such as chloride and bicarbonate. This process may alter cellular homeostasis with possible effects on internal ions concentration and pH levels triggering several and diverse biological effects. In this article, an overview of the recent results on the study of aniontransporters, mainly acting with a carrier-type mechanism, is given with emphasis on the structure/activity relationship and on their biological activity as antibiotic and anticancer agents and in the development of new drugs for treating conditions derived from dysregulation of natural anion channels.

Chemometric Analysis for the Classification of some Groups of Drugs with Divergent Pharmacological Activity on the Basis of some Chromatographic and Molecular Modeling Parameters

2018 ◽  
Vol 21 (2) ◽  
pp. 125-137
Author(s):  
Jolanta Stasiak ◽  
Marcin Koba ◽  
Marcin Gackowski ◽  
Tomasz Baczek
Keyword(s):  
Correlation Analysis ◽  
Pharmacological Activity ◽  
Correlation Coefficients ◽  
Principal Component ◽  
Cardiovascular Drugs ◽  
New Drugs ◽  
Analgesic Drugs ◽  
Starting Point ◽  
Chromatographic Parameters

Aim and Objective: In this study, chemometric methods as correlation analysis, cluster analysis (CA), principal component analysis (PCA), and factor analysis (FA) have been used to reduce the number of chromatographic parameters (logk/logkw) and various (e.g., 0D, 1D, 2D, 3D) structural descriptors for three different groups of drugs, such as 12 analgesic drugs, 11 cardiovascular drugs and 36 “other” compounds and especially to choose the most important data of them. Material and Methods: All chemometric analyses have been carried out, graphically presented and also discussed for each group of drugs. At first, compounds’ structural and chromatographic parameters were correlated. The best results of correlation analysis were as follows: correlation coefficients like R = 0.93, R = 0.88, R = 0.91 for cardiac medications, analgesic drugs, and 36 “other” compounds, respectively. Next, part of molecular and HPLC experimental data from each group of drugs were submitted to FA/PCA and CA techniques. Results: Almost all results obtained by FA or PCA, and total data variance, from all analyzed parameters (experimental and calculated) were explained by first two/three factors: 84.28%, 76.38 %, 69.71% for cardiovascular drugs, for analgesic drugs and for 36 “other” compounds, respectively. Compounds clustering by CA method had similar characteristic as those obtained by FA/PCA. In our paper, statistical classification of mentioned drugs performed has been widely characterized and discussed in case of their molecular structure and pharmacological activity. Conclusion: Proposed QSAR strategy of reduced number of parameters could be useful starting point for further statistical analysis as well as support for designing new drugs and predicting their possible activity.

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