Exploring Secondary Metabolites Database of Apocynaceae, Menispermaceae, and Annonaceae to Select Potential Anti-HCV Compounds

2019 ◽  
Vol 19 (11) ◽  
pp. 900-913 ◽  
Author(s):  
Renata P.C. Barros ◽  
Luciana Scotti ◽  
Marcus T. Scotti
Keyword(s):  
Natural Products ◽  
Hepatitis C ◽  
Virtual Screening ◽  
Secondary Metabolites ◽  
New Drugs ◽  
Starting Point ◽  
Combine Structure ◽  
Forest Models ◽  
Random Forest Models ◽  
Test Sets

Background: Hepatitis C is a disease that constitutes a serious global health problem, is often asymptomatic and difficult to diagnose and about 60-80% of infected patients develop chronic diseases over time. As there is no vaccine against hepatitis C virus (HCV), developing new cheap treatments is a big challenge. Objective: The search for new drugs from natural products has been outstanding in recent years. The aim of this study was to combine structure-based and ligand-based virtual screening (VS) techniques to select potentially active molecules against four HCV target proteins from in-house secondary metabolite dataset (SistematX). Materials and Methods: From the ChEMBL database, we selected four sets of 1199, 355, 290 and 237chemical structures with inhibitory activity against different targets of HCV to create random forest models with an accuracy value higher than 82% for cross-validation and test sets. Afterward, a ligandbased virtual screen of the entire 1848 secondary metabolites database stored in SistematX was performed. In addition, a structure-based virtual screening was also performed for the same set of secondary metabolites using molecular docking. Results: Finally, using consensus analyses approach combining ligand-based and structure-based VS, three alkaloids were selected as potential anti-HCV compounds. Conclusion: The selected structures are a starting point for further studies in order to develop new anti- HCV compounds based on natural products.

scholarly journals Based on Principles and Insights of COVID-19 Epidemiology, Genome Sequencing, and Pathogenesis: Retrospective Analysis of Sinigrin and ProlixinRX (Fluphenazine) Provides Off-Label Drug Candidates

2020 ◽  
Vol 25 (10) ◽  
pp. 1123-1140
Author(s):  
Jilan Nazeam ◽  
Esraa Z. Mohammed ◽  
Mariam Raafat ◽  
Mariam Houssein ◽  
Asmaa Elkafoury ◽  
...  
Keyword(s):  
Natural Products ◽  
Evidence Synthesis ◽  
Drug Repurposing ◽  
New Drugs ◽  
Future Research ◽  
Nitrogenous Compounds ◽  
Future Research Agenda ◽  
Starting Point

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative pathogen of pandemic coronavirus disease 2019 (COVID-19). So far, no approved therapy has been developed to halt the spread of the pathogen, and unfortunately, the strategies for developing a new therapy will require a long time and very extensive resources. Therefore, drug repurposing has emerged as an ideal strategy toward a smart, versatile, quick way to confine the lethal disease. In this endeavor, natural products have been an untapped source for new drugs. This review represents the confederated experience of multidisciplinary researchers of 99 articles using several databases: Google Scholar, Science Direct, MEDLINE, Web of Science, Scopus, and PubMed. To establish the hypothesis, a Bayesian perspective of a systematic review was used to outline evidence synthesis. Our docking documentation of 69 compounds and future research agenda assumptions were directed toward finding an effective and economic anti-COVID-19 treatment from natural products. Glucosinolate, flavones, and sulfated nitrogenous compounds demonstrate direct anti-SARS-CoV-2 activity through inhibition protease enzymes and may be considered potential candidates against coronavirus. These findings could be a starting point to initiate an integrative study that may encompass interested scientists and research institutes to test the hypothesis in vitro, in vivo, and in clinics after satisfying all ethical requirements.

Virtual Screening, Molecular Dynamics and ADME-Tox Tools for Finding Potential Inhibitors of Phosphoglycerate Mutase 1 from Plasmodium falciparum

2018 ◽  
Vol 18 (18) ◽  
pp. 1610-1617 ◽  
Author(s):  
Lluvia Ríos-Soto ◽  
Claudia Avitia-Domínguez ◽  
Erick Sierra-Campos ◽  
Mónica Valdez-Solana ◽  
Jorge Cisneros-Martínez ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Structural Changes ◽  
Treatment Resistance ◽  
Binding Energies ◽  
New Drugs ◽  
Phosphoglycerate Mutase ◽  
Chemical Library ◽  
Starting Point ◽  
Potential Inhibitors ◽  
Molecular Dynamic Analysis

Background: Nowadays, malaria is still one of the most important and lethal diseases worldwide, causing 445,000 deaths in a year. Due to the actual treatment resistance, there is an emergency to find new drugs. Objective: The aim of this work was to find potential inhibitors of phosphoglycerate mutase 1 from P. falciparum. Results: Through virtual screening of a chemical library of 15,123 small molecules, analyzed by two programs, four potential inhibitors of phosphoglycerate mutase 1 from P. falciparum were found: ZINC64219552, ZINC39095354, ZINC04593310, and ZINC04343691; their binding energies in SP mode were -7.3, -7.41, -7.4, and -7.18 kcal/mol respectively. Molecular dynamic analysis revealed that these molecules interact with residues important for enzyme catalysis and molecule ZINC04343691 provoked the highest structural changes. Physiochemical and toxicological profiles evaluation of these inhibitors with ADME-Tox method suggested that they can be considered as potential drugs. Furthermore, analysis of human PGAM-B suggested that these molecules could be selective for the parasitic enzyme. Conclusion: The compounds reported here are the first selective potential inhibitors of phosphoglycerate mutase 1 from P. falciparum, and can serve as a starting point in the search of a new chemotherapy against malaria.

scholarly journals Structure-Based Virtual Screening and De Novo Design of PIM1 Inhibitors with Anticancer Activity from Natural Products

2021 ◽  
Vol 14 (3) ◽  
pp. 275
Author(s):  
Hwangseo Park ◽  
Jinwon Jeon ◽  
Kewon Kim ◽  
Soyeon Choi ◽  
Sungwoo Hong
Keyword(s):  
Natural Products ◽  
Virtual Screening ◽  
Kinase Inhibitors ◽  
De Novo ◽  
Binding Free Energy ◽  
De Novo Design ◽  
Breast Cancer Cell Lines ◽  
Free Energy Function ◽  
Pim1 Kinase ◽  
Starting Point

Background: the proviral insertion site of Moloney murine leukemia (PIM) 1 kinase has served as a therapeutic target for various human cancers due to the enhancement of cell proliferation and the inhibition of apoptosis. Methods: to identify effective PIM1 kinase inhibitors, structure-based virtual screening of natural products of plant origin and de novo design were carried out using the protein–ligand binding free energy function improved by introducing an adequate dehydration energy term. Results: as a consequence of subsequent enzyme inhibition assays, four classes of PIM1 kinase inhibitors were discovered, with the biochemical potency ranging from low-micromolar to sub-micromolar levels. The results of extensive docking simulations showed that the inhibitory activity stemmed from the formation of multiple hydrogen bonds in combination with hydrophobic interactions in the ATP-binding site. Optimization of the biochemical potency by chemical modifications of the 2-benzylidenebenzofuran-3(2H)-one scaffold led to the discovery of several nanomolar inhibitors with antiproliferative activities against human breast cancer cell lines. Conclusions: these new PIM1 kinase inhibitors are anticipated to serve as a new starting point for the development of anticancer medicine.

scholarly journals Secondary Metabolites from the Marine Sponges of the Genus Petrosia: A Literature Review of 43 Years of Research

Marine Drugs ◽  
2021 ◽  
Vol 19 (3) ◽  
pp. 122
Author(s):  
Yeon-Ju Lee ◽  
Yeonwoo Cho ◽  
Huynh Nguyen Khanh Tran
Keyword(s):  
Natural Products ◽  
Secondary Metabolites ◽  
Literature Review ◽  
Biological Activities ◽  
Marine Sponges ◽  
Biologically Active ◽  
New Drugs ◽  
Chemical Structures ◽  
Active Natural

Sponges are prolific sources of various natural products that have provided the chemical scaffolds for new drugs. The sponges of the genus Petrosia inhabit various regions and contain a variety of biologically active natural products such as polyacetylenes, sterols, meroterpenoids, and alkaloids. This review aims to provide a comprehensive summary of the chemical structures and biological activities of Petrosia metabolites covering a period of more than four decades (between 1978 and 2020). It is also described in this review that the major groups of metabolites from members of the genus Petrosia differed with latitude. The polyacetylenes were identified to be the most predominant metabolites in Petrosia sponges in temperate regions, while tropical Petrosia species were sources of a greater variety of metabolites, such as meroterpenoids, sterols, polyacetylenes, and alkaloids.

Virtual screening of natural products database

2020 ◽  
Vol 20 ◽  
Author(s):  
José Alixandre de Sousa Luis ◽  
Renata Priscila Costa Barros ◽  
Natália Ferreira de Sousa ◽  
Eugene Muratov ◽  
Luciana Scotti ◽  
...  
Keyword(s):  
Natural Products ◽  
Virtual Screening ◽  
Biological Systems ◽  
New Drugs ◽  
Drug Candidate ◽  
Search Term ◽  
Drug Candidates ◽  
Search Criterion ◽  
Biological Tests ◽  
New Research

: Constant research with natural products has generated, over time, a large number of compounds with potential to be evaluated in several biological tests and subsequently have been cataloged in databases that allow other researchers perform virtual screenings on activity in various biological systems. This considerably reduces the time for the development of new drugs. This review describes the main databases of Natural Products available for searching for bioactive compounds. It also describes the main features of Virtual Screening strategies for identification of molecules with potential to be used as new drugs. In adittion, a search was made in the Web of Science database, using as search term "Virtual screening of natural products databases" from 2003 to 2018. The search criterion resulted in 230 articles, which had their abstracts evaluated as to the pertinence to the criteria required for this work, which are: a) be a research article; b) performing a virtual screening from databases of natural products or containing natural products; c) works that identified drug candidate molecules. Based on these criteria, the bibliographic review work on the topic was excluded. After this analysis, 104 works were selected for this review. Were selected relevant papers describing the obtaining of potential drug candidates that were distributed in 15 classes, of which the anticancer, antibacterial and anti-inflammatory hits were the most abundant. There are also described works showing efforts to search for new molecules against various other diseases in distinct biological systems. In this way, this work shows an overview of several methodologies and we hope they can help and inspire the development of new research to improve people's quality of life.

scholarly journals Non-Extensive Fragmentation of Natural Products and Pharmacophore-Based Virtual Screening as a Practical Approach to Identify Novel Promising Chemical Scaffolds

2021 ◽  
Vol 9 ◽  
Author(s):  
Andrés Felipe Vásquez ◽  
Alejandro Reyes Muñoz ◽  
Jorge Duitama ◽  
Andrés González Barrios
Keyword(s):  
Natural Products ◽  
Virtual Screening ◽  
Natural Product ◽  
Structural Diversity ◽  
Pharmacophore Modeling ◽  
Classical Type ◽  
Starting Point ◽  
Novel Drugs ◽  
Before And After ◽  
Good Starting Point

Fragment-based drug design (FBDD) and pharmacophore modeling have proven to be efficient tools to discover novel drugs. However, these approaches may become limited if the collection of fragments is highly repetitive, poorly diverse, or excessively simple. In this article, combining pharmacophore modeling and a non-classical type of fragmentation (herein called non-extensive) to screen a natural product (NP) library may provide fragments predicted as potent, diverse, and developable. Initially, we applied retrosynthetic combinatorial analysis procedure (RECAP) rules in two versions, extensive and non-extensive, in order to deconstruct a virtual library of NPs formed by the databases Traditional Chinese Medicine (TCM), AfroDb (African Medicinal Plants database), NuBBE (Nuclei of Bioassays, Biosynthesis, and Ecophysiology of Natural Products), and UEFS (Universidade Estadual de Feira de Santana). We then developed a virtual screening (VS) using two groups of natural-product-derived fragments (extensive and non-extensive NPDFs) and two overlapping pharmacophore models for each of 20 different proteins of therapeutic interest. Molecular weight, lipophilicity, and molecular complexity were estimated and compared for both types of NPDFs (and their original NPs) before and after the VS proceedings. As a result, we found that non-extensive NPDFs exhibited a much higher number of chemical entities compared to extensive NPDFs (45,355 vs. 11,525 compounds), accounting for the larger part of the hits recovered and being far less repetitive than extensive NPDFs. The structural diversity of both types of NPDFs and the NPs was shown to diminish slightly after VS procedures. Finally, and most interestingly, the pharmacophore fit score of the non-extensive NPDFs proved to be not only higher, on average, than extensive NPDFs (56% of cases) but also higher than their original NPs (69% of cases) when all of them were also recognized as hits after the VS. The findings obtained in this study indicated that the proposed cascade approach was useful to enhance the probability of identifying innovative chemical scaffolds, which deserve further development to become drug-sized candidate compounds. We consider that the knowledge about the deconstruction degree required to produce NPDFs of interest represents a good starting point for eventual synthesis, characterization, and biological activity studies.

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.

Discovery of Antibacterial Agents Inhibiting the Energy-Coupling Factor (ECF) Transporters by Structure-Based Virtual Screening

2020 ◽  
Author(s):  
Eleonora Diamanti ◽  
Inda Setyawati ◽  
Spyridon Bousis ◽  
leticia mojas ◽  
lotteke Swier ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Antibacterial Agents ◽  
Antimicrobial Agents ◽  
Energy Coupling ◽  
Coupling Factor ◽  
Design Synthesis ◽  
Screening Design ◽  
Starting Point ◽  
Wide Range ◽  
Vitamin Uptake

Here, we report on the virtual screening, design, synthesis and structure–activity relationships (SARs) of the first class of selective, antibacterial agents against the energy-coupling factor (ECF) transporters. The ECF transporters are a family of transmembrane proteins involved in the uptake of vitamins in a wide range of bacteria. Inhibition of the activity of these proteins could reduce the viability of pathogens that depend on vitamin uptake. Because of their central role in the metabolism of bacteria and their absence in humans, ECF transporters are novel potential antimicrobial targets to tackle infection. The hit compound’s metabolic and plasma stability, the potency (20, MIC Streptococcus pneumoniae = 2 µg/mL), the absence of cytotoxicity and a lack of resistance development under the conditions tested here suggest that this scaffold may represent a promising starting point for the development of novel antimicrobial agents with an unprecedented mechanism of action.<br>

Natural Anti-inflammatory compounds as Drug candidates in Alzheimer’s disease

2020 ◽  
Vol 27 ◽  
Author(s):  
Reyaz Hassan Mir ◽  
Abdul Jalil Shah ◽  
Roohi Mohi-ud-din ◽  
Faheem Hyder Potoo ◽  
Mohd. Akbar Dar ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Natural Products ◽  
Protective Action ◽  
New Drugs ◽  
Huperzine A ◽  
Brain Disorder ◽  
Anti Inflammatory

: Alzheimer's disease (AD) is a chronic neurodegenerative brain disorder characterized by memory impairment, dementia, oxidative stress in elderly people. Currently, only a few drugs are available in the market with various adverse effects. So to develop new drugs with protective action against the disease, research is turning to the identification of plant products as a remedy. Natural compounds with anti-inflammatory activity could be good candidates for developing effective therapeutic strategies. Phytochemicals including Curcumin, Resveratrol, Quercetin, Huperzine-A, Rosmarinic acid, genistein, obovatol, and Oxyresvertarol were reported molecules for the treatment of AD. Several alkaloids such as galantamine, oridonin, glaucocalyxin B, tetrandrine, berberine, anatabine have been shown anti-inflammatory effects in AD models in vitro as well as in-vivo. In conclusion, natural products from plants represent interesting candidates for the treatment of AD. This review highlights the potential of specific compounds from natural products along with their synthetic derivatives to counteract AD in the CNS.

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